bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–12–19
ninety papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Ferroptosis: The Silver Lining of Cancer Therapy.
  2. Galangin: A metabolite that suppresses anti-neoplastic activities through modulation of oncogenic targets.
  3. Recent Metabolomics Analysis in Tumor Metabolism Reprogramming.
  4. Ketogenic diet and cancer: Fad or fabulous?
  5. Prostate cancer: Therapeutic prospect with herbal medicine.
  6. Near infrared light triggered ternary synergistic cancer therapy via L-arginine-loaded nanovesicles with modification of PEGylated indocyanine green.
  7. Targeting Mutated KRAS Genes to Treat Solid Tumours.
  8. The purple mangosteen (Garcinia mangostana): Defining the anticancer potential of selected xanthones.
  9. Loss of hexokinase 1 sensitizes ovarian cancer to high-dose metformin.
  10. Defining the landscape of metabolic dysregulations in cancer metastasis.
  11. Cascade Tumor Therapy Platform for Sensitized Chemotherapy and Penetration Enhanced Photothermal Therapy.
  12. Enzymatic Delivery of Magnetic Nanoparticles into Mitochondria of Live Cells.
  13. Cell line-directed breast cancer research based on glucose metabolism status.
  14. Molecular mechanisms of ferroptosis and their role in inflammation.
  15. Chitosan: A versatile bio-platform for breast cancer theranostics.
  16. Autophagy and Hepatic Tumor Microenvironment Associated Dormancy.
  17. [Quercetin for the treatment of prostate cancer: Progress in studies].
  18. Metabolic Reprogramming and Reconstruction: Integration of Experimental and Computational Studies to Set the Path Forward in ADPKD.
  19. PKM2 is essential for bladder cancer growth and maintenance.
  20. Targeted Drug Delivery via Folate Decorated Nanocarriers Based on Linear Polymer for Treatment of Breast Cancer.
  21. Broad Anti-Cancer Activity Produced by Targeted Nutrients Deprivation (TND) of Multiple Non-Essential Amino Acids.
  22. Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis.
  23. Camouflaged Hybrid Cancer Cell-Platelet Fusion Membrane Nanovesicles Deliver Therapeutic MicroRNAs to Presensitize Triple-Negative Breast Cancer to Doxorubicin.
  24. Ultrasound-Mediated Cancer Therapeutics Delivery using Micelles and Liposomes: A Review.
  25. Glutathione-Responsive Chemodynamic Therapy of Manganese(III/IV) Cluster Nanoparticles Enhanced by Electrochemical Stimulation via Oxidative Stress Pathway.
  26. The synergistic effect of chemo-photothermal therapies in SN-38-loaded gold-nanoshell-based colorectal cancer treatment.
  27. A carrier-free supramolecular nanoprodrug based on lactose-functionalized dimeric camptothecin via self-assembly in water for targeted and fluorescence imaging-guided chemo-photodynamic therapy.
  28. Theranostic Nanoplatform with Sequential SDT and ADV Effects in Response to Well-Programmed LIFU Irradiation for Cervical Cancer.
  29. Untangling the KRAS mutated lung cancer subsets and its therapeutic implications.
  30. Functionalized layered double hydroxide nanoparticles as an intelligent nanoplatform for synergistic photothermal therapy and chemotherapy of tumors.
  31. Carbon Nitride Nanomaterials with Application in Photothermal and Photodynamic Therapies.
  32. Anticancer Activity of Ethnopharmacological Plants of Golestan Province/Iran against AGS, HT-29 and KYSE-30 Cell Lines through Promoting the Apoptosis and Immunomodulatory Effects.
  33. Potential metabolic activities of raspberry ketone.
  34. Vitamin C, From Supplement to Treatment: A Re-Emerging Adjunct for Cancer Immunotherapy?
  35. Exploring silver nanoparticles for cancer therapy and diagnosis.
  36. Nanoparticles: A Promising Tool to Promote Reactive Oxygen Species in Cancer Therapy.
  37. Low Carbohydrate Diets in Cancer Therapeutics: Current Evidence.
  38. Inorganic Nanozymes: Prospects for Disease Treatments and Detection Applications.
  39. Liposome-encapsulated anthraquinone improves efficacy and safety in triple negative breast cancer.
  40. Insights on functionalized carbon nanotubes for cancer theranostics.
  41. Biodegradable reduce expenditure bioreactor for augmented sonodynamic therapy via regulating tumor hypoxia and inducing pro-death autophagy.
  42. Simultaneous nanocarrier-mediated delivery of siRNAs and chemotherapeutic agents in cancer therapy and diagnosis: Recent advances.
  43. Nutritional Regulation of Hepatic FGF21 by Dietary Restriction of Methionine.
  44. Diabetic neuropathy: an insight on the transition from synthetic drugs to herbal therapies.
  45. Engineered gold/black phosphorus nanoplatforms with remodeling tumor microenvironment for sonoactivated catalytic tumor theranostics.
  46. Photoacoustic nanodroplets for oxygen enhanced photodynamic therapy of cancer.
  47. Cobimetinib Plus Gemcitabine: An Active Combination in KRAS G12R-Mutated Pancreatic Ductal Adenocarcinoma Patients in Previously Treated and Failed Multiple Chemotherapies.
  48. Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence.
  49. 2D antimonene-integrated composite nanomedicine for augmented low-temperature photonic tumor hyperthermia by reversing cell thermoresistance.
  50. Nanocarbon Framework-Supported Ultrafine Mo2C@MoOx Nanoclusters for Photothermal-Enhanced Tumor-Specific Tandem Catalysis Therapy.
  51. Engineering Bacteria and Bionic Bacterial Derivatives with Nanoparticles for Cancer Therapy.
  52. Microbial arginine deiminase: A multifaceted green catalyst in biomedical sciences.
  53. Recent Progress on the Synergistic Antitumor Effect of a Borneol-Modified Nanocarrier Drug Delivery System.
  54. A Potent Strategy of Combinational Blow Toward Enhanced Cancer Chemo-Photodynamic Therapy via Sustainable GSH Elimination.
  55. Gold Nanoclusters: Imaging, Therapy, and Theranostic Roles in Biomedical Applications.
  56. Persistent luminescence phosphor as in-vivo light source for tumoral cyanobacterial photosynthetic oxygenation and photodynamic therapy.
  57. A Self-Degradable Conjugated Polymer for Photodynamic Therapy with Reliable Postoperative Safety.
  58. Complementing Cancer Photodynamic Therapy with Ferroptosis through Iron Oxide Loaded Porphyrin-Grafted Lipid Nanoparticles.
  59. Identification of RAS mutant biomarkers for EGFR inhibitor sensitivity using a systems biochemical approach.
  60. Oxygen-Deficient BiOCl Combined with L-Buthionine-Sulfoximine Synergistically Suppresses Tumor Growth through Enhanced Singlet Oxygen Generation under Ultrasound Irradiation.
  61. Co-delivery of dihydroartemisinin and pyropheophorbide-iron elicits ferroptosis to potentiate cancer immunotherapy.
  62. Nutritional supplementation in the prevention and treatment of Glaucoma.
  63. Effect of high-dose intravenous ascorbic acid on cancer patients following ketogenic diet.
  64. Enhancement of Proton Therapy Efficiency by Noble Metal Nanoparticles Is Driven by the Number and Chemical Activity of Surface Atoms.
  65. Beneficial Effects on Brain Micro-Environment by Caloric Restriction in Alleviating Neurodegenerative Diseases and Brain Aging.
  66. Cu2- x Sx Capped AuCu Nanostars for Efficient Plasmonic Photothermal Tumor Treatment in the Second Near-Infrared Window.
  67. Components of the phosphatidylserine endoplasmic reticulum to plasma membrane transport mechanism as targets for KRAS inhibition in pancreatic cancer.
  68. A pH-sensitive liposome formulation of a peptidomimetic-Dox conjugate for targeting HER2 + cancer.
  69. Olive oil and wine as source of multi-target agents in the prevention of Alzheimer disease.
  70. The benefits of ascorbate to protect healthy cells in the prevention and treatment of oncological diseases.
  71. I.p.-injected cationic liposomes are retained and accumulate in peritoneally disseminated tumors.
  72. In silico comparative analysis of KRAS mutations at codons 12 and 13: Structural modifications of P-Loop, switch I&II regions preventing GTP hydrolysis.
  73. Surface functionalized biomimetic bioreactors enable the targeted starvation-chemotherapy to glioma.
  74. Strategies for Liposome Drug Delivery Systems to Improve Tumor Treatment Efficacy.
  75. From Apoptosis to Necroptosis: The Death Wishes to Cancer.
  76. A New Nanomaterial Based on Extracellular Vesicles Containing Chrysin-Induced Cell Apoptosis Through Let-7a in Tongue Squamous Cell Carcinoma.
  77. Eudragit S100 prepared pH-responsive liposomes-loaded betulinic acid against colorectal cancer in vitro and in vivo.
  78. Modified N-Terminal Fragments of Galanin: Cardioprotective Properties and Mechanisms of Action.
  79. Rosmarinic acid suppresses inflammation, angiogenesis, and improves paclitaxel induced apoptosis in a breast cancer model via NF3 κB-p53-caspase-3 pathways modulation.
  80. Fabrication Methods and Form Factors of Gellan Gum-Based Materials for Drug Delivery and Anti-Cancer Applications.
  81. KRAS mutation-independent downregulation of MAPK/PI3K signaling in colorectal cancer.
  82. Multifunctional Immunoliposomes Enhance the Immunotherapeutic Effects of PD-L1 Antibodies against Melanoma by Reprogramming Immunosuppressive Tumor Microenvironment.
  83. Cell-Penetrating Peptide-Modified Graphene Oxide Nanoparticles Loaded with Rictor siRNA for the Treatment of Triple-Negative Breast Cancer.
  84. Ketogenic diet: a tool for the management of neuroendocrine neoplasms?
  85. Self-assembled ternary hybrid nanodrugs for overcoming tumor resistance and metastasis.
  86. [Anthocyanins as functional food components].
  87. Metabolic drug survey highlights cancer cell dependencies and vulnerabilities.
  88. Polymeric PD-L1 blockade nanoparticles for cancer photothermal-immunotherapy.
  89. Irinotecan/scFv co-loaded liposomes coaction on tumor cells and CAFs for enhanced colorectal cancer therapy.
  90. Withaferin A in the treatment of liver diseases: progress and pharmacokinetic insights.
  1. Front Cell Dev Biol. 2021 ;9 765859
    Ferroptosis: The Silver Lining of Cancer Therapy.
    Zhengming Tang, Zhijie Huang, Yisheng Huang, Yuanxin Chen, Mingshu Huang, Hongyu Liu, Q Adam Ye, Jianjiang Zhao, Bo Jia.
      Regulatory cell death has been a major focus area of cancer therapy research to improve conventional clinical cancer treatment (e.g. chemotherapy and radiotherapy). Ferroptosis, a novel form of regulated cell death mediated by iron-dependent lipid peroxidation, has been receiving increasing attention since its discovery in 2012. Owing to the highly iron-dependent physiological properties of cancer cells, targeting ferroptosis is a promising approach in cancer therapy. In this review, we summarised the characteristics of ferroptotic cells, associated mechanisms of ferroptosis occurrence and regulation and application of the ferroptotic pathway in cancer therapy, including the use of ferroptosis in combination with other therapeutic modalities. In addition, we presented the challenges of using ferroptosis in cancer therapy and future perspectives that may provide a basis for further research.
    Keywords:  cancer therapy; ferroptosis; lipid peroxidation; reactive oxygen species; regulatory cell death
    DOI:  https://doi.org/10.3389/fcell.2021.765859
  2. Exp Biol Med (Maywood). 2021 Dec 14. 15353702211062510
    Galangin: A metabolite that suppresses anti-neoplastic activities through modulation of oncogenic targets.
    Hardeep Singh Tuli, Katrin Sak, Shubham Adhikary, Ginpreet Kaur, Diwakar Aggarwal, Jagjit Kaur, Manoj Kumar, Nidarshana Chaturvedi Parashar, Gaurav Parashar, Uttam Sharma, Aklank Jain.
      With the dramatic increase in cancer incidence all over the world in the last decades, studies on identifying novel efficient anti-cancer agents have been intensified. Historically, natural products have represented one of the most important sources of new lead compounds with a wide range of biological activities. In this article, the multifaceted anti-cancer action of propolis-derived flavonoid, galangin, is presented, discussing its antioxidant, anti-inflammatory, antiproliferative, pro-apoptotic, anti-angiogenic, and anti-metastatic effects in various cancer cells. In addition, co-effects with standard chemotherapeutic drugs as well as other natural compounds are also under discussion, besides highlighting modern nanotechnological advancements for overcoming the low bioavailability issue characteristic of galangin. Although further studies are needed for confirming the anti-cancer potential of galangin in vivo malignant systems, exploring this natural compound might open new perspectives in molecular oncology.
    Keywords:  Galangin; absorption; anti-cancer; epigenetics; nano-delivery; synergistic
    DOI:  https://doi.org/10.1177/15353702211062510
  3. Front Mol Biosci. 2021 ;8 763902
    Recent Metabolomics Analysis in Tumor Metabolism Reprogramming.
    Jingjing Han, Qian Li, Yu Chen, Yonglin Yang.
      Metabolic reprogramming has been suggested as a hallmark of cancer progression. Metabolomic analysis of various metabolic profiles represents a powerful and technically feasible method to monitor dynamic changes in tumor metabolism and response to treatment over the course of the disease. To date, numerous original studies have highlighted the application of metabolomics to various aspects of tumor metabolic reprogramming research. In this review, we summarize how metabolomics techniques can help understand the effects that changes in the metabolic profile of the tumor microenvironment on the three major metabolic pathways of tumors. Various non-invasive biofluids are available that produce accurate and useful clinical information on tumor metabolism to identify early biomarkers of tumor development. Similarly, metabolomics can predict individual metabolic differences in response to tumor drugs, assess drug efficacy, and monitor drug resistance. On this basis, we also discuss the application of stable isotope tracer technology as a method for the study of tumor metabolism, which enables the tracking of metabolite activity in the body and deep metabolic pathways. We summarize the multifaceted application of metabolomics in cancer metabolic reprogramming to reveal its important role in cancer development and treatment.
    Keywords:  biomarkers; drug resistance; metabolic reprogramming; metabolomics; stable isotope resolved metabolomics
    DOI:  https://doi.org/10.3389/fmolb.2021.763902
  4. JPEN J Parenter Enteral Nutr. 2021 Nov;45(S2): 26-32
    Ketogenic diet and cancer: Fad or fabulous?
    Manpreet S Mundi, Osman Mohamed Elfadil, Ishani Patel, Jalpan Patel, Ryan T Hurt.
      As the prevalence of smoking continues to decline, dietary factors are rapidly becoming the leading preventable cause of disease. Diet and obesity are also leading to a shift in cancer prevalence with increases noted in breast, liver, pancreas, and uterine cancers. Once cancer is detected, obesity is also associated with poorer outcomes with therapy as well as higher morbidity and mortality. Key factors are associated with the link between obesity and cancer including chronic inflammation, change in sex hormones, alteration in insulin-IGF-1 axis, alteration in adipokines, as well as cancer stem cells that are derived from adipose tissue. Because of these associations, a great deal of effort is being placed in implementing lifestyle changes that mitigate obesity-associated factors that contribute to development of cancer, reduce side effects of treatment, and improve survival. Ketogenic diet is emerging as an attractive option in countering obesity-related tumor-promoting factors, as it is associated with weight loss as well as a reduction in insulin resistance and inflammation. Ketogenic diet can also deprive cancer cells of glucose, a fuel source that is predominantly used by many cancer lines through aerobic glycolysis in the setting of dysregulated mitochondria. Current manuscript reviews the theoretical benefits for use of ketogenic diet in cancer as well as the data available from clinical trials.
    Keywords:  cancer; ketogenic diet; nutrition; obesity
    DOI:  https://doi.org/10.1002/jpen.2226
  5. Curr Res Pharmacol Drug Discov. 2021 ;2 100034
    Prostate cancer: Therapeutic prospect with herbal medicine.
    Suvranil Ghosh, Joyita Hazra, Koustav Pal, Vinod K Nelson, Mahadeb Pal.
      Prostate cancer (PCa) is a major cause of morbidity and mortality in men worldwide. A geographic variation on the burden of the disease suggested that the environment, genetic makeup, lifestyle, and food habits modulate one's susceptibility to the disease. Although it has been generally thought to be an older age disease, and awareness and timely execution of screening programs have managed to contain the disease in the older population over the last decades, the incidence is still increasing in the population younger than 50. Existing treatment is efficient for PCa that is localized and responsive to androgen. However, the androgen resistant and metastatic PCa are challenging to treat. Conventional radiation and chemotherapies are associated with severe side effects in addition to being exorbitantly expensive. Many isolated phytochemicals and extracts of plants used in traditional medicine are known for their safety and diverse healing properties, including many with varying levels of anti-PCa activities. Many of the phytochemicals discussed here, as shown by many laboratories, inhibit tumor cell growth and proliferation by interfering with the components in the pathways responsible for the enhanced proliferation, metabolism, angiogenesis, invasion, and metastasis in the prostate cells while upregulating the mechanisms of cell death and cell cycle arrest. Notably, many of these agents simultaneously target multiple cellular pathways. We analyzed the available literature and provided an update on this issue in this review article.
    Keywords:  Chemotherapy; Natural products; Phytochemicals; Plant extract and compounds; Prostate cancer; Radiation therapy
    DOI:  https://doi.org/10.1016/j.crphar.2021.100034
  6. Acta Biomater. 2021 Dec 10. pii: S1742-7061(21)00819-9. [Epub ahead of print]
    Near infrared light triggered ternary synergistic cancer therapy via L-arginine-loaded nanovesicles with modification of PEGylated indocyanine green.
    Kesi Wang, Linping Jiang, Liyan Qiu.
      L-arginine (L-Arg) is an important nitric oxide (NO) donor, and its exploration in NO gas therapy has received widespread attention. Application of nano-platforms that can efficiently deliver L-Arg and induce its rapid conversion to NO becomes a predominant strategy to achieve promising therapeutic effects in tumor treatment. Herein, an enhanced nano-vesicular system of ternary synergistic treatment combining NO therapy, photodynamic therapy (PDT) along with mild photothermal therapy (MPTT) was developed for cancer therapy. We integrated photosensitizer PEGylated indocyanine green (mPEG-ICG) into polyphosphazene PEP nano-vesicles through co-assembly and simultaneously encapsulated NO donor L-Arg into the vesicle center chambers to form mPEG-ICG/L-Arg co-loaded system IA-PEP. The unique nanostructure of vesicle provided considerable loading capacity for mPEG-ICG and L-Arg with 15.9% and 17.95% loading content, respectively, and efficiently prevented mPEG-ICG and L-Arg from leaking. Significantly, the reactive oxygen species (ROS) was produced by IA-PEP under 808 nm laser irradiation to perform PDT against tumors, which concurrently reacted with L-Arg to release NO and arouse gas therapy effectively. Moreover, the mild heat produced by IA-PEP could exhibit cooperative anti-tumor effect with minimal damage. As a consequence, in vivo antitumor investigation on nude mice bearing xenograft MCF-7 tumors verified the potent anti-tumor efficacy of IA-PEP under 808 nm laser irradiation with complete tumor elimination. Taken together, the IA-PEP nano-vesicle system designed in this work may provide a promising treatment paradigm for synergistic cancer treatment. STATEMENT OF SIGNIFICANCE: : Nitric oxide (NO) gas therapy has drawn widespread attention due to its "green" treatment paradigm with negligible side effects. L-arginine (L-Arg) is an important NO donor. However, how to efficiently deliver L-Arg and induce NO generation remains a big challenge since L-Arg is a water-soluble small molecule. Herein, we developed a nano-vesicle system IA-PEP to integrate photosensitizer PEGylated indocyanine green and L-Arg with high loading content and to produce a ternary synergistic treatment combining NO therapy, photodynamic therapy (PDT) along with mild-temperature photothermal therapy (MPTT) under 808 nm laser irradiation. The in vivo investigation on nude mice bearing xenograft MCF-7 tumors verified its potent anti-tumor efficacy with complete tumor elimination.
    Keywords:  L-arginine; Mild phtothermal therapy; Nitric oxide; Photodynamic therapy; Synergistic cancer therapy
    DOI:  https://doi.org/10.1016/j.actbio.2021.12.012
  7. Mol Diagn Ther. 2021 Dec 16.
    Targeting Mutated KRAS Genes to Treat Solid Tumours.
    Tharani Krishnan, Rachel Roberts-Thomson, Vy Broadbridge, Timothy Price.
      Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenes in solid tumours. It encodes an important signalling pathway that drives cellular proliferation and growth. It is frequently mutated in aggressive advanced solid tumours, particularly colorectal, lung and pancreatic cancer. Since the first mutated KRAS was discovered in the 1980s, decades of research to develop targeted inhibitors of mutant KRAS have fallen short of the task, until recently. Multiple agents are now in clinical trials, including specific mutant KRAS inhibitors, pan-KRAS inhibitors, therapeutic vaccines and other targeted inhibitors. Mutant-specific KRAS G12C inhibitors are the most advanced, with two inhibitors, adagrasib and sotorasib, achieving approval in 2021 for the second-line treatment of patients with KRAS G12C mutant lung cancer. In this review, we summarise the importance of mutant KRAS in solid tumours, prior attempts at inhibiting mutant KRAS, and the current promising targeted agents being investigated in clinical trials, along with future challenges.
    DOI:  https://doi.org/10.1007/s40291-021-00564-0
  8. Pharmacol Res. 2021 Dec 09. pii: S1043-6618(21)00616-2. [Epub ahead of print] 106032
    The purple mangosteen (Garcinia mangostana): Defining the anticancer potential of selected xanthones.
    Mirielle C Nauman, Jeremy J Johnson.
      The purple mangosteen (Garcinia mangostana) is a popular Southeast Asian fruit that has been used traditionally for its health promoting benefits for years. Unique to the mangosteen are a class of phytochemicals known as xanthones that have been reported to display significant anti-cancer and anti-tumor activities, specifically through the promotion of apoptosis, targeting of specific cancer-related proteins, or modulation of cell signaling pathways. α-Mangostin, the most abundant xanthone isolated from the mangosteen, has received substantial attention as it has proven to be a potent phytochemical, specifically as an anticancer agent, in numerous different cancer cell studies and cancer animal models. While the mechanisms for these anticancer effects have been reported in many studies, lesser xanthones, including gartanin, β-mangostin, γ-mangostin, garcinone C, and garcinone E, and mangosteen extracts from the pericarp, roots, rind, and stem show promise for their anticancer activity but their mechanisms of action are not as well developed and remain to be determined. Mangosteen products appear safe and have been well tolerated in human clinical trials where they show antioxidant activity, though their clinical anticancer activity has not yet been evaluated. This review summarizes the work that has been done to explore and explain the anticancer and antitumor activities of α-mangostin, lesser xanthones, and mangosteen extracts in vitro, in vivo, and in humans in various cancers.
    Keywords:  Garcinia mangostana; Garcinone C (PubChem CID: 44159808); Garcinone E (10298511); Gartanin (PubChem CID: 5281633); Xanthones; anticancer; chemoprevention; mangosteen; prostate cancer; α-Mangostin (PubChem CID: 5281650); β-Mangostin (PubChem CID: 5495925); γ-Mangostin (PubChem CID: 5464078)
    DOI:  https://doi.org/10.1016/j.phrs.2021.106032
  9. Cancer Metab. 2021 Dec 11. 9(1): 41
    Loss of hexokinase 1 sensitizes ovarian cancer to high-dose metformin.
    Daniela Šimčíková, Dominik Gardáš, Kateřina Hložková, Martin Hruda, Petr Žáček, Lukáš Rob, Petr Heneberg.
       BACKGROUND: Hexokinases (HKs) are well-studied enzymes catalyzing the first step of glycolysis. However, non-canonical regulatory roles of HKs are still incompletely understood. Here, we hypothesized that HKs comprise one of the missing links between high-dose metformin and the inhibition of the respiratory chain in cancer.
    METHODS: We tested the isoenzyme-specific regulatory roles of HKs in ovarian cancer cells by examining the effects of the deletions of HK1 and HK2 in TOV-112D ovarian adenocarcinoma cells. We reverted these effects by re-introducing wild-type HK1 and HK2, and we compared the HK1 revertant with the knock-in of catalytically dead HK1 p.D656A. We subjected these cells to a battery of metabolic and proliferation assays and targeted GC×GC-MS metabolomics.
    RESULTS: We found that the HK1 depletion (but not the HK2 depletion) sensitized ovarian cancer cells to high-dose metformin during glucose starvation. We confirmed that this newly uncovered role of HK1 is glycolysis-independent by the introduction of the catalytically dead HK1. The expression of catalytically dead HK1 stimulated similar changes in levels of TCA intermediates, aspartate and cysteine, and in glutamate as were induced by the HK2 deletion. In contrast, HK1 deletion increased the levels of branched amino acids; this effect was completely eliminated by the expression of catalytically dead HK1. Furthermore, HK1 revertants but not HK2 revertants caused a strong increase of NADPH/NADP ratios independently on the presence of glucose or metformin. The HK1 deletion (but not HK2 deletion) suppressed the growth of xenotransplanted ovarian cancer cells and nearly abolished the tumor growth when the mice were fed the glucose-free diet.
    CONCLUSIONS: We provided the evidence that HK1 is involved in the so far unknown glycolysis-independent HK1-metformin axis and influences metabolism even in glucose-free conditions.
    Keywords:  Aerobic glycolysis; Hexokinase; Metabolism reprogramming; Metformin; Nicotinamide adenine dinucleotide phosphate; Oxidative phosphorylation
    DOI:  https://doi.org/10.1186/s40170-021-00277-2
  10. Clin Exp Metastasis. 2021 Dec 18.
    Defining the landscape of metabolic dysregulations in cancer metastasis.
    Sara Abdul Kader, Shaima Dib, Iman W Achkar, Gaurav Thareja, Karsten Suhre, Arash Rafii, Anna Halama.
      Metastasis is the primary cause of cancer related deaths due to the limited number of efficient druggable targets. Signatures of dysregulated cancer metabolism could serve as a roadmap for the determination of new treatment strategies. However, the metabolic signatures of metastatic cells remain vastly elusive. Our aim was to determine metabolic dysregulations associated with high metastatic potential in breast cancer cell lines. We have selected 5 triple negative breast cancer (TNBC) cell lines including three with high metastatic potential (HMP) (MDA-MB-231, MDA-MB-436, MDA-MB-468) and two with low metastatic potential (LMP) (BT549, HCC1143). The normal epithelial breast cell line (hTERT-HME1) was also investigated. The untargeted metabolic profiling of cells and growth media was conducted and total of 479 metabolites were quantified. First we characterized metabolic features differentiating TNBC cell lines from normal cells as well as identified cell line specific metabolic fingerprints. Next, we determined 92 metabolites in cells and 22 in growth medium that display significant differences between LMP and HMP. The HMP cell lines had elevated level of molecules involved in glycolysis, TCA cycle and lipid metabolism. We identified metabolic advantages of cell lines with HMP beyond enhanced glycolysis by pinpointing the role of branched chain amino acids (BCAA) catabolism as well as molecules supporting coagulation and platelet activation as important contributors to the metastatic cascade. The landscape of metabolic dysregulations, characterized in our study, could serve as a roadmap for the identification of treatment strategies targeting cancer cells with enhanced metastatic potential.
    Keywords:  Branch chain amino acid metabolism; Metabolic profiling; Metastasis; Metastatic potential; TCA cycle; Triple negative breast cancer
    DOI:  https://doi.org/10.1007/s10585-021-10140-9
  11. Macromol Biosci. 2021 Dec 15. e2100429
    Cascade Tumor Therapy Platform for Sensitized Chemotherapy and Penetration Enhanced Photothermal Therapy.
    Sen Liu, Can Shen, Dongsheng Jiang, Cheng Qian, Zhongmei Yang, Jianquan Wang, Wei Ye.
      As a stand-alone therapy strategy may not be sufficient for effective cancer treatment, and a combination of chemotherapy with other therapies is a main trend in cancer treatment. In this study, we report on a combination of chemotherapy and photothermal therapy (PTT) to achieve the goal of cascade multistage cancer treatment. A thermally responsive amphiphilic copolymer (PDP) was designed, and then a CuS nanoparticle (NP)-based CO photo-induced release system (COPIRS) and doxorubicin (Dox) were encapsulated to construct the nano-medicine (COPIRS&Dox@PDP NPs). The large-sized COPIRS&Dox@PDP NPs can accumulate in tumors after long circulation in vivo, and will generate heat to act as a photothermal therapeutic agent by near infrared (NIR) light. Moreover, synergically release of CO and Dox was achieved, and acted as a sensitized chemotherapeutic agent. The combination of PTT and chemotherapy sensitization could effectively eliminate active tumor cells in the periphery of the tumor. CuS NPs were also released after the degradation of COPIRS&Dox@PDP NPs, and small-sized CuS NPs possess better tumor penetration and achieve penetration-enhanced PTT by further NIR irradiation, thereby effectively eliminating tumor cells inside solid tumors. Hence, cascade multistage cancer treatment of "combined PTT and chemotherapy sensitization" - "penetration-enhanced PTT" was achieved. Through the above-mentioned strategy, tumor cells were comprehensively and effectively eliminated. This article is protected by copyright. All rights reserved.
    Keywords:  cascade therapy; penetration enhanced; photothermal therapy; sensitized chemotherapy; tumor therapy
    DOI:  https://doi.org/10.1002/mabi.202100429
  12. ChemNanoMat. 2021 Oct;7(10): 1104-1107
    Enzymatic Delivery of Magnetic Nanoparticles into Mitochondria of Live Cells.
    Hongjian He, Jiaqi Guo, Bing Xu.
      Delivering magnetic nanoparticles (MNPs) into mitochondria provide a facile approach to manipulate cell life because mitochondria play essential roles in cell survival and death. Here we report the use of enzyme-responsive peptide assemblies to deliver MNPs into mitochondria of live cells. The mitochondria-targeting peptide (Mito-Flag), as the substrate of enterokinase (ENTK), assembles with MNPs in solution. The MNPs that are encapsulated by Mito-Flag peptides selectively accumulate to the mitochondria of cancer cells, rather than normal cells. The mitochondrial localization of MNPs reduces the viability of the cancer cells, but hardly affects the survival of the normal cell. This work demonstrates a new and facile strategy to specifically transport MNPs to the mitochondria in cancer cells for exploring the applications of MNPs as the targeted drug for biomedicine and cancer therapy.
    Keywords:  Enzyme; Magnetic Nanoparticle; Mitochondria; Peptide; Self-Assembly
    DOI:  https://doi.org/10.1002/cnma.202100249
  13. Biomed Pharmacother. 2021 Dec 11. pii: S0753-3322(21)01313-5. [Epub ahead of print]146 112526
    Cell line-directed breast cancer research based on glucose metabolism status.
    Pegah Farhadi, Reza Yarani, Elahe Valipour, Sarah Kiani, Zohreh Hoseinkhani, Kamran Mansouri.
      Metabolic reprogramming is a potential hallmark of tumor cells to support continuous proliferation. Metabolic heterogeneity in breast cancer patients has been highlighted as the driving cause of tumor progression and resistance to anticancer drugs. Studying and identifying distinct metabolic alterations in breast cancer subtypes could offer new perspectives for faster diagnosis and treatment. Given cancer cell dependency on glycolysis, the primary energy source, this enzymatic pathway will play a critical role in targeting therapies. Knowledge about the specific metabolic dependencies of tumors for growth and proliferation can be promising for novel targeted and cell-based therapies. Here, the metabolic status with emphasis on glycolysis of breast cancer cell lines according to their classification was reviewed.
    Keywords:  Breast cancer cell lines; Glycolysis; Metabolism status; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.biopha.2021.112526
  14. Int Rev Immunol. 2021 Dec 17. 1-11
    Molecular mechanisms of ferroptosis and their role in inflammation.
    Feng Wang, Jingya He, Ruxiao Xing, Tong Sha, Bin Sun.
      Ferroptosis is a type of non-apoptotic cell death, which demonstrates a definite iron-dependent expression pattern and is associated with lipid peroxidation. Glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis. Ferroptosis is involved in the development and progression of various diseases, such as cancer, tissue ischemia-reperfusion injury, neurological diseases, and respiratory diseases. It has been established previously that ferroptotic cells trigger the innate immune system by releasing inflammation-linked damage-related molecules, and immune cells stimulate the inflammatory response by recognizing the operational mechanism of ferroptosis. Some anti-inflammatory drugs have been shown to inhibit ferroptosis in certain cell models. Conversely, some ferroptosis inhibitors also exert anti-inflammatory effects in certain diseases. The present review evaluated the relationship between ferroptosis and inflammation, as well as the underlying internal mechanism, and provided valuable insights into developing novel treatment strategies for inflammatory diseases and cancer.
    Keywords:  Ferroptosis; GSH; inflammation; iron; lipid peroxidation
    DOI:  https://doi.org/10.1080/08830185.2021.2016739
  15. J Control Release. 2021 Dec 11. pii: S0168-3659(21)00663-5. [Epub ahead of print]
    Chitosan: A versatile bio-platform for breast cancer theranostics.
    Vijay Sagar Madamsetty, Shima Tavakol, Saeid Moghassemi, Arezoo Dadashzadeh, John D Schneible, Iman Fatemi, Abdolsamad Shirvani, Ali Zarrabi, Fereshteh Azedi, Ali Dehshahri, Abbas Aghaei Afshar, Kian Aghaabbasi, Abbas Pardakhty, Reza Mohammadinejad, Prashant Kesharwani.
      Breast cancer is considered one of the utmost neoplastic diseases globally, with a high death rate of patients. Over the last decades, many approaches have been studied to early diagnose and treat it, such as chemotherapy, hormone therapy, immunotherapy, and MRI and biomarker tests; do not show the optimal efficacy. These existing approaches are accompanied by severe side effects, thus recognizing these challenges, a great effort has been done to find out the new remedies for breast cancer. Main finding: Nanotechnology opened a new horizon to the treatment of breast cancer. Many nanoparticulate platforms for the diagnosis of involved biomarkers and delivering antineoplastic drugs are under either clinical trials or just approved by the Food and Drug Administration (FDA). It is well known that natural phytochemicals are successfully useful to treat breast cancer because these natural compounds are safer, available, cheaper, and have less toxic effects. Chitosan is a biocompatible and biodegradable polymer. Further, it has outstanding features, like chemical functional groups that can easily modify our interest with an exceptional choice of promising applications. Abundant studies were directed to assess the chitosan derivative-based nanoformulation's abilities in delivering varieties of drugs. However, the role of chitosan in diagnostics and theranostics not be obligated. The present servey will discuss the application of chitosan as an anticancer drug carrier such as tamoxifen, doxorubicin, paclitaxel, docetaxel, etc. and also, its role as a theranostics (i.e. photo-responsive and thermo-responsive) moieties. The therapeutic and theranostic potential of chitosan in cancer is promising and it seems that to have a good potential to get to the clinic.
    Keywords:  Anticancer drug; Breast cancer; Chitosan; Drug delivery; Nanoparticles; Phytochemicals
    DOI:  https://doi.org/10.1016/j.jconrel.2021.12.012
  16. J Gastrointest Cancer. 2021 Dec 18.
    Autophagy and Hepatic Tumor Microenvironment Associated Dormancy.
    Yunus Akkoc, Devrim Gozuacik.
      The goal of successful cancer treatment is targeting the eradication of cancer cells. Although surgical removal of the primary tumors and several rounds of chemo- and radiotherapy reduce the disease burden, in some cases, asymptomatic dormant cancer cells may still exist in the body. Dormant cells arise from the disseminated tumor cells (DTCs) from the primary lesion. DTCs escape from immune system and cancer therapy and reside at the secondary organ without showing no sign of proliferation. However, under some conditions. dormant cells can be re-activated and enter a proliferative state even after decades. As a stress response mechanism, autophagy may help the adaptation of DTCs at this futile foreign microenvironment and may control the survival and re-activation of dormant cells. Studies indicate that hepatic microenvironment serves a favorable condition for cancer cell dormancy. Although, no direct study was pointing out the role of autophagy in liver-assisted dormancy, involvement of autophagy in both liver microenvironment, health, and disease conditions has been indicated. Therefore, in this review article, we will summarize cancer dormancy and discuss the role and importance of autophagy and hepatic microenvironment in this context.
    Keywords:  Autophagy; Dormancy; Liver; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12029-021-00774-z
  17. Zhonghua Nan Ke Xue. 2021 Jul;27(7): 654-658
    [Quercetin for the treatment of prostate cancer: Progress in studies].
    Longyuhe Yang, Yue-Qiang Wang, Xi Huang, Zhi-Ming Yang.
      Prostate cancer (PCa) is a common urinary malignancy, and advanced PCa has a poor prognosis and a high mortality. Drug therapies currently available for this malignancy often cause serious adverse reactions, and therefore new drugs with fewer adverse effects or the potential to reduce the adverse effects of traditional chemotherapeutic drugs are badly needed for the management of PCa. Quercetin, as a natural flavonoid, has been extensively studied in recent years for its anti-cancer effects, as in cell signal transduction, apoptosis promotion, anti-proliferation and -oxidation, and growth inhibition. In fact, quercetin has a variety of biological effects and can inhibit various enzymes involved in cell proliferation and signal transduction pathways. Besides, quercetin is also reported to have potential synergistic effects when used in combination with radiotherapy or chemotherapeutic drugs. This review summarizes the advances in the treatment of PCa with quercetin, focusing on its effects of promoting the apoptosis, inhibiting the proliferation and reducing the invasiveness and migration of tumor cells, and reversing drug resistance, aiming to provide a new theoretical basis and some new ideas for the studies of the treatment of PCa.
    Keywords:   chemotherapy; drug resistance; invasion and migration ; paclitaxel; quercetin; prostate cancer
  18. Front Med (Lausanne). 2021 ;8 740087
    Metabolic Reprogramming and Reconstruction: Integration of Experimental and Computational Studies to Set the Path Forward in ADPKD.
    Roberto Pagliarini, Christine Podrini.
      Metabolic reprogramming is a key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD) characterized by changes in cellular pathways occurring in response to the pathological cell conditions. In ADPKD, a broad range of dysregulated pathways have been found. The studies supporting alterations in cell metabolism have shown that the metabolic preference for abnormal cystic growth is to utilize aerobic glycolysis, increasing glutamine uptake and reducing oxidative phosphorylation, consequently resulting in ADPKD cells shifting their energy to alternative energetic pathways. The mechanism behind the role of the polycystin proteins and how it leads to disease remains unclear, despite the identification of numerous signaling pathways. The integration of computational data analysis that accompanies experimental findings was pivotal in the identification of metabolic reprogramming in ADPKD. Here, we summarize the important results and argue that their exploitation may give further insights into the regulative mechanisms driving metabolic reprogramming in ADPKD. The aim of this review is to provide a comprehensive overview on metabolic focused studies and potential targets for treatment, and to propose that computational approaches could be instrumental in advancing this field of research.
    Keywords:  ADPKD; drug repositioning; metabolism; systems biology; systems medicine; therapeutics
    DOI:  https://doi.org/10.3389/fmed.2021.740087
  19. Cancer Res. 2021 Dec 13. pii: canres.CAN-21-0403-A.2021. [Epub ahead of print]
    PKM2 is essential for bladder cancer growth and maintenance.
    Yong Xia, Xing Wang, Yan Liu, Ellen Shapiro, Herbert Lepor, Moon-Shong Tang, Tung-Tien Sun, Xue-Ru Wu.
      Pyruvate kinase M2 (PKM2) has been shown to promote tumorigenesis by facilitating the Warburg effect and enhancing the activities of oncoproteins. However, this paradigm has recently been challenged by studies in which the absence of PKM2 failed to inhibit and instead accelerated tumorigenesis in mouse models. These results seem inconsistent with the fact that most human tumors overexpress PKM2. To further elucidate the role of PKM2 in tumorigenesis, we investigated the effect of PKM2 knockout in oncogenic HRAS-driven urothelial carcinoma. While PKM2 ablation in mouse urothelial cells did not affect tumor initiation, it impaired the growth and maintenance of HRAS-driven tumors. Chemical inhibition of PKM2 recapitulated these effects. Both conditions substantially reduced complex formation of PKM2 with STAT3, their nuclear translocation, and HIF1α- and VEGF-related angiogenesis. The reduction in nuclear STAT3 in the absence of PKM2 also correlated with decreased autophagy and increased apoptosis. Time-controlled, inducible PKM2 overexpression in simple urothelial hyperplasia did not trigger tumorigenesis, while overexpression of PKM2, but not PKM1, in nodular urothelial hyperplasia with angiogenesis strongly accelerated tumorigenesis. Finally, in human patients, PKM2 was overexpressed in low-grade non-muscle invasive and high-grade muscle-invasive bladder cancer. Based on these data, PKM2 is not required for tumor initiation but is essential for tumor growth and maintenance by enhancing angiogenesis and metabolic addiction. The PKM2-STAT3-HIF1α/VEGF signaling axis may play a critical role in bladder cancer and may serve as an actionable therapeutic target.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0403
  20. Pharm Dev Technol. 2021 Dec 13. 1-10
    Targeted Drug Delivery via Folate Decorated Nanocarriers Based on Linear Polymer for Treatment of Breast Cancer.
    Mostafa Zamani, Mozhgan Aghajanzadeh, Ali Sharafi, Kobra Rostamizadeh, Hossein Danafar.
      In this project, a biocompatible block copolymer including poly ethylene glycol and poly caprolactone was synthesized using ring opening reaction. Then, the copolymer was conjugated to folic acid using lysine as a linker. Also, curcumin was used as a therapeutic anticancer agent. Nanoprecipitation method was used to prepare curcumin loaded polymeric micelles. Different methods including Fourier-transform infrared spectroscopy, transmission electron microscopy, and dynamic light scattering were used to characterize the prepared nanocarriers. MTT assay and hemolysis assay were used to evaluate in vitro anticancer efficiency and biocompatibility of the prepared nanocarriers, respectively. The results proved efficiency of nanocarriers as a drug delivery system in various aspects such as physicochemical properties and biocompatibility. Also, in vivo results showed that nanocarriers did not show any severe weight loss and side effects on mice, and the anti-cancer study results of the curcumin-loaded nanocarriers proved that the conjugation of folic acid on the surface of nanocarriers as a targeting agent could increase the therapeutic efficacy of curcumin.
    Keywords:  Curcumin; breast cancer; folate receptor; targeted drug delivery
    DOI:  https://doi.org/10.1080/10837450.2021.2018457
  21. Nutr Cancer. 2021 Dec 15. 1-15
    Broad Anti-Cancer Activity Produced by Targeted Nutrients Deprivation (TND) of Multiple Non-Essential Amino Acids.
    Zehui Li, Shuang Zhou, Xiaodong Yang, Xiyan Li, Grace Xiaolu Yang, John Chant, Michael Snyder, Xin Wang.
      It has been known for close to 100 years that the metabolism of cancer cells is altered and different than that of healthy cells in the body. On that basis, we have developed an entirely novel approach to managing cancer, termed Targeted Nutrients Deprivation (TND). TND employs a formulated diet depleted of multiple non-essential amino acids (NEAAs) that are required by tumor cells but not by normal cells. Cancer cells specifically require those NEAAs due to their heightened and rewired metabolism. We demonstrated that our first proprietary formulated TND diet-FTN203-significantly reduced the growth of multiple human tumor xenografts in mouse. In combination with chemotherapy and immunotherapy, FTN203 further enhanced therapeutic efficacy. Reliance on FTN203 as the sole nutrition source was shown to be safe without causing detrimental body-weight loss or internal organ damage. Our findings indicate that TND is a novel and safe approach to managing cancer.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.2013904 .
    DOI:  https://doi.org/10.1080/01635581.2021.2013904
  22. Nat Commun. 2021 Dec 15. 12(1): 7311
    Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis.
    Divya Ramchandani, Mirela Berisa, Diamile A Tavarez, Zhuoning Li, Matthew Miele, Yang Bai, Sharrell B Lee, Yi Ban, Noah Dephoure, Ronald C Hendrickson, Suzanne M Cloonan, Dingcheng Gao, Justin R Cross, Linda T Vahdat, Vivek Mittal.
      Copper serves as a co-factor for a host of metalloenzymes that contribute to malignant progression. The orally bioavailable copper chelating agent tetrathiomolybdate (TM) has been associated with a significant survival benefit in high-risk triple negative breast cancer (TNBC) patients. Despite these promising data, the mechanisms by which copper depletion impacts metastasis are poorly understood and this remains a major barrier to advancing TM to a randomized phase II trial. Here, using two independent TNBC models, we report a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit elevated intracellular copper levels and a marked sensitivity to TM. Global proteomic and metabolomic profiling identifies TM-mediated inactivation of Complex IV as the primary metabolic defect in the SOX2/OCT4+ cell population. We also identify AMPK/mTORC1 energy sensor as an important downstream pathway and show that AMPK inhibition rescues TM-mediated loss of invasion. Furthermore, loss of the mitochondria-specific copper chaperone, COX17, restricts copper deficiency to mitochondria and phenocopies TM-mediated alterations. These findings identify a copper-metabolism-metastasis axis with potential to enrich patient populations in next-generation therapeutic trials.
    DOI:  https://doi.org/10.1038/s41467-021-27559-z
  23. Adv Funct Mater. 2021 Oct 08. pii: 2103600. [Epub ahead of print]31(41):
    Camouflaged Hybrid Cancer Cell-Platelet Fusion Membrane Nanovesicles Deliver Therapeutic MicroRNAs to Presensitize Triple-Negative Breast Cancer to Doxorubicin.
    Yi Liu, Uday K Sukumar, Masamitsu Kanada, Anandi Krishnan, Tarik F Massoud, Ramasamy Paulmurugan.
      Camouflaged cell-membrane-based nanoparticles have been gaining increasing attention owing to their improved biocompatibility and immunomodulatory properties. Using nanoparticles prepared from the membranes of specific cell types, or fusions derived from different cells membranes, can improve their functional performance in several aspects. Here, we used cell membranes extracted from breast cancer cells and platelets to fabricate a hybrid-membrane vesicle fusion (cancer cell-platelet-fusion-membrane vesicle, CPMV) in which we loaded therapeutic microRNAs (miRNAs) for the treatment of triple-negative breast cancer (TNBC). We used a clinically scalable microfluidic platform for the fusion of cell membranes. The reconstitution process during synthesis allows for efficient loading of miRNAs into CPMVs. We systematically optimized the conditions for preparation of miRNA-loaded CPMVs and demonstrated their property of homing to source cells using in vitro experiments, and by therapeutic evaluation in vivo. In vitro, the CPMVs exhibited significant recognition of their source cells and avoided engulfment by macrophages. After systemic delivery in mice, the CPMVs showed a prolonged circulation time and site-specific accumulation at implanted TNBC-xenografts. The delivered antimiRNAs sensitized TNBCs to doxorubicin, resulting in an improved therapeutic response and survival rate. This strategy has considerable potential for clinical translation to improve personalized therapy for breast cancer and other malignancies.
    Keywords:  Cancer cell-platelet membrane fusion vesicle; chemotherapy; doxorubicin; microRNAs; microfluidics; presensitization; triple-negative breast cancer
    DOI:  https://doi.org/10.1002/adfm.202103600
  24. Recent Pat Anticancer Drug Discov. 2021 ;16(4): 498-520
    Ultrasound-Mediated Cancer Therapeutics Delivery using Micelles and Liposomes: A Review.
    Debasmita Mukhopadhyay, Catherine Sano, Nour AlSawaftah, Raafat El-Awady, Ghaleb A Husseini, Vinod Paul.
       BACKGROUND: Existing cancer treatment methods have many undesirable side effects that greatly reduce the quality of life of cancer patients.
    OBJECTIVE: This review will focus on the use of ultrasound-responsive liposomes and polymeric micelles in cancer therapy.
    METHODS: This review presents a survey of the literature regarding ultrasound-triggered micelles and liposomes using articles recently published in various journals, as well as some new patents in this field.
    RESULTS: Nanoparticles have proven promising as cancer theranostic tools. Nanoparticles are selective in nature, have reduced toxicity, and controllable drug release patterns making them ideal carriers for anticancer drugs. Numerous nanocarriers have been designed to combat malignancies, including liposomes, micelles, dendrimers, solid nanoparticles, quantum dots, gold nanoparticles, and, more recently, metal-organic frameworks. The temporal and spatial release of therapeutic agents from these nanostructures can be controlled using internal and external triggers, including pH, enzymes, redox, temperature, magnetic and electromagnetic waves, and ultrasound. Ultrasound is an attractive modality because it is non-invasive, can be focused on the diseased site, and has a synergistic effect with anticancer drugs.
    CONCLUSION: The functionalization of micellar and liposomal surfaces with targeting moieties and the use of ultrasound as a triggering mechanism can help improve the selectivity and enable the spatiotemporal control of drug release from nanocarriers.
    Keywords:  Nanomedicine; cancer therapy.; drug delivery; liposomes; polymeric micelles; ultrasound
    DOI:  https://doi.org/10.2174/1574892816666210706155110
  25. Bioconjug Chem. 2021 Dec 14.
    Glutathione-Responsive Chemodynamic Therapy of Manganese(III/IV) Cluster Nanoparticles Enhanced by Electrochemical Stimulation via Oxidative Stress Pathway.
    Yang Chen, Ming Chen, Tianli Zhai, Han Zhou, Zhiguo Zhou, Xiaoming Liu, Shiping Yang, Hong Yang.
      Escalating the level of reactive oxygen species (ROS) in a tumor microenvironment is one of the effective strategies to improve the efficacy of anticancer therapy. In this work, manganese cluster nanoparticles (Mn12) encapsulated with heparin (Mn12-heparin) were developed as a chemodynamic therapeutic agent for cancer treatment by raising ROS levels in tumor cells via cascade reactions. The manganese cluster is a cluster of mixed valence (III/IV) with acetate as the ligand. The cluster is readily subject to reduction by glutathione (GSH) to release Mn(II), which reacts with H2O2 to generate hydroxyl radicals via a Fenton-like pathway. The generation of hydroxyl radicals could be enhanced by the stimulation of an external alternative electric field during which GSH acts as an electron mediator to enhance the release of Mn(II) from the cluster. The relatively high levels of both H2O2 and GSH and the acidic environment in tumor cells strengthen its specificity when the manganese cluster system is employed to suppress or eliminate tumors. Both in vitro and in vivo results suggest that, in addition to the cytotoxicity imposed by the raised ROS level due to the presence of Mn(II) species, the depletion of endogenous GSH leads indirectly to the inhibition of glutathione peroxidase 4 (GPX4), consequently raising the lipid peroxidation (LPO) level to cause ferroptosis. The apoptosis and ferroptosis jointly render the manganese-based agent potent efficacy with tumor-targeting specificity in antitumor treatment under electric stimulation.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.1c00512
  26. Nanomedicine (Lond). 2021 Dec 17.
    The synergistic effect of chemo-photothermal therapies in SN-38-loaded gold-nanoshell-based colorectal cancer treatment.
    Shu-Jyuan Yang, Hsiao-Ting Huang, Chung-Huan Huang, Jui-An Pai, Chung-Hao Wang, Ming-Jium Shieh.
      Aim: 7-Ethyl-10-hydroxycamptothecin (SN-38)-loaded gold nanoshells nanoparticles (HSP@Au NPs) were developed for combined chemo-photothermal therapy to treat colorectal cancer. Materials & methods: SN-38-loaded nanoparticles (HSP NPs) were prepared by the lyophilization-hydration method, and then developed into gold nanoshells. The nanoparticles were characterized and assessed for photothermal properties, cytotoxicity and hemocompatibility in vitro. In vivo anticancer activity was tested in a tumor mouse model. Results: The HSP@Au NPs (diameter 186.9 nm, zeta potential 33.4 mV) led to significant cytotoxicity in cancer cells exposed to a near-infrared laser. Moreover, the HSP@Au NP-mediated chemo-photothermal therapy displayed significant tumor growth suppression and disappearance (25% of tumor clearance rate) without adverse side effects in vivo. Conclusion: HSP@Au NPs may be promising in the treatment of colorectal cancer in the future.
    Keywords:  7-ethyl-10-hydroxycamptothecin; chemotherapy; colorectal cancer; gold nanoshell; human serum albumin; multifunctional therapy; near-infrared laser; photothermal therapy; polyethylenimine
    DOI:  https://doi.org/10.2217/nnm-2021-0187
  27. J Colloid Interface Sci. 2021 Dec 02. pii: S0021-9797(21)02119-6. [Epub ahead of print]609 353-363
    A carrier-free supramolecular nanoprodrug based on lactose-functionalized dimeric camptothecin via self-assembly in water for targeted and fluorescence imaging-guided chemo-photodynamic therapy.
    Ke Ma, Jingtao Shi, Yuxin Pei, Zhichao Pei.
      Most carrier-based nano drug delivery systems (nano-DDSs) are subjected to complex preparation or purification processes, metabolic instability and potential systemic toxicity. To overcome these issues, it is urgent to develop a multifunctional carrier-free nano-DDS that can be fabricated by a simple approach for enhanced anticancer efficacy. In this work, the carrier-free supramolecular nanoprodrug (CF SNPD) based on lactose (Lac) functionalized dimeric camptothecin (CPT) was developed, in which Lac and CPT were conjugated by the aromatized thioacetal (ATA, a reactive oxygen species (ROS)-responsive bond). The obtained Lac-ATA-CPT2 prodrug and the photosensitizer Chlorin e6 (Ce6) formed CF SNPD (denoted as Ce6@Lac-ATA-CPT2 NPs) in water by supramolecular self-assembly. The design of dimeric CPT endowed Ce6@Lac-ATA-CPT2 NPs with ultrahigh drug-loading capacity (up to 94%) and excellent stability. The Lac-functionalized CF SNPD displayed active specific targetability to HepG2 cells resulting from the carbohydrate-protein interactions. Furthermore, the fluorescence signal of Ce6 facilitated the precise tracking and localization of Ce6@Lac-ATA-CPT2 NPs within the cell. Meanwhile, the ROS generated by Ce6 not only cleaved ATA linker to trigger on-demand CPT release, but also exhibited a killing effect on tumor cells, enabling synergistic therapy via CPT-mediated chemotherapy (CT) and Ce6-induced photodynamic therapy (PDT). Therefore, the multifunctional CF SNPD may be one of the promising therapeutic options for liver cancer.
    Keywords:  Carrier-free; Chemo-photodynamic therapy; Lactose-functionalized; Self-assembly in water; Supramolecular nanoprodrug
    DOI:  https://doi.org/10.1016/j.jcis.2021.12.002
  28. Int J Nanomedicine. 2021 ;16 7995-8012
    Theranostic Nanoplatform with Sequential SDT and ADV Effects in Response to Well-Programmed LIFU Irradiation for Cervical Cancer.
    Jun Zhou, Jingxin Hou, Shuling Liu, Jie Xu, Ying Luo, Jun Zheng, Xin Li, Zhigang Wang, Haitao Ran, Dajing Guo.
       Background: Some patients with cervical cancer have the need to preserve fertility; therefore, a minimally invasive treatment option that can effectively inactivate tumors in these patients is necessary.
    Methods: In this paper, we designed and prepared nanoparticles (NPs) carrying IR780 and perfluorohexane (PFH) and characterized their properties. We focused on the promotion of programmed low-intensity focused ultrasound (LIFU) irradiation on the penetration and treatment of cervical cancer. First we used penetration-enhancing LIFU irradiation to promote the penetration of the NPs into 3D multicellular tumor spheroids (MCTSs) and tumors in tumor-bearing nude mice. Then we used re-therapeutic LIFU irradiation to achieve antitumor effects in vitro and in vivo. Photoacoustic (PA) and magnetic resonance (MR) imaging were used to monitor and evaluate the targeting and therapeutic effects of these NPs on tumor tissues.
    Results: The NPs prepared in this paper exhibited high affinity for HeLa cells, and can selectively achieve mitochondrial localization in the cell due to IR780 assistance. The penetration-enhancing LIFU irradiation have the ability to promote the penetration of the NPs into cervical cancer models in vivo and in vitro. Under LIFU irradiation, the cytotoxic reactive oxygen species (ROS) produced by IR780 during the first half of the re-therapeutic LIFU irradiation and the physical acoustic droplet vaporization (ADV) effect after PFH phase transition during the second half of the re-therapeutic LIFU irradiation can achieve synergistic minimally invasive treatment of tumors, which can be visualized and evaluated by PA and MR imaging in vivo.
    Conclusion: Well-programmed LIFU irradiation can promote NP penetration into deep tumor tissue and achieve antitumor effects simultaneously. Linking ROS + ADV effects can induce cell coagulation necrosis and lead to a comprehensive, long-term impact on tumor tissue, providing a conceptual theranostic nanoplatform for cervical cancer.
    Keywords:  HeLa cell; acoustic droplet vaporization; cervical cancer; magnetic resonance; reactive oxygen species; sonodynamic therapy
    DOI:  https://doi.org/10.2147/IJN.S339257
  29. Mol Biomed. 2021 Dec 17. 2(1): 40
    Untangling the KRAS mutated lung cancer subsets and its therapeutic implications.
    Kulshrestha Ritu, Pawan Kumar, Amit Singh, K Nupur, Sonam Spalgias, Parul Mrigpuri, Rajkumar.
      The Kirsten rat sarcoma virus transforming protein (KRAS) mutations (predominate in codons 12, 13, and 61) and genomically drive nearly one-third of lung carcinomas. These mutations have complex functions in tumorigenesis, and influence the tumor response to chemotherapy and tyrosine kinase inhibitors resulting in a poorer patient prognosis. Recent attempts using targeted therapies against KRAS alone have met with little success. The existence of specific subsets of lung cancer based on KRAS mutations and coexisting mutations are suggested. Their interactions need further elaboration before newer promising targeted therapies for KRAS mutant lung cancers can be used as earlier lines of therapy. We summarize the existing knowledge of KRAS mutations and their coexisting mutations that is relevant to lung cancer treatment, in this review. We elaborate on the prognostic impact of clinical and pathologic characteristics of lung cancer patients associated with KRAS mutations. We briefly review the currently available techniques for KRAS mutation detection on biopsy and cytology samples. Finally, we discuss the new therapeutic strategies for targeting KRAS-mutant non-small cell lung cancer (NSCLC). These may herald a new era in the treatment of KRASG12Cmutated NSCLC as well as be helpful to develop demographic subsets to predict targeted therapies and prognosis of lung cancer patients.
    Keywords:  KRAS mutation; KRAS targeted therapies; KRAS- signaling pathway; Lung cancer
    DOI:  https://doi.org/10.1186/s43556-021-00061-0
  30. Colloids Surf B Biointerfaces. 2021 Dec 07. pii: S0927-7765(21)00707-4. [Epub ahead of print]210 112261
    Functionalized layered double hydroxide nanoparticles as an intelligent nanoplatform for synergistic photothermal therapy and chemotherapy of tumors.
    Yuhan Ye, David H Bremner, Hongmei Zhang, Xia Chen, Jiadong Lou, Li-Min Zhu.
      In this work, a novel layered double hydroxide (LDH)-based multifunctional nanoplatform was built for synergistic photothermal therapy (PTT)/chemotherapy. The platform was modified using the peptide B3int to target cancer cells with overexpression of integrin αvβ3. Indocyanine green (ICG) and doxorubicin (DOX) were loaded into the nanocarrier (LDH-PEG-B3int NPs) to form a system having a high drug loading (18.62%) and a remarkable photothermal conversion efficiency of 25.38%. It also showed pH-responsive and near-infrared (NIR)-triggered DOX release. In vitro and in vivo studies indicated that the anti-tumor activity of the combined delivery system was significantly higher than that of a single delivery system. This co-delivery nanosystem may be helpful for future application in the clinical treatment of cancer.
    Keywords:  B3int; Layered double hydroxide; Nano-drug delivery system; Stimulus-responsive drug release
    DOI:  https://doi.org/10.1016/j.colsurfb.2021.112261
  31. Photodiagnosis Photodyn Ther. 2021 Dec 13. pii: S1572-1000(21)00500-7. [Epub ahead of print] 102683
    Carbon Nitride Nanomaterials with Application in Photothermal and Photodynamic Therapies.
    Gabriela N Bosio, Daniel O Mártire.
      Phototherapies are noninvasive treatments of tumors with high spatial selectivity. Photodynamic therapy (PDT) consists in the administration of a photosensitizer (PS) followed by local photoirradiation with light of specific wavelength. The excited states of the PS interact with biomolecules and molecular oxygen producing reactive oxygen species (ROS), which initiate cell death. Photothermal therapy (PTT) employs photothermal agents to harvest the energy from light and convert it into heat to produce a temperature increase of the surrounding environment leading to cell death. Due to their good biocompatibility and unique photophysical properties, carbon-based materials are suitable for application in PDT and PTT. In particular, graphitic carbon nitride (g-C3N4), is a low-cost, non-toxic, and environment-friendly material, which is currently being used in the development of new nanomaterials with application in PDT and PTT. This brief review includes recent advances in the development of g-C3N4-based nanomaterials specifically designed for achieving red-shifted band gaps with the aim of generating oxygen molecules via water splitting upon red light or NIR irradiation to tackle the hypoxic condition of the tumor area. Nanomaterials designed for theranostics, combining medical imaging applications with PDT and/or PTT treatments are also included. The recent developments of g-C3N4-nanomaterials containing lanthanide-based upconversion nanoparticles are also covered. Finally, g-C3N4-based nanomaterials employed in microwave induced photodynamic therapy, sonodynamic therapy, and magnetic hyperthermia are considered.
    Keywords:  g-C(3)N(4); hypoxia; photodynamic therapy; photothermal therapy; theranostics
    DOI:  https://doi.org/10.1016/j.pdpdt.2021.102683
  32. Iran J Pharm Res. 2021 ;20(3): 636-646
    Anticancer Activity of Ethnopharmacological Plants of Golestan Province/Iran against AGS, HT-29 and KYSE-30 Cell Lines through Promoting the Apoptosis and Immunomodulatory Effects.
    Mahdieh Naghavi Alhosseini, Masoumeh Mazandarani, Ayesheh Enayati, Mohsen Saiedi, Homa Davoodi.
      The anticancer and immunomodulatory effects of medicinal plants from Golestan province, as a promising source of cancer therapy against gastrointestinal cancer cell lines, were investigated in this study. The ethanolic root/aerial part extracts of 9 medicinal plants were screened for their cytotoxicity against normal mouse fibroblast cells (L-929) and three human cancer cell lines including gastric adenocarcinoma (AGS), colorectal adenocarcinoma (HT-29), and esophagus adenocarcinoma (KYSE-30) by performing MTT assay to determine the IC50 of the extracts. The in-vitro antioxidant activity, total phenolic (TPC), and total flavonoid content (TFC) of extracts was evaluated. Flow cytometry and Real-Time PCR were used for apoptosis assay and evaluation of expression of some genes involved in cell signaling; TLR-4, AKT, ERK1/2, and NFκB. Out of the 9 plant extracts screened, Arctiumlappa root (ALR), showed the most potent cytotoxicity against AGS, KYSE-30, and HT-29 cells with IC50 values of 10, 200, and 2030 µg/mL, respectively. In addition, ALR exerts high TPC (215.8 ± 0.3 mg GAE/g), TFC (69.03 ± 0.7 mg QUE/g) and high radical scavenging activity with IC50 (1250 ‎±‎ 0.1 µg/mL) in DPPH method. Also, ALR stimulates TLR-4 signaling, increased apoptosis, and decreased cancer cell attachment to the surface compared to the untreated cells. This plant, with a strong cytotoxic effect on cancer cells as well as increased apoptosis and its effect on molecules involved in TLR4 signaling as the immunomodulatory effect can be a suitable candidate for in-vivo studies in the future for cancer therapy.
    Keywords:  AKT/ ERK; Cytotoxicity; Ethnopharmacological plants; Gastrointestinal cancer; NFκB; TLR-4
    DOI:  https://doi.org/10.22037/ijpr.2021.114451.14858
  33. J Food Biochem. 2021 Dec 16. e14018
    Potential metabolic activities of raspberry ketone.
    Xiaoping Li, Teng Wei, Min Wu, Fang Chen, Peng Zhang, Ze-Yuan Deng, Ting Luo.
      Novel food and food compounds interventions have attracted a lot of attention nowadays for the prevention and treatment of metabolic diseases. Raspberry ketone (RK) is aromatic compound found within red fruits and berries, has been used as an over-the-counter product for weight loss. However, actually, the effect of RK on weight loss is still controversial, and the mechanism is largely unknown. Besides, in vivo and in vitro studies have demonstrated the beneficial effect of RK on the development of other metabolic diseases. In this review, we comprehensively highlighted the synthesis, bioavailability, and metabolism of RK, and summarized the progress made in our understanding of the potential biological activities of RK, including antiobesity, antidiabetes, cardioprotection, and hepatoprotection, as well as their underlying mechanisms. This paper provides a critical overview about the current findings and proposes the future studies in the area of RK on human health. PRACTICAL APPLICATIONS: Raspberry ketone (RK) has been used for weight control for years, but this effect is controversial considering food intake. Additionally, RK is beneficial for T2DM, liver and heart injury. The underlying mechanisms of the protective effect of RK including accelerating fatty acid oxidation, balancing serum glucose level, anti-inflammation, antioxidant process, and so on. In this context, we provide a comprehensive analysis of the benefits of RK against many metabolic diseases and discuss the underlying molecular mechanisms. We hope our work will be helpful for further researches on RK and improve its public recognition.
    Keywords:  bioavailability; biological activities; metabolites; raspberry ketone
    DOI:  https://doi.org/10.1111/jfbc.14018
  34. Front Immunol. 2021 ;12 765906
    Vitamin C, From Supplement to Treatment: A Re-Emerging Adjunct for Cancer Immunotherapy?
    Léonce Kouakanou, Christian Peters, Christine E Brown, Dieter Kabelitz, Leo D Wang.
      Vitamin C (VitC), in addition to its role as a general antioxidant, has long been considered to possess direct anti-cancer activity at high doses. VitC acts through oxidant and epigenetic mechanisms, which at high doses can exert direct killing of tumor cells in vitro and delay tumor growth in vivo. Recently, it has also been shown that pharmacologic-dose VitC can contribute to control of tumors by modulating the immune system, and studies have been done interrogating the role of physiologic-dose VitC on novel adoptive cellular therapies (ACTs). In this review, we discuss the effects of VitC on anti-tumor immune cells, as well as the mechanisms underlying those effects. We address important unanswered questions concerning both VitC and ACTs, and outline challenges and opportunities facing the use of VitC in the clinical setting as an adjunct to immune-based anti-cancer therapies.
    Keywords:  CAR (chimeric antigen receptor) T cells; cancer biology; cancer immunotherapies; immune checkpoint therapy (ICT); vitamin C (ascorbic acid)
    DOI:  https://doi.org/10.3389/fimmu.2021.765906
  35. Colloids Surf B Biointerfaces. 2021 Nov 29. pii: S0927-7765(21)00700-1. [Epub ahead of print]210 112254
    Exploring silver nanoparticles for cancer therapy and diagnosis.
    Renata Rank Miranda, Isabella Sampaio, Valtencir Zucolotto.
      Nanomaterials have emerged as promising candidates for cancer therapy and diagnosis as they can solve long-term issues such as drug solubility, systemic distribution, tumor acquired resistance, and improve the performance of diagnostic methods. Among inorganic nanomaterials, AgNPs have been extensively studied in the context of cancer treatment and the reported results have raised exciting expectations. In this review, we provide an overview of the recent research on AgNPs antitumoral properties, their application in different cancer treatment modalities, their potential in biosensors development, and also highlight the main challenges and possible strategies to enable its translation to clinical use.
    Keywords:  AgNPs; Biomimetic nanoparticles; Biosensor; Cancer therapy; Drug delivery
    DOI:  https://doi.org/10.1016/j.colsurfb.2021.112254
  36. Curr Protein Pept Sci. 2021 Dec 09.
    Nanoparticles: A Promising Tool to Promote Reactive Oxygen Species in Cancer Therapy.
    Mahima Chauhan, Saurabh Shekhar, Bhavna Yadav, Vandana Garg, Rohit Dutt, Sonali, Rahul Pratap Singh.
      
    Keywords:  Cancer cell death; Cancer therapy; Drug delivery technology; Nanomedicines; Reactive Oxygen Species
    DOI:  https://doi.org/10.2174/1389203722666211210115819
  37. Front Nutr. 2021 ;8 662952
    Low Carbohydrate Diets in Cancer Therapeutics: Current Evidence.
    Christopher Haskins, Justin Cohen, Rupesh Kotecha, Adeel Kaiser.
      Low carbohydrate diets have a promising mechanistic rationale in the treatment of cancer with favorable preclinical data. The strongest data suggest synergistic effects of dietary interventions with traditional cancer therapies. Recent prospective clinical trials suggest that low carbohydrate diets are safely and feasibly added within a busy oncology clinic, with hopeful additive effects in treatment enhancement.
    Keywords:  cancer; carbohydrate restriction; chemotherapy; immunotherapy; ketogenic diet (KD); metabolism; radiation
    DOI:  https://doi.org/10.3389/fnut.2021.662952
  38. Front Chem. 2021 ;9 773285
    Inorganic Nanozymes: Prospects for Disease Treatments and Detection Applications.
    Peng Wang, Dongyu Min, Guoyou Chen, Minghui Li, Liquan Tong, Yonggang Cao.
      In recent years, with the development of nanomaterials, a slice of nanomaterials has been demonstrated to possess high catalytic activity similar to natural enzymes and counter the dilemmas including easy inactivation and low yield natural of enzymes, which are labeled as nanozymes. The catalytic activity of nanozymes could be easily regulated by size, structure, surface modification and other factors. In comparison with natural enzymes, nanozymes featured with a more stable structure, economical preparation and preservation, diversity of functions and adjustable catalytic activity, thus becoming the potentially ideal substitute for natural enzymes. Generally, the are mainly three types containing metal oxide nanozymes, noble metal nanozymes and carbon-based nanozymes, owing various applications in biomedical, energy and environmental fields. In this review, to summarize the recent representative applications of nanozymes, and potentially explore the scientific problems in this field at the same time, we are going to discuss the catalytic mechanisms of diverse nanozymes, with the emphasis on their applications in the fields of tumor therapy, anti-inflammatory and biosensing, hoping to help and guide the future development of nanozymes.
    Keywords:  anti-inflammatory; biosensing; catalytic mechanisms; nanozyme; tumor therapy
    DOI:  https://doi.org/10.3389/fchem.2021.773285
  39. J Control Release. 2021 Dec 08. pii: S0168-3659(21)00652-0. [Epub ahead of print]
    Liposome-encapsulated anthraquinone improves efficacy and safety in triple negative breast cancer.
    Thomashire A George, Max M Chen, Andreas Czosseck, Hsiang-Pei Chen, Hsu-Shan Huang, David J Lundy.
      Breast cancer is the most common cancer among women and a leading cause of death worldwide. Triple negative breast cancer (TNBC) is a highly aggressive subtype which is the most challenging to treat. Due to heterogeneity and a lack of specific molecular targets, small molecule-based chemotherapy is the preferred course of treatment. However, these drugs have high toxicity due to off-target effects on healthy tissues, and tumors may develop resistance. Here, we present a polyethylene glycol-modified nanoscale liposomal formulation (LipoRV) of a new anthraquinone derivative which has potent effects on multiple TNBC cell lines. LipoRV readily inhibited the cell cycle, induced cell apoptosis, and reduced long-term proliferative potential of TNBC cells. In a xenograft animal model, LipoRV successfully cleared tumors and demonstrated a good safety profile, without detrimental effects on biochemical markers. Finally, RNA sequencing of LipoRV-treated TNBC cells was carried out, indicating that LipoRV may have immunomodulatory properties. These findings demonstrate that a liposomal anthraquinone-based molecule has excellent promise for TNBC therapy in the future.
    Keywords:  Anthraquinone; Breast cancer; Liposome; Polyethylene glycol
    DOI:  https://doi.org/10.1016/j.jconrel.2021.12.001
  40. J Nanobiotechnology. 2021 Dec 16. 19(1): 423
    Insights on functionalized carbon nanotubes for cancer theranostics.
    Lu Tang, Qiaqia Xiao, Yijun Mei, Shun He, Ziyao Zhang, Ruotong Wang, Wei Wang.
      Despite the exciting breakthroughs in medical technology, cancer still accounts for one of the principle triggers of death and conventional therapeutic modalities often fail to attain an effective cure. Recently, nanobiotechnology has made huge advancement in cancer therapy with gigantic application potential because of their ability in achieving precise and controlled drug release, elevating drug solubility and reducing adverse effects. Carbon nanotubes (CNTs), one of the most promising carbon-related nanomaterials, have already achieved much success in biomedical field. Due to their excellent optical property, thermal and electronic conductivity, easy functionalization ability and high drug loading capacity, CNTs can be applied in a multifunctional way for cancer treatment and diagnosis. In this review, we will give an overview of the recent progress of CNT-based drug delivery systems in cancer theranostics, which emphasizes their targetability to intracellular components of tumor cells and extracellular elements in tumor microenvironment. Moreover, a detailed introduction on how CNTs penetrate inside the tumor cells to reach their sites of action and achieve the therapeutic effects, as well as their diagnostic applications will be highlighted.
    Keywords:  Cancer theranostics; Carbon nanotubes; Intracellular targeting; Targeted drug delivery; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12951-021-01174-y
  41. J Nanobiotechnology. 2021 Dec 13. 19(1): 418
    Biodegradable reduce expenditure bioreactor for augmented sonodynamic therapy via regulating tumor hypoxia and inducing pro-death autophagy.
    Weijuan Zou, Junnian Hao, Jianrong Wu, Xiaojun Cai, Bing Hu, Zhigang Wang, Yuanyi Zheng.
       BACKGROUNDS: Sonodynamic therapy (SDT) as an emerging reactive oxygen species (ROS)-mediated antitumor strategy is challenged by the rapid depletion of oxygen, as well as the hypoxic tumor microenvironment. Instead of the presently available coping strategies that amplify the endogenous O2 level, we have proposed a biodegradable O2 economizer to reduce expenditure for augmenting SDT efficacy in the present study.
    RESULTS: We successfully fabricated the O2 economizer (HMME@HMONs-3BP-PEG, HHBP) via conjugation of respiration inhibitor 3-bromopyruvate (3BP) with hollow mesoporous organosilica nanoparticles (HMONs), followed by the loading of organic sonosensitizers (hematoporphyrin monomethyl ether; HMME) and further surface modification of poly(ethylene glycol) (PEG). The engineered HHBP features controllable pH/GSH/US-sensitive drug release. The exposed 3BP could effectively inhibit cell respiration for restraining the oxygen consumption, which could alleviate the tumor hypoxia conditions. More interestingly, it could exorbitantly elevate the autophagy level, which in turn induced excessive activation of autophagy for promoting the therapeutic efficacy. As a result, when accompanied with suppressing O2-consumption and triggering pro-death autophagy strategy, the HHBP could achieve the remarkable antitumor activity, which was systematically validated both in vivo and in vitro assays.
    CONCLUSIONS: This work not only provides a reduce expenditure means for enduring SDT, but also represents an inquisitive strategy for tumor treatments by inducing pro-death autophagy.
    Keywords:  Biodegradable; Hollow mesoporous organosilica; Hypoxia regulation; Pro-death autophagy; Sonodynamic therapy
    DOI:  https://doi.org/10.1186/s12951-021-01166-y
  42. Eur J Pharmacol. 2021 Dec 14. pii: S0014-2999(21)00795-0. [Epub ahead of print] 174639
    Simultaneous nanocarrier-mediated delivery of siRNAs and chemotherapeutic agents in cancer therapy and diagnosis: Recent advances.
    Negar Bidar, Majid Darroudi, Ailin Ebrahimzadeh, Mohammadreza Safdari, Miguel de la Guardia, Behzad Baradaran, Vahabodin Goodarzi, Fatemeh Oroojalian, Ahad Mokhtarzadeh.
      Recently, investigations have revealed that RNA interference (RNAi) has a remarkable potential to decrease cancer burden by downregulating genes. Among various RNAi molecules, small interfering RNA (siRNA) has been more attractive for this goal and is able to silence a target pathological path and promote the degradation of a certain mRNA, resulting in either gain or loss of function of proteins. Moreover, therapeutic siRNAs have exhibited low side effects compared to other therapeutic molecular candidates. Nevertheless, siRNA delivery has its own limitations including quick degradation in circulation, ineffective internalization and low passive uptake by cells, possible toxicity against off-target sites, and inducing unfavorable immune responses. Therefore, delivery tools must be able to specifically direct siRNAs to their target locations without inflicting detrimental effects on other sites. To conquer the mentioned problems, nanocarrier-mediated delivery of siRNAs, using inorganic nanoparticles (NPs), polymers, and lipids, has been developed as a biocompatible delivery approach. In this review, we have discussed recent advances in the siRNA delivery methods that employ nanoparticles, lipids, and polymers, as well as the inorganic-based co-delivery systems used to deliver siRNAs and anticancer agents to target cells.
    Keywords:  Chemotherapeutic; Nanocarrier; RNA interference; Simultaneous delivery; Small interfering RNA
    DOI:  https://doi.org/10.1016/j.ejphar.2021.174639
  43. Front Endocrinol (Lausanne). 2021 ;12 773975
    Nutritional Regulation of Hepatic FGF21 by Dietary Restriction of Methionine.
    Han Fang, Kirsten P Stone, Laura A Forney, Desiree Wanders, Thomas W Gettys.
      FGF21 is a potent metabolic regulator of energy balance, body composition, lipid metabolism, and glucose homeostasis. Initial studies reported that it was increased by fasting and the associated increase in ketones, but more recent work points to the importance of dietary protein and sensing of essential amino acids in FGF21 regulation. For example, dietary restriction of methionine produces a rapid transcriptional activation of hepatic FGF21 that results in a persistent 5- to 10-fold increase in serum FGF21. Although FGF21 is a component of a complex transcriptional program activated by methionine restriction (MR), loss-of-function studies show that FGF21 is an essential mediator of the resulting effects of the MR diet on energy balance, remodeling of adipose tissue, and enhancement of insulin sensitivity. These studies also show that FGF21 signaling in the brain is required for the MR diet-induced increase in energy expenditure (EE) and reduction of adiposity. Collectively, the evidence supports the view that the liver functions as a sentinel to detect and respond to changes in dietary amino acid composition, and that the resulting mobilization of hepatic FGF21 is a key element of the homeostatic response. These findings raise the interesting possibility that therapeutic diets could be developed that produce sustained, biologically effective increases in FGF21 by nutritionally modulating its transcription and release.
    Keywords:  energy expenditure; essential amino acids (EAA); methionine restriction; nutrient sensing mechanisms; protein restriction
    DOI:  https://doi.org/10.3389/fendo.2021.773975
  44. J Diabetes Metab Disord. 2021 Dec;20(2): 1773-1784
    Diabetic neuropathy: an insight on the transition from synthetic drugs to herbal therapies.
    Komal Arora, Pushpa C Tomar, Vandana Mohan.
      The global pandemic of prediabetes and diabetes has led to a severe corresponding complication of these disorders. Neuropathy is one of the most prevalent complication of diabetes is, affecting blood supply of the peripheral nervous system that may eventually results into loss of sensations, injuries, diabetic foot and death. The utmost identified risk of diabetic neuropathy is uncontrolled high blood glucose levels. However, aging, body mass index (BMI), oxidative stress, inflammation, increased HbA1c levels and blood pressure are among the other key factors involved in the upsurge of this disease. The so far treatment to deal with diabetic neuropathy is controlling metabolic glucose levels. Apart from this, drugs like reactive oxygen species (ROS) inhibitors, aldose reductase inhibitors, PKC inhibitors, Serotonin-norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, N-methyl-D-aspartate receptor (NMDAR) antagonists, are the other prescribed medications. However, the related side-effects (hallucinations, drowsiness, memory deficits), cost, poor pharmacokinetics and drug resistance brought the trust of patients down and thus herbal renaissance is occurring all over the word as the people have shifted their intentions from synthetic drugs to herbal remedies. Medicinal plants have widely been utilized as herbal remedies against number of ailments in Indian medicinal history. Their bioactive components are very much potent to handle different chronic disorders and complications with lesser-known side effects. Therefore, the current article mainly concludes the etiology and pathophysiology of diabetic neuropathy. Furthermore, it also highlights the important roles of medicinal plants and their naturally occurring bioactive compounds in addressing this disease.
    Keywords:  Bioactive compounds; Diabetes; Diabetic neuropathy; Herbal therapy; Medicinal plants; Peripheral nervous system; Traditional medicine
    DOI:  https://doi.org/10.1007/s40200-021-00830-2
  45. Bioact Mater. 2022 Apr;10 515-525
    Engineered gold/black phosphorus nanoplatforms with remodeling tumor microenvironment for sonoactivated catalytic tumor theranostics.
    Ting Chen, Weiwei Zeng, Changjun Tie, Mian Yu, Huisong Hao, Yang Deng, Qianqian Li, Hairong Zheng, Meiying Wu, Lin Mei.
      The imbalance between oxidants and antioxidants in cancer cells would evoke oxidative stress-induced cell death, which has been demonstrated to be highly effective in treating malignant tumors. Sonodynamic therapy (SDT) adopts ultrasound (US) as the excitation source to induce the production of reactive oxygen species (ROS), which emerges as a noninvasive therapeutic strategy with deep tissue penetration depth and high clinical safety. Herein, we construct novel sonoactivated oxidative stress amplification nanoplatforms by coating MnO2 on Au nanoparticle-anchored black phosphorus nanosheets and decorating soybean phospholipid subsequently (Au/BP@MS). The Au/BP@MS exhibit increased ROS generation efficiency under US irradiation in tumor tissues due to Au/BP nanosensitizer-induced improvement of electron-hole separation as well as MnO2-mediated O2 generation and GSH depletion, thus leading to notable inhibition effect on tumor growth. Moreover, tumor microenvironment-responsive biodegradability of Au/BP@MS endows them with enhanced magnetic resonance imaging guidance and clinical potential for cancer theranostics.
    Keywords:  Black phosphorus; Oxidative stress; Sonodynamic therapy; Theranostic; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.09.016
  46. Photoacoustics. 2022 Mar;25 100306
    Photoacoustic nanodroplets for oxygen enhanced photodynamic therapy of cancer.
    Marvin Xavierselvan, Jason Cook, Jeanne Duong, Nashielli Diaz, Kimberly Homan, Srivalleesha Mallidi.
      Photodynamic therapy (PDT) is a well-known cancer therapy that utilizes light to excite a photosensitizer and generate cytotoxic reactive oxygen species (ROS). The efficacy of PDT primarily depends on the photosensitizer and oxygen concentration in the tumor. Hypoxia in solid tumors promotes treatment resistance, resulting in poor PDT outcomes. Hence, there is a need to combat hypoxia while delivering sufficient photosensitizer to the tumor for ROS generation. Here we showcase our unique theranostic perfluorocarbon nanodroplets as a triple agent carrier for oxygen, photosensitizer, and indocyanine green that enables light triggered spatiotemporal delivery of oxygen to the tumors. We evaluated the characteristics of the nanodroplets and validated their ability to deliver oxygen via photoacoustic monitoring of blood oxygen saturation and subsequent PDT efficacy in a murine subcutaneous tumor model. The imaging results were validated with an oxygen sensing probe, which showed a 9.1 fold increase in oxygen content inside the tumor, following systemic administration of the nanodroplets. These results were also confirmed with immunofluorescence. In vivo studies showed that nanodroplets held higher rates of treatment efficacy than a clinically available benzoporphyrin derivative formulation. Histological analysis showed higher necrotic area within the tumor with perfluoropentane nanodroplets. Overall, the photoacoustic nanodroplets can significantly enhance image-guided PDT and has demonstrated substantial potential as a valid theranostic option for patient-specific photodynamic therapy-based treatments.
    Keywords:  1O2, singlet oxygen; BPD, benzoporphyrin derivative; DLS, dynamic light scattering; DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; DSPE-mPEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]; H&E, hematoxylin and eosin; HbT, total hemoglobin; Hypoxia; ICG, indocyanine green; IF, immunofluorescence; Image guided PDT; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NIR, near infrared radiation; PA, photoacoustic; PBS, phosphate buffered saline; PDT, photodynamic therapy; PFC, perfluorocarbon; PFP, perfluoropentane; PS, photosensitizer; Perfluorocarbon nanodroplets; Photoacoustic imaging; Photodynamic therapy; ROS, reactive oxygen species; SOSG, singlet oxygen sensor green; StO2, oxygen saturation; TBAI, tertbutylammonium iodide; pO2, partial pressure of oxygen
    DOI:  https://doi.org/10.1016/j.pacs.2021.100306
  47. J Pancreat Cancer. 2021 ;7(1): 65-70
    Cobimetinib Plus Gemcitabine: An Active Combination in KRAS G12R-Mutated Pancreatic Ductal Adenocarcinoma Patients in Previously Treated and Failed Multiple Chemotherapies.
    Bach Ardalan, Jose Azqueta, Danny Sleeman.
      Purpose: The KRAS proto-oncogene is involved in the RAS/MAPK pathway. KRAS is present in the wild type or mutated forms. The oncogene KRAS is frequently mutated in various cancers. At the time that amino acid glycine is mutated, KRAS protein acquires oncogenic properties that result in the tumor cell growth, proliferation, and cancer progression. There has been limited understanding of the different mutations at codon 12. The consequences of such mutations is not fully understood. Various G12X mutations in pancreatic cancer patients have been examined, with the most common mutations being G12D (40%), G12V (30%), and G12R (15-20%). Now we are understanding that G12X mutations in the KRAS are not all equal. Methods: In a single-arm exploratory study, we accrued 13 KRAS-G12X-mutated pancreatic patients (KRAS G12D, G12V, and G12R). They were divided into two groups: group 1 consisted of seven patients with G12D and G12V and group 2 included six patients with the KRAS G12R mutation. All patients were treated with the combination of gemcitabine at 1250 mg/m2 intravenous weekly for 3 weeks and oral cobimetinib 20 mg b.i.d. for 3 weeks. This was followed by a week of rest before the initiation of the next cycle. Results: In the first cohort, seven patients were on treatment, all of whom progressed and died within the 2 months of the study. In the second cohort, one of six patients achieved partial response, and five achieved stable disease. Median progression-free survival was 6 months (9% confidence interval 3.0-9.3 months) and overall survival has been reached at 8 months. Common adverse reactions included rash, fatigue, nausea, and vomiting (grades 2 and 3). Cancer antigen CA19-9 decreased by >50% in all group 2 patients. Conclusion: Our pancreatic cancer patients were heavily pretreated (all had received FOLFIRINOX and gemcitabine/nab-paclitaxel) before the entry into our trial. Upon entry into our trial, all patients were treated with the combination of gemcitabine and oral cobimetinib. Therefore, this constituted the second exposure of the patients to gemcitabine. This study illustrates a new discovery, which can potentially target 15-20% of pancreatic cancer patients and allow for a significant improvement in their prognosis. We will be conducting randomized phase II trials to substantiate our findings.
    Keywords:  KRAS G12R; KRAS-mutant; MEK inhibitor; next-generation sequencing; pancreatic cancer
    DOI:  https://doi.org/10.1089/pancan.2021.0006
  48. EMBO Rep. 2021 Dec 16. e54384
    Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence.
    Leal Oburoglu, Els Mansell, Isaac Canals, Valgardur Sigurdsson, Carolina Guibentif, Shamit Soneji, Niels-Bjarne Woods.
      During embryonic development, hematopoiesis occurs through primitive and definitive waves, giving rise to distinct blood lineages. Hematopoietic stem cells (HSCs) emerge from hemogenic endothelial (HE) cells, through endothelial-to-hematopoietic transition (EHT). In the adult, HSC quiescence, maintenance, and differentiation are closely linked to changes in metabolism. However, metabolic processes underlying the emergence of HSCs from HE cells remain unclear. Here, we show that the emergence of blood is regulated by multiple metabolic pathways that induce or modulate the differentiation toward specific hematopoietic lineages during human EHT. In both in vitro and in vivo settings, steering pyruvate use toward glycolysis or OXPHOS differentially skews the hematopoietic output of HE cells toward either an erythroid fate with primitive phenotype, or a definitive lymphoid fate, respectively. We demonstrate that glycolysis-mediated differentiation of HE toward primitive erythroid hematopoiesis is dependent on the epigenetic regulator LSD1. In contrast, OXPHOS-mediated differentiation of HE toward definitive hematopoiesis is dependent on cholesterol metabolism. Our findings reveal that during EHT, metabolism is a major regulator of primitive versus definitive hematopoietic differentiation.
    Keywords:  OXPHOS; endothelial-to-hematopoietic transition; glycolysis; hematopoiesis; pyruvate metabolism
    DOI:  https://doi.org/10.15252/embr.202154384
  49. Bioact Mater. 2022 Apr;10 295-305
    2D antimonene-integrated composite nanomedicine for augmented low-temperature photonic tumor hyperthermia by reversing cell thermoresistance.
    Jianrong Wu, Xiaojun Cai, Gareth R Williams, Zheying Meng, Weijuan Zou, Li Yao, Bing Hu, Yu Chen, Yuanyi Zheng.
      The overexpression of heat shock proteins (HSPs) in tumor cells can activate inherent defense mechanisms during hyperthermia-based treatments, inducing thermoresistance and thus diminishing the treatment efficacy. Here, we report a distinct "non-inhibitor involvement" strategy to address this issue through engineering a calcium-based nanocatalyst (G/A@CaCO3-PEG). The constructed nanocatalyst consists of calcium carbonate (CaCO3)-supported glucose oxidase (GOD) and 2D antimonene quantum dots (AQDs), with further surface modification by lipid bilayers and polyethylene glycol (PEG). The engineered G/A@CaCO3-PEG nanocatalyst features prolonged blood circulation, which is stable at neutral pH but rapidly degrades under mildly acidic tumor microenvironment, resulting in rapid release of drug cargo in the tumor microenvironment. The integrated GOD effectively catalyzes the depletion of glucose for reducing the supplies of adenosine triphosphate (ATP) and subsequent down-regulation of HSP expression. This effect then augments the therapeutic efficacy of photothermal hyperthermia induced by 2D AQDs upon irradiation with near-infrared light as assisted by reversing the cancer cells' thermoresistance. Consequently, synergistic antineoplastic effects can be achieved via low-temperature photothermal therapy. Systematic in vitro and in vivo evaluations have demonstrated that G/A@CaCO3-PEG nanocatalysts feature potent antitumor activity with a high tumor-inhibition rate (83.92%). This work thus paves an effective way for augmenting the hyperthermia-based tumor treatments via restriction of the ATP supply.
    Keywords:  Antimonene; Calcium carbonate; Glucose oxidase; Heat shock proteins; Photothermal therapy
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.08.018
  50. ACS Appl Mater Interfaces. 2021 Dec 12.
    Nanocarbon Framework-Supported Ultrafine Mo2C@MoOx Nanoclusters for Photothermal-Enhanced Tumor-Specific Tandem Catalysis Therapy.
    Li Wang, Liang Zhuang, Shan He, Fangzhen Tian, Xueting Yang, Shanyue Guan, Geoffrey I N Waterhouse, Shuyun Zhou.
      Recent advances in the synthesis of multifunctional nanomaterials create new opportunities for the rational design of multimodal chemodynamic therapy (CDT) agents. Precisely tailoring the nanostructure and composition of CDT nanoagents for maximum efficacy remains a challenge. Herein, we report the successful synthesis of nanocarbon framework-supported ultrafine Mo2C@MoOx nanoclusters (C/Mo2C@MoOx) via a pyrolysis of a Mo/ZIF-8 MOF precursor at 900 °C followed by mild surface oxidation. The developed C/Mo2C@MoOx composite demonstrated outstanding performance in photothermal-enhanced tumor-specific tandem catalysis therapy. Specifically, C/Mo2C@MoOx efficiently catalyzed the conversion of endogenous H2O2 to cytotoxic 1O2 via a Russell mechanism, while also converting the O2 byproduct to cytotoxic ·O2- via an oxidase-like mechanism. A high dispersion of active Mo5+ sites in the exposed MoOx shell enhanced the reactive oxygen species (ROS)-generating efficiency of C/Mo2C@MoOx. Moreover, the Mo2C core in the ultrafine Mo2C@MoOx nanoclusters allowed NIR-II (1064 nm)-driven photothermal heating, which significantly boosted the CDT process through photothermal effects. Additionally, the CDT process relied on a redox cycle involving Mo5+/Mo6+ species, which could be sustained by glutathione (GSH) consumption. Given these advantages, C/Mo2C@MoOx demonstrated remarkable synergistic therapeutic efficacy for cancer treatment (both in vitro and in vivo) through tumor microenvironment-stimulated generation of multiple ROS and NIR-II photothermal activity.
    Keywords:  chemodynamic therapy; multifunctional nanoagents; photothermal therapy; synergistic therapy; ultrafine nanoclusters
    DOI:  https://doi.org/10.1021/acsami.1c17085
  51. Small. 2021 Dec 15. e2104643
    Engineering Bacteria and Bionic Bacterial Derivatives with Nanoparticles for Cancer Therapy.
    Ting Yin, Zhenying Diao, Nicholas Thomas Blum, Long Qiu, Aiqing Ma, Peng Huang.
      Natural bacteria are interesting subjects for cancer treatments owing to their unique autonomy-driven and hypoxic target properties. Genetically modified bacteria (such as bacteria with msbB gene and aroA gene modifications) can effectively cross sophisticated physiological barriers and transport antitumor agents into deep tumor tissues, and they have good biosafety. Additionally, bacteria can secrete cytokines (such as interleukin-224, interferon-gamma [IFN-γ], and interleukin-1β) and activate antitumor immune responses in the tumor microenvironment, resulting in tumor inhibition. All of these characteristics can be easily utilized to develop synergistic antitumor strategies by combining bacteria-based agents with other therapeutic approaches. Herein, representative studies of bacteria-instructed multimodal synergistic cancer therapy are introduced (e.g., photothermal therapy, chemoimmunotherapy, photodynamic therapy, and photocontrolled bacterial metabolite therapy), and their key advantages are systematically expounded. The current challenges and future prospects in advancing the development of bacteria-based micro/nanomedicines in the field of synthetic biology research are also emphasized, which will hopefully promote the development of related bacteria-based cancer therapies.
    Keywords:  bacteria; bionic bacterial derivatives; cancer; nanoparticles; treatments
    DOI:  https://doi.org/10.1002/smll.202104643
  52. Int J Biol Macromol. 2021 Dec 14. pii: S0141-8130(21)02631-3. [Epub ahead of print]
    Microbial arginine deiminase: A multifaceted green catalyst in biomedical sciences.
    Anubhuti Kawatra, Rakhi Dhankhar, Pooja Gulati.
      Arginine deiminase is a well-recognized guanidino-modifying hydrolase that catalyzes the conversion of L-arginine to citrulline and ammonia. Their biopotential to regress tumors via amino acid deprivation therapy (AADT) has been well established. PEGylated formulation of recombinant Mycoplasma ADI is in the last-phase clinical trials against various arginine-auxotrophic cancers like hepatocellular carcinoma, melanoma, and mesothelioma. Recently, ADIs have attained immense importance in several other biomedical applications, namely. Treatment of Alzheimer's, as an antiviral drug, bioproduction of nutraceutical L-citrulline and bio-analytics involving L-arginine detection. Considering the wide applications of this biodrug, the demand for ADI is expected to escalate several-fold in the coming years. However, the sustainable production aspects of the enzyme with improved pharmacokinetics is still limited, creating bottlenecks for effective biopharmaceutical development. To circumvent the lacunae in enzyme production with appropriate paradigms of 'quality-by-design' an explicit overview of its properties with 'biobetter' formulations strategies are required. Present review provides an insight into all the potential biomedical applications of ADI along with the improvements required for its reach to clinics. Recent research advances with special emphasis on the development of ADI as a 'biobetter' enzyme have also been comprehensively elaborated.
    Keywords:  Antiviral; Applications; Arginine deiminase (ADI); Biomedical sciences; Improvement strategies; cancer
    DOI:  https://doi.org/10.1016/j.ijbiomac.2021.12.015
  53. Front Med (Lausanne). 2021 ;8 750170
    Recent Progress on the Synergistic Antitumor Effect of a Borneol-Modified Nanocarrier Drug Delivery System.
    Jinxiu Li, Qian Xie, Rong Ma, Yong Li, Jianmei Yuan, Mihong Ren, Hongyan Li, Jiajun Wang, Danni Lu, Zhuo Xu, Jian Wang.
      Borneol, a traditional Chinese medicine, can enhance therapeutic efficacy by guiding the active ingredients to the target site. Reportedly, borneol improves the penetration capacity of the nasal, cornea, transdermal, intestinal, and blood-brain barriers. Although nanotechnology dramatically changed the face of oncology by targeting tumor sites, the efficiency of nanoparticles delivered to tumor sites is very low, with only 0.7% of the total particles delivered. Thus, based on the penetration ability and the inhibition drug efflux of borneol, it was expected to increase the targeting and detention efficacy of drugs into tumor sites in nanocarriers with borneol modification. Borneol modified nanocarriers used to improve drug-targeting has become a research focus in recent years, but few studies in this area, especially in the antitumor application. Hence, this review summarizes the recent development of nanocarriers with borneol modification. We focus on the updated works of improving therapeutic efficacy, reducing toxicity, inhibiting tumor metastasis, reversing multidrug resistance, and enhancing brain targeting to expand their application and provide a reference for further exploration of targeting drug delivery systems for solid tumor treatment.
    Keywords:  borneol; drug delivery; drug resistance; nanocarrier; targeting; tumor therapy
    DOI:  https://doi.org/10.3389/fmed.2021.750170
  54. Small. 2021 Dec 15. e2106100
    A Potent Strategy of Combinational Blow Toward Enhanced Cancer Chemo-Photodynamic Therapy via Sustainable GSH Elimination.
    Jie Yu, Hua Xiao, Zuo Yang, Chaoqiang Qiao, Bin Zhou, Qian Jia, Zhongdi Wang, Xiaofei Wang, Ruili Zhang, Yang Yang, Zhongliang Wang, Jianxiong Li.
      Excessive glutathione (GSH), which is produced owing to abnormal metabolism of tumor cells, scavenges photo-induced reactive oxygen species (ROS) and consumes chemotherapeutic drugs, thereby attenuating the efficacy of photodynamic therapy and chemotherapy, respectively. Predominant strategies for GSH inhibition involve its chemical depletion, which only leads to a temporary therapeutic effect because GSH is replenished via various compensatory routes in tumor cells. Here, a versatile GSH-inhibiting nanosystem (termed PCNPs) for persistent synergistic therapy of cancer is reported. The porous skeleton of PCNPs allows easy encapsulation of buthionine sulfoximine (BSO) to sustainably suppress the biosynthesis of GSH. Thus, PCNPs not only demonstrate a prolonged release of BSO and improve drug utilization for efficient chemotherapy, but also act as an efficient photo-induced singlet oxygen radical generator that prevents the loss of ROS, thereby enhancing photodynamic therapy. In addition, the liposomal coating prevents cargo release in the blood, improves the accumulation of PCNPs at the tumor site, and promotes the cellular uptake of oxaliplatin and BSO. This strategy is applicable to ROS-based therapy and chemotherapy, which are suppressed by GSH, and may further enhance the synergistic effect of GSH-restrained therapy.
    Keywords:  chemotherapy; glutathione; metal-organic frameworks (MOFs); photodynamic therapy; theranostics
    DOI:  https://doi.org/10.1002/smll.202106100
  55. Bioconjug Chem. 2021 Dec 12.
    Gold Nanoclusters: Imaging, Therapy, and Theranostic Roles in Biomedical Applications.
    Sanne M van de Looij, Erik R Hebels, Martina Viola, Mathew Hembury, Sabrina Oliveira, Tina Vermonden.
      For the past two decades, atomic gold nanoclusters (AuNCs, ultrasmall clusters of several to 100 gold atoms, having a total diameter of <2 nm) have emerged as promising agents in the diagnosis and treatment of cancer. Owing to their small size, significant quantization occurs to their conduction band, which leads to emergent photonic properties and the disappearance of the plasmonic responses observed in larger gold nanoparticles. For example, AuNCs exhibit native luminescent properties, which have been well-explored in the literature. Using proteins, peptides, or other biomolecules as structural scaffolds or capping ligands, required for the stabilization of AuNCs, improves their biocompatibility, while retaining their distinct optical properties. This paved the way for the use of AuNCs in fluorescent bioimaging, which later developed into multimodal imaging combined with computer tomography and magnetic resonance imaging as examples. The development of AuNC-based systems for diagnostic applications in cancer treatment was then made possible by employing active or passive tumor targeting strategies. Finally, the potential therapeutic applications of AuNCs are extensive, having been used as light-activated and radiotherapy agents, as well as nanocarriers for chemotherapeutic drugs, which can be bound to the capping ligand or directly to the AuNCs via different mechanisms. In this review, we present an overview of the diverse biomedical applications of AuNCs in terms of cancer imaging, therapy, and combinations thereof, as well as highlighting some additional applications relevant to biomedical research.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.1c00475
  56. Bioact Mater. 2022 Apr;10 131-144
    Persistent luminescence phosphor as in-vivo light source for tumoral cyanobacterial photosynthetic oxygenation and photodynamic therapy.
    Meiqi Chang, Wei Feng, Li Ding, Hongguang Zhang, Caihong Dong, Yu Chen, Jianlin Shi.
      Tumor oxygenation level has been regarded as an attractive target to elevate the efficiency of photodynamic therapy (PDT). Cyanobacterial photosynthesis-mediated reversal of tumor hypoxia could enable an oxygen-boosted PDT, but is limited by scant penetration depth and efficiency of external light. Herein, aiming at the dual purposes of reducing biological toxicity induced by long-term light irradiation and alleviating hypoxia, we here introduce a novel-designed CaAl2O4:Eu,Nd blue persistent luminescence material (PLM) as the in vivo light source after pre-excited in vitro. The ingenious construction of blue-emitting PLM with "optical battery" characteristics activates cyanobacterial cells and verteporfin simultaneously, which performs the successive oxygen supply and singlet oxygen generation without the long-term external excitation, resulting in the modulated tumor hypoxic microenvironment and enhanced photodynamic tumor proliferation inhibition efficiency. Both in vitro cellular assessment and in vivo tumor evaluation results affirm the advantages of self-produced oxygen PDT system and evidence the notable antineoplastic outcome. This work develops an irradiation-free photosynthetic bacteria-based PDT platform for the optimization of both oxygen production capacity and light utilization efficiency in cancer treatment, which is expected to promote the clinical progress of microbial-based photonic therapy.
    Keywords:  Cyanobacteria; Irradiation-free; Oxygenation; Persistent luminescence; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.08.030
  57. Adv Sci (Weinh). 2021 Dec 13. e2104101
    A Self-Degradable Conjugated Polymer for Photodynamic Therapy with Reliable Postoperative Safety.
    Hongye Huang, Wensheng Xie, Qing Wan, Liucheng Mao, Danning Hu, Hua Sun, Xiaoyong Zhang, Yen Wei.
      As a noninvasive therapeutic technique, photodynamic therapy (PDT) has attracted numerous research interests for cancer therapy. Nevertheless, the residual photosensitizers (PSs) still produce reactive oxygen species (ROS) and damage normal cells under sunlight after PDT, which limits their practical application in clinic. Herein, the authors propose a self-degradable type-I PS based on conjugated polymer, which is composed of aggregation-induced emission (AIE) and imidazole units. Due to the effective conjugated skeleton and unique AIE properties, thus-obtained polymers can effectively generate superoxide radical (O2 -• ) through the type-I process under light irradiation, which is ideal for hypoxic tumors treatment. Intriguingly, under light irradiation, O2 -• produced by the conjugated polymers can further lead to the self-degradation of the polymer to form nontoxic micro-molecules. It not only helps to resolve the potential phototoxicity problems of residual PSs, but also can accelerate the metabolism of the conjugated polymers to avoid the potential biotoxicity of drug accumulation. This work develops a self-degradable type-I PS, which can turn off the generation of ROS in time after PDT, providing a novel strategy to balance the PDT effect and postoperative safety.
    Keywords:  aggregation-induced emission; biodegradable materials; conjugated polymers; photodynamic therapy
    DOI:  https://doi.org/10.1002/advs.202104101
  58. ACS Nano. 2021 Dec 13.
    Complementing Cancer Photodynamic Therapy with Ferroptosis through Iron Oxide Loaded Porphyrin-Grafted Lipid Nanoparticles.
    Xiaolong Liang, Min Chen, Pravin Bhattarai, Sadaf Hameed, Yida Tang, Zhifei Dai.
      Nanomaterials that combine multimodality imaging and therapeutic functions within a single nanoplatform have drawn extensive attention for molecular medicines and biological applications. Herein, we report a theranostic nanoplatform based on a relatively smaller (<20 nm) iron oxide loaded porphyrin-grafted lipid nanoparticles (Fe3O4@PGL NPs). The amphiphilic PGL easily self-assembled on the hydrophobic exterior surface of ultrasmall Fe3O4 NPs, resulting in a final ultrasmall Fe3O4@PGL NPs with diameter of ∼10 nm. The excellent self-assembling nature of the as-synthesized PGL NPs facilitated a higher loading of porphyrins, showed a negligible dark toxicity, and demonstrated an excellent photodynamic effect against HT-29 cancer cells in vitro. The in vivo experimental results further confirmed that Fe3O4@PGL NPs were ideally qualified for both the fluorescence and magnetic resonance (MR) imaging guided nanoplatforms to track the biodistribution and therapeutic responses of NPs as well as to simultaneously trigger the generation of highly cytotoxic reactive oxygen species (ROS) necessary for excellent photodynamic therapy (PDT). After recording convincing therapeutic responses, we further evaluated the ability of Fe3O4@PGL NPs/Fe3O4@Lipid NPs for ferroptosis therapy (FT) via tumor microenvironment (TME) modulation for improved anticancer activity. We hypothesized that tumor-associated macrophages (TAMs) could significantly improve the efficacy of FT by accelerating the Fenton reaction in vitro. In our results, the Fe ions released in vitro directly contributed to the Fenton reaction, whereas the presence of RAW 264.7 macrophages further accelerated the ROS generation as observed by the fluorescence imaging. The significant increase in the ROS during the coincubation of NPs, endocytosed by HT-29 cells and RAW264.7 cells, further induced increased cellular toxicity of cancer cells.
    Keywords:  ferroptosis; iron oxide; macrophages; photodynamic therapy; porphyrin
    DOI:  https://doi.org/10.1021/acsnano.1c08108
  59. Cell Rep. 2021 Dec 14. pii: S2211-1247(21)01590-4. [Epub ahead of print]37(11): 110096
    Identification of RAS mutant biomarkers for EGFR inhibitor sensitivity using a systems biochemical approach.
    Thomas McFall, Edward C Stites.
      Mutations can be important biomarkers that influence the selection of specific cancer treatments. We recently combined mathematical modeling of RAS signaling network biochemistry with experimental cancer cell biology to determine why KRAS G13D is a biomarker for sensitivity to epidermal growth factor receptor (EGFR)-targeted therapies. The critical mechanistic difference between KRAS G13D and the other most common KRAS mutants is impaired binding to tumor suppressor Neurofibromin (NF1). Here, we hypothesize that impaired binding to NF1 is a "biophysical biomarker" that defines other RAS mutations that retain therapeutic sensitivity to EGFR inhibition. Both computational and experimental investigations support our hypothesis. By screening RAS mutations for this biophysical characteristic, we identify 10 additional RAS mutations that appear to be biomarkers for sensitivity to EGFR inhibition. Altogether, this work suggests that personalized medicine may benefit from migrating from gene-based and allele-based biomarker strategies to biomarkers based on biophysically defined subsets of mutations.
    Keywords:  KRAS; biophysical biomarkers; systems modeling; targeted therapies
    DOI:  https://doi.org/10.1016/j.celrep.2021.110096
  60. Small. 2021 Dec 15. e2104550
    Oxygen-Deficient BiOCl Combined with L-Buthionine-Sulfoximine Synergistically Suppresses Tumor Growth through Enhanced Singlet Oxygen Generation under Ultrasound Irradiation.
    Hui Wang, Weitao Yang, Kexin Bian, Weiwei Zeng, Xiao Jin, Ruizhuo Ouyang, Yan Xu, Chenyu Dai, Shuang Zhou, Bingbo Zhang.
      Excess generation of reactive oxygen species (ROS) based on sensitizers under ultrasound (US) excitation can cause the death of tumor cells via oxidative damage, but sonosensitizers are largely unexplored. Herein, oxygen-deficient black BiOCl (B-BiOCl) nanoplates (NPs) are reported, with post-treatment on conventional BiOCl by simple UV excitation, showing stronger singlet oxygen (1 O2 ) generation than commercial TiO2 nanoparticles and their derivatives under US irradiation. Moreover, L-buthionine-sulfoximine (BSO), a GSH biosynthesis inhibitor, is incorporated into B-BiOCl NPs. The authors find that BSO can be released owing to the degradation of B-BiOCl NPs in the presence of acid and GSH, which are overexpressed in tumors. The results show that BSO/B-BiOCl-PEG NPs have a multifunctional synergistic effect on improving ROS production. In particular, BiOCl has remarkable near-infrared light absorption after UV treatment and is good for photoacoustic imaging that can guide subsequent sonodynamic therapy. This work shows that just with a simple oxygen deficiency treatment, strong 1 O2 generation can be provided to a conventional material under US irradiation and, interestingly, this effect can be amplified by using a small inhibitor BSO, and this is clearly demonstrated in cell and mice experiments.
    Keywords:  BiOCl; GSH inhibitors; defect engineering; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1002/smll.202104550
  61. Biomaterials. 2021 Dec 09. pii: S0142-9612(21)00671-2. [Epub ahead of print]280 121315
    Co-delivery of dihydroartemisinin and pyropheophorbide-iron elicits ferroptosis to potentiate cancer immunotherapy.
    Wenbo Han, Xiaopin Duan, Kaiyuan Ni, Youyou Li, Christina Chan, Wenbin Lin.
      Dihydroartemisinin (DHA) has shown cytotoxicity against various tumor cells in vitro in an iron-dependent manner, but its in vivo antitumor efficacy is compromised by its rapid degradation and clearance. Here we show the induction of ferroptosis by DHA in an immunogenic fashion and the maximization of in vivo antitumor efficacy of DHA by co-delivering a cholesterol derivative of DHA (Chol-DHA) and Pyropheophorbide-iron (Pyro-Fe) in ZnP@DHA/Pyro-Fe core-shell nanoparticles. ZnP@DHA/Pyro-Fe particles stabilize DHA against hydrolysis and prolong blood circulation of Chol-DHA and Pyro-Fe for their enhanced uptake in tumors. Co-delivery of an exogenous iron complex and DHA induces more ROS production and causes significant tumor inhibition in vivo. By increasing tumor immunogenicity, the combination of DHA and Pyro-Fe sensitizes non-immunogenic colorectal tumors to anti-PD-L1 checkpoint blockade immunotherapy. These findings suggest the potential of using nanotechnology to repurpose DHA and other drugs with excellent safety profiles for combination with immune checkpoint blockade to treat cancers.
    Keywords:  Artemisinin; Cancer; Ferroptosis; Immunotherapy; Iron; Nanoparticle
    DOI:  https://doi.org/10.1016/j.biomaterials.2021.121315
  62. Surv Ophthalmol. 2021 Dec 08. pii: S0039-6257(21)00220-4. [Epub ahead of print]
    Nutritional supplementation in the prevention and treatment of Glaucoma.
    Sarah Chaudhry, Hamish Dunn, Nicole Carnt, Andrew White.
      Glaucoma is a chronic optic neuropathy that creates a significant burden on public health. Oxidative stress is hypothesised to play a role to glaucoma progression, and its reduction is being analysed as a therapeutic target. Dietary antioxidants play a crucial role in helping provide insight into this hypothesis. We reviewed 71 trials, interventional, I -vivo and I -vitro, including 11 randomised controlled trials, to determine if adjunctive nutritional supplementation could lead to a reduction in oxidative stress and prevent glaucomatous progression. Many laboratory findings show that vitamins and natural compounds contain an abundance of intrinsic antioxidative, neuroprotective and vasoprotective properties that show promise in the treatment and prevention of glaucoma. Although there is encouraging early evidence, most clincial findings are inconclusive. The group of B vitamins appear to have the greatest amount of evidence. Other compounds such as flavonoids, carotenoids, curcumin, saffron, CoQ10, Ggngko Biloba and Resveratrol however warrant further investigation in glaucoma patients. Studies of these antioxidants and other nutrients could create adjunctive or alternative preventative and treatment modalities for glaucoma to those currently available.
    Keywords:  AA, Ascorbic acid; ARMD, Age Related Macular Degeneration; CoQ10, Coenzyme Q10; GON, Glaucomatous Optic Neuropathy; Hcy, Homocysteine; IOP, Intraocular pressure; NO, Nitric Oxide; NOS, Nitric Oxide Synthase; NTG, Normal Tension Glaucoma; POAG, Primary open angle Glaucoma;PEXG, Exfoliation Glaucoma; PVD Primary vascular dysregulation; RGC, Retinal Ganglion Cells; ROS, Reactive Oxygen Species; SC, Schlemm's Canal; TM Trabecular Meshwork; Vitamins, Nutrients, Glaucoma, Supplements, Reactive Oxygen Species, Open Angle Glaucoma, Trabecular Meshwork, Retinal Ganglion Cells, Oxidative Stress. Abbreviations
    DOI:  https://doi.org/10.1016/j.survophthal.2021.12.001
  63. J Cancer Res Ther. 2021 Oct-Dec;17(6):17(6): 1583-1586
    Effect of high-dose intravenous ascorbic acid on cancer patients following ketogenic diet.
    Stelvin Sebastian, Aby Paul, Joel Joby, Sanjo Saijan, Jobin Kunjumon Vilapurathu.
       Background: The role of ascorbic acid in cancer therapy is mainly due to its structural similarity with glucose. When supplemented intravenously in high dose, ascorbic acid can get into the cancer cells and induce apoptosis by causing mitochondrial damage.
    Aim: The aim was to study the efficacy of high-dose intravenous (IV) ascorbic acid as monotherapy in cancer patients following ketogenic diet and its role in improving the quality of life.
    Results: C-reactive protein (CRP) and erythrocyte sedimentation rates (ESRs) were considered as parameters to determine the efficacy of the treatment, and substantial decrease in both the levels was observed within 1-week treatment. CRP levels declined from 3.1946 ± 3.2508 mg/L to 1.0606 ± 0.6706 mg/L (P = 2.27E-10), whereas ESR levels declined from 64.1333 ± 38.8253 mm/h to 31.6 ± 16.5520 mm/h (P = 0.0041). A decline in these parameters shows the association of ascorbic acid in reducing the inflammatory response in cancer. The renal effect of ascorbic acid was also studied by analyzing the creatinine level pre- and postascorbic acid treatment sessions, and it raised from 0.8526 ± 0.22904 to 1.1666 ± 0.2894 mg/dL (P = 1.18E-14). This showed the renal impact of ascorbic acid.
    Conclusion: The study highlighted the clinical benefit of IV ascorbic acid in the reduction of inflammatory response in cancer patients. The renal adverse events associated with ascorbic acid alarm the use with caution and therapeutic drug monitoring for ascorbic acid.
    Keywords:  Ascorbic acid; chemotherapy; ketogenic diet
    DOI:  https://doi.org/10.4103/jcrt.JCRT_973_19
  64. Small. 2021 Dec 17. e2106383
    Enhancement of Proton Therapy Efficiency by Noble Metal Nanoparticles Is Driven by the Number and Chemical Activity of Surface Atoms.
    Sandra Zwiehoff, Jacob Johny, Carina Behrends, Alina Landmann, Florian Mentzel, Christian Bäumer, Kevin Kröninger, Christoph Rehbock, Beate Timmermann, Stephan Barcikowski.
      Proton-based radiotherapy is a modern technique for the treatment of solid tumors with significantly reduced side effects to adjacent tissues. Biocompatible nanoparticles (NPs) with high atomic numbers are known to serve as sensitizers and to enhance treatment efficacy, which is commonly believed to be attributed to the generation of reactive oxygen species (ROS). However, little systematic knowledge is available on how either physical effects due to secondary electron generation or the particle surface chemistry affect ROS production. Thereto, ligand-free colloidal platinum (Pt) and gold (Au) NPs with well-controlled particle size distributions and defined total surface area are proton-irradiated. A fluorescence-based assay is developed to monitor the formation of ROS using terephthalic acid as a cross-effect-free dye. The findings indicate that proton irradiation (PI)-induced ROS formation sensitized by noble metal NPs is driven by the total available particle surface area rather than particle size or mass. Furthermore, a distinctive material effect with Pt being more active than Au is observed which clearly indicates that the chemical reactivity of the NP surface is a main contributor to ROS generation upon PI. These results pave the way towards an in-depth understanding of the NP-induced sensitizing effects upon PI and hence a well-controlled enhanced therapy.
    Keywords:  Monte Carlo models; cancer treatments; fluorescent radical detectors; laser ablation in liquids; surfactant-free nanoparticles
    DOI:  https://doi.org/10.1002/smll.202106383
  65. Front Physiol. 2021 ;12 715443
    Beneficial Effects on Brain Micro-Environment by Caloric Restriction in Alleviating Neurodegenerative Diseases and Brain Aging.
    Li Zhang, Huachong Xu, Ning Ding, Xue Li, Xiaoyin Chen, Zhuangfei Chen.
      Aging and neurodegenerative diseases are frequently associated with the disruption of the extracellular microenvironment, which includes mesenchyme and body fluid components. Caloric restriction (CR) has been recognized as a lifestyle intervention that can improve long-term health. In addition to preventing metabolic disorders, CR has been shown to improve brain health owing to its enhancing effect on cognitive functions or retarding effect on the progression of neurodegenerative diseases. This article summarizes current findings regarding the neuroprotective effects of CR, which include the modulation of metabolism, autophagy, oxidative stress, and neuroinflammation. This review may offer future perspectives for brain aging interventions.
    Keywords:  brain aging; cognitive functions; extracellular microenvironment; metabolic homeostasis; neuroinflammation
    DOI:  https://doi.org/10.3389/fphys.2021.715443
  66. Small. 2021 Dec 16. e2103174
    Cu2- x Sx Capped AuCu Nanostars for Efficient Plasmonic Photothermal Tumor Treatment in the Second Near-Infrared Window.
    Qian Yu, Tingyu Peng, Jinfeng Zhang, Xiaoxuan Liu, Ye Pan, Dengfeng Ge, Long Zhao, Federico Rosei, Jianming Zhang.
      Plasmonic nanohybrids are promising photo energy conversion materials in photoelectronics and biomedicine, due to their unique surface plasmon resonance (SPR). Au and Cu2- x Sx nanostructures with strong SPR in the near-infrared (NIR) spectral region are classic plasmonic systems used to convert NIR photons into heat for photothermal therapy (PTT). The rational design of the Au/Cu2- x Sx nanohybrids is expected to induce better photothermal conversion; however, the construction of such hybrids via wet-chemistry methods with a well-controlled interfacial structure is still challenging. Here, the synthesis of an AuCu Star/Cu2 -x Sx nanohybrid is reported, where the Cu2- x Sx components are selectively grown on the AuCu nanostar tips to form "caps". The spatial formation of the Cu2- x Sx caps on star tips is mainly governed by surfactant concentration, tip curvature, and experimental manipulation. The nanohybrids show low cytotoxicity and superior photothermal conversion efficiency, enabling robust PTT to kill cancer cells in the second NIR window. Numerical simulation reveals that the coupling of Cu2- x Sx on nanostar tips generates strong interfacial electric field, improving photothermal conversion. Moreover, the spatial separation structure favors the continuous flow of hot charge carriers to produce active radicals, further promoting the tumor treatment effect.
    Keywords:  Au; Cu 2− xS x; photothermal therapy; plasmonics; spatial separation
    DOI:  https://doi.org/10.1002/smll.202103174
  67. Proc Natl Acad Sci U S A. 2021 Dec 21. pii: e2114126118. [Epub ahead of print]118(51):
    Components of the phosphatidylserine endoplasmic reticulum to plasma membrane transport mechanism as targets for KRAS inhibition in pancreatic cancer.
    Walaa E Kattan, Junchen Liu, Dina Montufar-Solis, Hong Liang, Bhargavi Brahmendra Barathi, Ransome van der Hoeven, Yong Zhou, John F Hancock.
      KRAS is mutated in 90% of human pancreatic ductal adenocarcinomas (PDACs). To function, KRAS must localize to the plasma membrane (PM) via a C-terminal membrane anchor that specifically engages phosphatidylserine (PtdSer). This anchor-binding specificity renders KRAS-PM localization and signaling capacity critically dependent on PM PtdSer content. We now show that the PtdSer lipid transport proteins, ORP5 and ORP8, which are essential for maintaining PM PtdSer levels and hence KRAS PM localization, are required for KRAS oncogenesis. Knockdown of either protein, separately or simultaneously, abrogated growth of KRAS-mutant but not KRAS-wild-type pancreatic cancer cell xenografts. ORP5 or ORP8 knockout also abrogated tumor growth in an immune-competent orthotopic pancreatic cancer mouse model. Analysis of human datasets revealed that all components of this PtdSer transport mechanism, including the PM-localized EFR3A-PI4KIIIα complex that generates phosphatidylinositol-4-phosphate (PI4P), and endoplasmic reticulum (ER)-localized SAC1 phosphatase that hydrolyzes counter transported PI4P, are significantly up-regulated in pancreatic tumors compared to normal tissue. Taken together, these results support targeting PI4KIIIα in KRAS-mutant cancers to deplete the PM-to-ER PI4P gradient, reducing PM PtdSer content. We therefore repurposed the US Food and Drug Administration-approved hepatitis C antiviral agent, simeprevir, as a PI4KIIIα inhibitor In a PDAC setting. Simeprevir potently mislocalized KRAS from the PM, reduced the clonogenic potential of pancreatic cancer cell lines in vitro, and abrogated the growth of KRAS-dependent tumors in vivo with enhanced efficacy when combined with MAPK and PI3K inhibitors. We conclude that the cellular ER-to-PM PtdSer transport mechanism is essential for KRAS PM localization and oncogenesis and is accessible to therapeutic intervention.
    Keywords:  KRAS; ORP5; ORP8; PI4KA; phosphatidylserine
    DOI:  https://doi.org/10.1073/pnas.2114126118
  68. Int J Pharm. 2021 Dec 09. pii: S0378-5173(21)01170-4. [Epub ahead of print] 121364
    A pH-sensitive liposome formulation of a peptidomimetic-Dox conjugate for targeting HER2 + cancer.
    Jafrin Jobayer Sonju, Achyut Dahal, Sitanshu S Singh, Xin Gu, William D Johnson, Chandra Mohan Reddy Muthumula, Sharon A Meyer, Seetharama D Jois.
      Cancer treatment faces the challenge of selective delivery of the cytotoxic drug to the desired site of action to minimize undesired side effects. The liposomal formulation containing targeting ligand conjugated cytotoxic drug can be an effective approach to specifically deliver chemotherapeutic drugs to cancer cells that overexpress a particular cell surface receptor. This research focuses on the in vitro and in vivo studies of a peptidomimetic ligand attached doxorubicin for the HER2 positive lung and breast cancer cells transported by a pH-dependent liposomal formulation system for the enhancement of targeted anticancer treatment. The selected pH-sensitive liposome formulation showed effective pH-dependent delivery of peptidomimetic-doxorubicin conjugate at lower pH conditions mimicking tumor microenvironment (pH-6.5) compared to normal physiological conditions (pH 7.4), leading to the improvement of cell uptake. In vivo results revealed the site-specific delivery of the formulation and enhanced antitumor activity with reduced toxicity compared to the free doxorubicin (Free Dox). The results suggested that the targeting ligand conjugated cytotoxic drug with the pH-sensitive liposomal formulation is a promising approach to chemotherapy.
    Keywords:  HER2; lung cancer; pH-sensitive liposome. Doxorubicin; peptide conjugate
    DOI:  https://doi.org/10.1016/j.ijpharm.2021.121364
  69. Nutr Res Rev. 2021 Dec 13. 1-43
    Olive oil and wine as source of multi-target agents in the prevention of Alzheimer disease.
    Paula Silva, María Rodríguez-Pérez, Óscar Gómez-Torres, Emma Burgos-Ramos.
      Olive oil and wine are consumed daily worldwide and they constitute the fundamental pillars of the healthy Mediterranean diet. Polyphenolic compounds, naturally present in both olive oil and wine, are responsible for their beneficial properties. Current studies have shown the neuroprotective effects of polyphenols independently of their well-known antioxidant action. In this work, we have focused on reviewing the protective effect of polyphenols from extra virgin olive oil and wine in Alzheimer´s disease (AD), to emphasize that both food could be a possible therapeutic tool. Beneficial effects have been described in β-aggregation, neurofibrillary tangles, autophagy and mitochondrial function, as well as in cerebral insulin resistance. Furthermore, to date a harmful dose has not been described. Both preclinical and clinical works demonstrate that polyphenols act on neuropathological and cognitive disorders of AD, preventing or stopping the onset of this devastating disease. However, there are certain limitations in these studies, since it is very difficult to research diseases that lead to cognitive impairment. Although all the findings obtained are very encouraging, more studies should be carried out to use the polyphenols from olive oil and wine as therapeutic agents in the progression of AD. Therefore, more longitudinal studies in humans with a homogeneous cohort of patients are necessary to corroborate the efficacy of these nutraceuticals, as well as analyze which is the most appropriate dose for this purpose.
    Keywords:  Alzheimer’s disease; Hydroxytyrosol; Mediterranean Diet; Oleuropein; Olive Oil; Polyphenols; Resveratrol; Wine
    DOI:  https://doi.org/10.1017/S095442242100041X
  70. J Appl Biomed. 2020 Mar;18(1): 1-7
    The benefits of ascorbate to protect healthy cells in the prevention and treatment of oncological diseases.
    Pavel Klener, Matthew Scott Alexander, Joseph John Cullen, Vera Stejskal, Jiri Sliva, Lucie Kotlarova, Pavel Kostiuk, Zdenek Prochazka, Marta Kucerova.
      Health status is determined by the balance of oxidants and antioxidants which protects healthy cells against the threat of internal and external risk factors. Antioxidants such as ascorbate (vitamin C, ascorbic acid) are of fundamental importance in this respect. Ascorbate neutralizes potential damage caused by cellular oxidative stress which may be the greatest risk of damage to healthy tissue. Cellular oxidative stress is mediated by external factors (e.g. psychological stress, physical exertion, drugs, various diseases, environmental pollution, preservatives, smoking, and alcohol) and internal factors (products of cellular metabolism including reactive oxygen species). When the products of oxidative stress are not sufficiently neutralized, healthy cells are at risk for both mitochondrial and DNA damage. In the short term, cell function may deteriorate, while an increased production of proinflammatory cytokines over time may lead to the development of chronic inflammatory changes and diseases, including cancer. Although pharmaceutical research continues to bring effective chemotherapeutic agents to the market, a limiting factor is often the normal tissue and organ toxicity of these substances, which leads to oxidative stress on healthy tissue. There is increasing interest and imperative to protect healthy tissues from the negative effects of radio-chemotherapeutic treatment. The action of ascorbate against the development of oxidative stress may justify its use not only in the prevention of carcinogenesis, but as a part of supportive or complementary therapy during treatment. Ascorbate (particularly when administered parentally at high doses) may have antioxidant effects that work to protect healthy cells and improve patient tolerability to some toxic radio-chemotherapy regimens. Additionally, ascorbate has demonstrated an immunomodulatory effect by supporting mechanisms essential to anti-tumor immunity. Intravenous administration of gram doses of vitamin C produce high plasma levels immediately, but the levels drop rapidly. Following oral vitamin C administration, plasma levels increase slowly to relatively low values, and then gradually decay. With an oral liposomal formulation, significantly higher levels are attainable than with standard oral formulations. Therefore, oral administration of liposomal vitamin C appears to be an optimal adjunct to intravenous administration. In this review, the basic mechanisms and clinical benefits of ascorbate as an antioxidant that may be useful as complementary therapy to chemotherapeutic regimens will be discussed.
    Keywords:  Ascorbic acid; Cancer; Complementary therapy; Intravenous vitamin C; Liposomal vitamin C; Oxidative stress; Vitamin C
    DOI:  https://doi.org/10.32725/jab.2020.003
  71. J Control Release. 2021 Dec 10. pii: S0168-3659(21)00655-6. [Epub ahead of print]341 524-532
    I.p.-injected cationic liposomes are retained and accumulate in peritoneally disseminated tumors.
    Rie Ando-Matsuoka, Hidenori Ando, Amr S Abu Lila, Noriyuki Maeda, Taro Shimizu, Yu Ishima, Tatsuhiro Ishida.
      Intraperitoneal (i.p) chemotherapy is an attractive approach to treat peritoneally disseminated cancers by delivering therapeutic agents directly to the peritoneal cavity where some disseminated tumors are located. Cationic liposomes (CLs) have been used as a viable delivery carrier for i.p. chemotherapy to improve the peritoneal retention of anticancer agents. However, there are no reports on the fate of CLs following i.p. administration to the peritoneal cavity in the presence of disseminated tumors. We prepared a tumor xenograft murine model of peritoneally disseminated gastric cancer by i.p. inoculation of human gastric cancer cells and followed the fate of either CLs or PEGylated CLs (PEG-CLs) after i.p. injection in the model. I.p.-injected CLs were retained in peritoneal cavity for at least 3 days post-injection as a result of clustering with ascites fluid proteins, mainly albumin, while i.p. PEG-CLs was rapidly cleared from the peritoneal cavity to the circulation within 3 h post-injection. Importantly, i.p. CLs efficiently accumulated in the targeted disseminated tumor cells, but not in other abdominal organs including liver, spleen, and kidney. The tumor selectivity upon i.p. administration of CLs may be associated with the lymphatic drainage system. A lipoplex formulation composed of CLs with short hairpin RNA (shRNA) against luciferase, a model therapeutic agent, suppressed luciferase activity in peritoneally disseminated tumors by 80%, with no cytokine secretion in serum. This suggests that i.p. CLs can efficiently deliver a therapeutic agent to peritoneally disseminated tumors with few systemic adverse events. These results suggest that i.p. treatment with CLs or non-PEGylated lipoplexes may be a promising approach for the treatment of peritoneally disseminated cancers through their ability to selectively deliver therapeutic agents to i.p. target sites with minimal systemic adverse events.
    Keywords:  Cationic liposomes; Gastric cancer; Intraperitoneal chemotherapy; Orthotopic model; Peritoneally disseminated cancer
    DOI:  https://doi.org/10.1016/j.jconrel.2021.12.004
  72. Comput Biol Med. 2021 Dec 09. pii: S0010-4825(21)00904-5. [Epub ahead of print]141 105110
    In silico comparative analysis of KRAS mutations at codons 12 and 13: Structural modifications of P-Loop, switch I&II regions preventing GTP hydrolysis.
    Michael Gerber, Sanjay Goel, Radhashree Maitra.
      KRAS mutation is prevalent in around 30% of all cancers and is an undruggable molecular target. Of seven mutations at codon 12 and 13, only one, the G12C mutant is finally proven to be druggable, as evidenced by the recent USFDA approval of sotorasib. Investigation of other small molecules targeting G12C and G12D are undergoing clinical trials. Understanding the fine structural details is a prerequisite to design specific inhibitors which also requires in depth molecular exploration. We used bioinformatics as a tool to analyze the KRAS protein's GTP (guanosine triphosphate) binding dynamics when mutated. KRAS undergoes significant conformational changes, affecting GTP binding conformation within the active site pocket of KRAS due to high torsional strains, hydrophobicity, and altered Switch I and II regions. GTP molecule for wildtype had a low torsional strain of 10.71, and is the only molecule, in comparison to KRAS mutant bound GTP, to have a glycine at position 10 interacting with its nitrogenous base. All mutant KRAS proteins lacked the interaction of glycine with the nitrogenous base. The binding affinity of wildtype (WT) KRAS for the gamma-phosphate was lower in scoring compared to the mutated KRAS protein in multiple analyses. This study provides an insight to the GTP-KRAS protein binding details that are important to define parameters required to be explored to design the appropriate inhibitor for each different type of mutant KRAS protein.
    Keywords:  3D-structure; Codon 12 and 13; KRAS; Kinetics; Simulation
    DOI:  https://doi.org/10.1016/j.compbiomed.2021.105110
  73. J Colloid Interface Sci. 2021 Dec 03. pii: S0021-9797(21)02138-X. [Epub ahead of print]609 307-319
    Surface functionalized biomimetic bioreactors enable the targeted starvation-chemotherapy to glioma.
    Ruifang Ke, Xueyan Zhen, Huai-Song Wang, Linhao Li, Hongying Wang, Sicen Wang, Xiaoyu Xie.
      Altering the glucose supply and the metabolic pathways would be an intriguing strategy in starvation therapy toward cancers. Nevertheless, starvation therapy alone could be inadequate to eliminate tumor cells completely. Herein, a multifunctional bioreactor was fabricated for synergistic starvation-chemotherapy through embedding glucose oxidase (GOx) and doxorubicin (DOX) in the tumor targeting ligands (RGD) modified red blood cell membrane camouflaged metal-organic framework (MOF) nanoparticle (denoted as RGD-mGZD). Owing to the remarkable biointerfacing property, the designed RGD-mGZD could not only possess enhanced blood retention time inherited from red blood cells, but also preferentially target the tumor site after the modification with RGD peptide. Once the bioreactor reached the desired region, GOx promptly consumed the intratumoral glucose and oxygen to starve cancer cells for robust starvation therapy. More importantly, the aggravated acidic microenvironment at the tumor region was found to induce the decomposition of the MOF structure, thus triggering the release of DOX for reinforced chemotherapy. This bioreactor would further prompt the development of synergistic patterns toward cancer treatment in a spatiotemporally controlled manner.
    Keywords:  Drug delivery; Metal-organic framework; Red blood cell membrane; Starvation-chemotherapy; Tumor-targeting
    DOI:  https://doi.org/10.1016/j.jcis.2021.12.009
  74. AAPS PharmSciTech. 2021 Dec 14. 23(1): 27
    Strategies for Liposome Drug Delivery Systems to Improve Tumor Treatment Efficacy.
    Jia Wang, Junbo Gong, Zhenping Wei.
      In the advancement of tumor therapy, in addition to the search for new antitumor compounds, the development of nano-drug delivery systems has opened up new pathways for tumor treatment by addressing some of the limitations of traditional drugs. Liposomes have received much attention for their high biocompatibility, low toxicity, high inclusivity, and improved drug bioavailability. They are one of the most studied nanocarriers, changing the size and surface characteristics of liposomes to better fit the tumor environment by taking advantage of the unique pathophysiology of tumors. They can also be designed as tumor targeting drug delivery vehicles for the precise delivery of active drugs into tumor cells. This paper reviews the current development of liposome formulations, summarizes the characterization methods of liposomes, and proposes strategies to improve the effectiveness of tumor treatment. Finally, it provides an outlook on the challenges and future directions of the field. Graphical abstract.
    Keywords:  liposome characterization; liposomes; targeted drug delivery; tumor targeting; tumor therapy
    DOI:  https://doi.org/10.1208/s12249-021-02179-4
  75. Cancer Control. 2021 Jan-Dec;28:28 10732748211066311
    From Apoptosis to Necroptosis: The Death Wishes to Cancer.
    Xianmei Meng, Tong Dang, Jianyuan Chai.
      DNA mutation is a common event in the human body, but in most situations, it is fixed right away by the DNA damage response program. In case the damage is too severe to repair, the programmed cell death system will be activated to get rid of the cell. However, if the damage affects some critical components of this system, the genetic scars are kept and multiply through mitosis, possibly leading to cancer someday. There are many forms of programmed cell death, but apoptosis and necroptosis represent the default and backup strategy, respectively, in the maintenance of optimal cell population as well as in cancer prevention. For the same reason, the ideal approach for cancer treatment is to induce apoptosis in the cancer cells because it proceeds 20 times faster than tumor cell proliferation and leaves no mess behind. Induction of necroptosis can be the second choice in case apoptosis becomes hard to achieve, however, necroptosis finishes the job at a cost-inflammation.
    Keywords:  apoptosis; autophagy; cancer; necroptosis; programmed cell death
    DOI:  https://doi.org/10.1177/10732748211066311
  76. Front Bioeng Biotechnol. 2021 ;9 766380
    A New Nanomaterial Based on Extracellular Vesicles Containing Chrysin-Induced Cell Apoptosis Through Let-7a in Tongue Squamous Cell Carcinoma.
    Zhijing Yang, Da Liu, Hengzong Zhou, Boqiang Tao, Lu Chang, Huimin Liu, Haoming Luo, Dongxu Wang, Weiwei Liu.
      Although the therapeutic strategy showed significant improvement, the therapeutic effect was poor on metastases in tongue squamous cell carcinoma (TSCC) which is the most malignant tumor found in the head and neck. Chrysin, similar to the flavonoids, plays an antitumor role by regulating the expression of ncRNAs in many kinds of cancers. Compared to flavonoids, gold nanoparticles (AuNPs) provide a novel insight into inhibiting cancer cell growth via photothermal therapy (PPT) which is irradiated by near-infrared radiation (NIR). However, most flavonoids and AuNPs lack specificity of tumor in vivo. The extracellular vesicles (EVs) which were abundant with ncRNAs are isolated from the cellular supernatant fluid and have the ability to carry drugs or nanoparticles to improve specificity. In the present study, we aimed to synthesize a new nanomaterial based on EVs containing chrysin and analyzed cell apoptosis in TSCC cells. Our results demonstrated that EVs-chrysin were isolated from SCC9 cells that were treated with chrysin. To improve the therapeutic effect, AuNPs were carried by EVs-chrysin (Au-EVs). Compared to BGC823 and HCC-LM3 cells, the uptake of Au-EVs was specific in SCC9 cells. Moreover, Au-EVs combined with NIR enhanced cell apoptosis in TSCC cells. To confirm the role of miRNAs in cell apoptosis, the differentially expressed miRNAs between EVs-Con and EVs-chrysin were screened by RNA-seq. The results revealed that the let-7a-3p family, which acts as the tumor suppressor, was upregulated in EVs-chrysin compared to EVs-Con. Thus, let-7a-3p was screened in the apoptosis pathway that was associated with the p53 protein. Furthermore, compared to the Con group, Au-EVs combined with the NIR group effectively inhibited tumor growth in vivo via increasing the expression of let-7a-3p. Together, as a new nanomaterial, Au-EVs induced cell apoptosis and inhibited tumor growth by regulating let-7a-3p expression in TSCC.
    Keywords:  cell apoptosis; extracellular vesicles; gold nanoparticles; let-7a; tongue squamous cell carcinoma
    DOI:  https://doi.org/10.3389/fbioe.2021.766380
  77. J Liposome Res. 2021 Dec 13. 1-15
    Eudragit S100 prepared pH-responsive liposomes-loaded betulinic acid against colorectal cancer in vitro and in vivo.
    Gang Wang, Yu Yang, Du Yi, Lu Yuan, Pei-Hao Yin, Xu Ke, Wang Jun-Jie, Min-Fang Tao.
      This study aimed to develop polymer Eudragit S100 for preparing pH-responsive liposomes-loaded betulinic acid (pH-BA-LP) to improve the therapeutic index of chemotherapy for colorectal cancer. BA-loaded liposomes were coated with Eudragit S100 by a thin film dispersion and easily scalable pH-driven method. The prepared liposomes were evaluated for size, surface morphology, entrapment efficiency, stability, in vitro drug release, and antitumor activity. In particular, pH-BA-LP showed advantages such as lower size (<100 nm), encapsulation efficiency of 90%, high stability, and stably cumulative release. By detecting the antitumor effects of pH-BA-LP in vivo, it showed that the tumor proliferation and cell migration were significantly inhibited in colorectal cancer. The pH-BA-LP also inhibited tumor growth via the regulation of Akt/TLR-mediated signalling and significantly down-regulated the expression of NFAT1 and NFAT4 proteins. It was found that pH-BA-LP can increase NK cells and CD3+ cells in tumor tissues, and the proportion of CD8+ cells in CD3+ cells was also increased, which proved that pH-BA-LP can play an antitumor effect by enhancing the autoimmunity level in tumor-bearing mice. The positive infiltration rates of CD8 and CD68 were increased and CD163 was relatively decreased by using pH-BA-LP, which proved that pH-BA-LP can regulate the immune infiltration levels in tumor-bearing mice. Therefore, the present work provides an effective method to prepare pH-responsive polymer-coated liposomes for colonic delivery with biologically active compounds.
    Keywords:  Betulinic acid; Eudragit S100; colorectal cancer; immunity; liposomes; pH targeting
    DOI:  https://doi.org/10.1080/08982104.2021.1999974
  78. Biochemistry (Mosc). 2021 Oct;86(10): 1342-1351
    Modified N-Terminal Fragments of Galanin: Cardioprotective Properties and Mechanisms of Action.
    Oleg I Pisarenko, Irina M Studneva, Oxana M Veselova.
      The design of new drugs for treatment of cardiovascular diseases based on endogenous peptide hormones is of undoubted interest and stimulates intensive experimental research. One of the approaches for development in this area is synthesis of the short bioactive peptides that mimic effects of the larger peptide molecules and have improved physicochemical characteristics. In recent years, it has been found that the N-terminal fragments of the neuropeptide galanin reduce metabolic and functional disorders in the experimental heart damage. The review presents literature data and generalized results of our own experiments on the effects of the full-size galanin and its chemically modified N-terminal fragments (2-11) and (2-15) on the heart in normal conditions and in modeling pathophysiological conditions in vitro and in vivo. It has been shown that the spectrum of the peptide actions on the damaged myocardium includes decrease in the necrotic death of cardiomyocytes, decrease in the damage of sarcolemma, improvement in the metabolic state of myocardium, decrease in the formation of reactive oxygen species (ROS) and lipid peroxidation (LPO) products. Mechanisms of the protective action of the modified galanin fragments associated with activation of the GalR2 receptor subtype and manifestation of antioxidant properties are discussed. The data summarized in the review indicate that the molecular design of pharmacological agonists of the GalR2 receptor is a promising approach, because they can serve as a basis for the development of cardioprotectors influencing processes of free radical oxidation and metabolic adaptation.
    Keywords:  antioxidant enzymes; cardiomyocyte membranes; experimental pathology; galanin; heart; lipid peroxidation; metabolism; reactive oxygen species
    DOI:  https://doi.org/10.1134/S000629792110014X
  79. J Appl Biomed. 2021 Dec;19(4): 202-209
    Rosmarinic acid suppresses inflammation, angiogenesis, and improves paclitaxel induced apoptosis in a breast cancer model via NF3 κB-p53-caspase-3 pathways modulation.
    Marwa A Mahmoud, Tark M Okda, Gamal A Omran, Mohammad M Abd-Alhaseeb.
      Rosmarinic acid is a natural polyphenolic compound that is found in different plant species and used for different medicinal purposes. This study aimed to investigate the chemo-preventive effect of rosmarinic acid and evaluate its antitumor efficacy alone or in combination with Paclitaxel in breast cancer mice model. Ehrlich induced mice mammary solid tumor model was used in the study. Mice were treated with oral rosmarinic acid and intraperitoneal Paclitaxel. Inflammation, angiogenesis, and apoptosis were checked. Enzyme linked immunosorbent assay (ELISA), quantitative real time PCR, and immunohistochemical methods were performed. Rosmarinic acid used prior to tumor induction suppressed NF-κB, TNF-α, vascular endothelial growth factor (VEGF) serum levels, and VEGF receptors. It also triggered apoptosis by restoring the levels of P53, Bcl-2, Bax, and caspase-3. Furthermore, in Ehrlich solid tumor mice, rosmarinic acid, and/or Paclitaxel significantly suppressed tumor growth with an increase in apoptotic markers P53 and Caspase-3 levels, and suppressed the Bcl2/Bax ratio. Rosmarinic acid exerted chemo-preventive and therapeutic potential alone or in combination with Paclitaxel. Moreover, rosmarinic acid targets numerous signaling pathways associated with breast cancer.
    Keywords:  Angiogenesis; Apoptosis; Breast cancer; Inflammation; Paclitaxel; Rosmarinic acid
    DOI:  https://doi.org/10.32725/jab.2021.024
  80. ACS Biomater Sci Eng. 2021 Dec 13.
    Fabrication Methods and Form Factors of Gellan Gum-Based Materials for Drug Delivery and Anti-Cancer Applications.
    Carolina Villarreal-Otalvaro, Jeannine M Coburn.
      Despite the success of cancer therapeutics, off target cell toxicity prevails as one of the main challenges of cancer treatment. Exploration of drug delivery methods is a growing field of research, which involves a variety of materials and processing techniques. A natural polymer, gellan gum presents physicochemical properties that enable drug loading for sustained release in a broad range of environmental conditions and anatomical locations. Gellan gum is an anionic exopolysaccharide, produced via fermentation by Sphingomonas elodea, which gels in the presence of cations. Additionally, it is biocompatible and nontoxic. Multiple physical and chemical gelation processes have been reported for the use of gellan gum in drug delivery applications to produced varying form factors, including hydrogels, nanohydrogels, beads, films, or patches, with tunable mechanical and physicochemical properties. The resulting formulations have shown promising outcomes for drug delivery including improving drug bioavailability, drug solubility, and drug release over time, without compromising biocompatibility or the introduction of adverse effects. This review presents studies in which gellan gum has been processed to enable the delivery of antibiotics, antiallergens, anti-inflammatory, or antifungal molecules with a special focus on drugs for anticancer applications.
    Keywords:  anionic exopolysaccharide; cancer treatment; gellan gum; processing methods; tunable material properties
    DOI:  https://doi.org/10.1021/acsbiomaterials.1c00685
  81. Mol Oncol. 2021 Dec 17.
    KRAS mutation-independent downregulation of MAPK/PI3K signaling in colorectal cancer.
    Kuen Kuen Lam, Choong Leong Tang, Emile Tan, Siew Heng Wong, Peh Yean Cheah.
      KRAS is a gatekeeper gene in human colorectal tumorigenesis. KRAS is "undruggable", hence efforts have been diverted to inhibit downstream RAF/MEK/ERK and PI3K/Akt signaling. Nevertheless, none of these inhibitors has progressed to clinical use despite extensive trials. We examined levels of phospho-ERK1/2(T202/Y204) and phospho-Akt1/2/3(S473) in human colorectal tumor compared to matched mucosa with semi-quantitative near-infrared western blot and confocal fluorescence immunohistochemistry imaging. Surprisingly, 75.5% (25/33) of tumors had lower or equivalent phospho-ERK1/2 and 96.9% (31/32) of tumors had lower phospho-Akt1/2/3 compared to matched mucosa, irrespective of KRAS mutation status. In contrast, we discovered KRAS-dependent SOX9 upregulation in 28 of the 31 (90.3%) tumors. These observations were substantiated by analysis of the public domain transcriptomics The Cancer Genome Atlas (TCGA) and NCBI Gene Expression Omnibus (GEO) datasets and proteomics Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset. These data suggest that RAF/MEK/ERK and PI3K/Akt signaling are unlikely to be activated in most human colorectal cancer.
    Keywords:  CPTAC; KRAS signaling; MAPK/PI3K; SOX9; TCGA; colorectal tumorigenesis
    DOI:  https://doi.org/10.1002/1878-0261.13163
  82. Small. 2021 Dec 16. e2105118
    Multifunctional Immunoliposomes Enhance the Immunotherapeutic Effects of PD-L1 Antibodies against Melanoma by Reprogramming Immunosuppressive Tumor Microenvironment.
    Yu Hei, Yang Chen, Qian Li, Zi Mei, Jijia Pan, Siqi Zhang, Chunyang Xiong, Xiaodong Su, Shicheng Wei.
      The immunosuppressive tumor microenvironment (TME) can significantly limit the immunotherapeutic effects of the PD-L1 antibody (aPDL1) by inhibiting the infiltration of CD8+ cytotoxic T cells (CTLs) into the tumor tissues. However, how to reprogram the immunosuppressive TME and promote the infiltration of CTLs remains a huge challenge for aPDL1 to achieve the maximum benefits. Herein, the authors design a multifunctional immunoliposome that encapsulates the adrenergic receptor blocker carvedilol (CAR) and connects the "don't eat me" signal antibody (aCD47) and aPDL1 in series via a reactive oxygen species (ROS)-sensitive linker on the surface. In ROS-enriched immunosuppressive TME, the multifunctional immunoliposome (CAR@aCD47/aPDL1-SSL) can first release the outer aCD47 to block the "do not eat me" pathway, promote the phagocytosis of tumor cells by phagocytic cells, and activate CTLs. Then, the aPDL1 on the liposome surface is exposed to block the PD-1/PD-L1 signaling pathway, thereby inducing CTLs to kill tumor cells. CAR encapsulated in CAR@aCD47/aPDL1-SSL can block the adrenergic nerves in the tumor tissues and reduce their densities, thereby inhibiting angiogenesis in the tumor tissues and reprogramming the immunosuppressive TME. According to the results, CAR@aCD47/aPDL1-SSL holds an effective way to reprogram the immunosuppressive TME and significantly enhance immunotherapeutic efficiency of aPDL1 against the primary cancer and metastasis.
    Keywords:  PD-L1 antibody (aPDL1); adrenergic nerve fibers; immunosuppressive tumor microenvironment; multifunctional immunoliposomes; “don't eat me” signal antibody (aCD47)
    DOI:  https://doi.org/10.1002/smll.202105118
  83. Drug Des Devel Ther. 2021 ;15 4961-4972
    Cell-Penetrating Peptide-Modified Graphene Oxide Nanoparticles Loaded with Rictor siRNA for the Treatment of Triple-Negative Breast Cancer.
    Yun-Yun Yang, Wei Zhang, Hui Liu, Jun-Jie Jiang, Wen-Jie Wang, Zheng-Yan Jia.
       Introduction: Breast cancer is a malignant tumor that seriously threatens women's life and health.
    Methods: In this study, we proposed to use graphene nanoparticles loaded with siRNA that can silence Rictor molecules essential for the mammalian target of rapamycin (mTOR) complex 2 (mTORC2) complex to enhance gene delivery to tumor cells through modification of cell-penetrating peptide (CPP) for the treatment of breast cancer.
    Results: Remarkably, we successfully synthesized graphene oxide (GO)/polyethyleneimine (PEI)/polyethylene glycol (PEG)/CPP/small interfering RNA (siRNA) system, and the results were observed by atomic force microscopy (AFM) and ultraviolet visible (UV-Vis) absorption spectra. The optimum mass ratio of siRNA to GO-PEI-PEG-CPP was 1:0.5. We screened out Rictor siRNA-2 from 9 candidates, which presented the highest inhibition rate, and this siRNA was selected for the subsequent experiments. We validated that Rictor siRNA-2 significantly reduced the Rictor expression in triple negative breast cancer (TNBC) cells. Confocal fluorescence microscope and flow cytometry analysis showed that GO-PEI-PEG-CPP/siRNA was able to be effectively uptake by TNBC cells. GO-PEI-PEG-CPP/siRNA improved the effect of siRNA on the inhibition of TNBC cell viability and the induction of TNBC cell apoptosis. The expression of Rictor and the phosphorylation of Akt and p70s6k were inhibited by GO-PEI-PEG-CPP/siRNA. Tumorigenicity analysis in nude mice showed that GO-PEI-PEG-CPP/siRNA significantly repressed the tumor growth of TNBC cells in vivo. The levels of ki-67 were repressed by GO-PEI-PEG-CPP/siRNA, and the apoptosis was induced by GO-PEI-PEG-CPP/siRNA in the system.
    Discussion: Therefore, we concluded that CPP-modified GO nanoparticles loaded with Rictor siRNA significantly repressed TNBC progression by the inhibition of PI3K/Akt/mTOR signaling. Our finding provides a promising therapeutic strategy for the treatment of TNBC.
    Keywords:  PI3K/Akt/mTOR signaling; Rictor; cell-penetrating peptide; graphene oxide; triple-negative breast cancer
    DOI:  https://doi.org/10.2147/DDDT.S330059
  84. Crit Rev Food Sci Nutr. 2020 Oct 14. 1-11
    Ketogenic diet: a tool for the management of neuroendocrine neoplasms?
    Giovanna Muscogiuri, Luigi Barrea, Federica Campolo, Emilia Sbardella, Concetta Sciammarella, Maria Grazia Tarsitano, Filomena Bottiglieri, Annamaria Colao, Antongiulio Faggiano.
      Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms, whose incidence has rapidly increased in the last years. Nutrition plays an important role in their management; indeed, malnutrition negatively impacts on rates of complications, hospitalization, hospital stay, costs and mortality. Furthermore, it has been reported that a poor nutritional status could influence the outcome of patients with pancreatic NENs. Moreover, obesity, predisposing to insulin resistance and compensatory hyperinsulinemia, could stimulate the growth of these neoplasms. Ketogenic diet (KD), a high-fat, low-carbohydrate diet with adequate amounts of protein, has been reported to be a promising approach for the management of several types of cancer, mostly gynecological and neurological ones. Indeed, it appears to sensitize most cancers to standard treatment by exploiting the reprogramed metabolism of cancer cells and thus resulting in a promising candidate as an adjuvant cancer therapy. Thus, the aim of this review is to provide an overview on the importance of nutrition in cancer management and in particular in NENs' setting. Furthermore, we reported the current evidence on the efficacy of KD in the management of cancer and based on molecular mechanisms; we also hypothesize the potential use of this nutritional pattern in the management of NENs.
    Keywords:  Cancer; ketogenic diet; neuroendocrine neoplasms; nutrition; obesity
    DOI:  https://doi.org/10.1080/10408398.2020.1832955
  85. Acta Pharm Sin B. 2021 Nov;11(11): 3595-3607
    Self-assembled ternary hybrid nanodrugs for overcoming tumor resistance and metastasis.
    Xu Cheng, Dapeng Li, Jiaxi Xu, Bing Wei, Qin Fang, Longshun Yang, Yanbing Xue, Xin Wang, Rupei Tang.
      Traditional chemotherapy exhibits a certain therapeutic effect toward malignant cancer, but easily induce tumor multidrug resistance (MDR), thereby resulting in the progress of tumor recurrence or metastasis. In this work, we deigned ternary hybrid nanodrugs (PEI/DOX@CXB-NPs) to simultaneously combat against tumor MDR and metastasis. In vitro results demonstrate this hybrid nanodrugs could efficiently increase cellular uptake at pH 6.8 by the charge reversal, break lysosomal sequestration by the proton sponge effect and trigger drugs release by intracellular GSH, eventually leading to higher drugs accumulation and cell-killing in drug-sensitive/resistant cells. In vivo evaluation revealed that this nanodrugs could significantly inhibit MDR tumor growth and simultaneously prevent A549 tumor liver/lung metastasis owing to the specifically drugs accumulation. Mechanism studies further verified that hybrid nanodrugs were capable of down-regulating the expression of MDR or metastasis-associated proteins, lead to the enhanced anti-MDR and anti-metastasis effect. As a result, the multiple combination strategy provided an option for effective cancer treatment, which could be potentially extended to other therapeutic agents or further use in clinical test.
    Keywords:  Charge reversal; Drugs dimer; Inflammation; Metastasis; Multidrug resistance; Polyethyleneimine; Proton sponge; Redox sensitive
    DOI:  https://doi.org/10.1016/j.apsb.2021.03.041
  86. Vavilovskii Zhurnal Genet Selektsii. 2021 Mar;25(2): 178-189
    [Anthocyanins as functional food components].
    R S Yudina, E I Gordeeva, O Yu Shoeva, M A Tikhonova, E K Khlestkina.
      Among the natural pigments, anthocyanins are assumed to represent one of the most studied groups. Starting with the first studies on the physicochemical properties of anthocyanins carried out in the 17th century by British naturalist Robert Boyle, the science about these unique compounds has progressed substantially. To date, the structure and functions of anthocyanins in plant cells have been well studied, and the pathway of their biosynthesis is one of the most fully characterized pathways of secondary metabolite biosynthesis at both the biochemical and genetic levels. Along with these fundamental achievements, we are beginning to realize the potential of anthocyanins as compounds of industrial importance, as pigments themselves, as well as components of functional food that contribute to the prevention and reduction of risk of chronic diseases. For a long time, the biological activity of anthocyanins has been underestimated, in particular, due to the data on their low bioavailability. However, studies showed that in humans and animals, these compounds are actively metabolized and the bioavailability, estimated taking into account their metabolites, exceeded 12 %. It has been experimentally shown that anthocyanins have antioxidant, anti-inflammatory, hypoglycemic, antimutagenic, antidiabetic, anti-cancer, neuroprotective properties, and they are beneficial for eye health. However, the studies conducted cannot always explain the molecular mechanism of action of anthocyanins in the human body. According to some reports, the observed effects are not due to the action of anthocyanins themselves, but to their metabolites, which can be more biologically active because of their increased bioavailability. Other data ascribe the positive effect on human health not to individual anthocyanins, but to the whole complex of polyphenolic compounds consumed. The review summarizes the results of the studies of anthocyanins as components of functional food. Special attention is paid to genetic control of the pigment synthesis. These data are of particular importance in respect to the initiated breeding programs aimed at increasing the content of anthocyanins in cultural plants.
    Keywords:  anthocyanins; antioxidants; biological activity; flavonoids; pigments; plants; regulatory genes; secondary metabolites; structural genes
    DOI:  https://doi.org/10.18699/VJ21.022
  87. Nat Commun. 2021 Dec 14. 12(1): 7190
    Metabolic drug survey highlights cancer cell dependencies and vulnerabilities.
    Tea Pemovska, Johannes W Bigenzahn, Ismet Srndic, Alexander Lercher, Andreas Bergthaler, Adrián César-Razquin, Felix Kartnig, Christoph Kornauth, Peter Valent, Philipp B Staber, Giulio Superti-Furga.
      Interrogation of cellular metabolism with high-throughput screening approaches can unravel contextual biology and identify cancer-specific metabolic vulnerabilities. To systematically study the consequences of distinct metabolic perturbations, we assemble a comprehensive metabolic drug library (CeMM Library of Metabolic Drugs; CLIMET) covering 243 compounds. We, next, characterize it phenotypically in a diverse panel of myeloid leukemia cell lines and primary patient cells. Analysis of the drug response profiles reveals that 77 drugs affect cell viability, with the top effective compounds targeting nucleic acid synthesis, oxidative stress, and the PI3K/mTOR pathway. Clustering of individual drug response profiles stratifies the cell lines into five functional groups, which link to specific molecular and metabolic features. Mechanistic characterization of selective responses to the PI3K inhibitor pictilisib, the fatty acid synthase inhibitor GSK2194069, and the SLC16A1 inhibitor AZD3965, bring forth biomarkers of drug response. Phenotypic screening using CLIMET represents a valuable tool to probe cellular metabolism and identify metabolic dependencies at large.
    DOI:  https://doi.org/10.1038/s41467-021-27329-x
  88. Biomaterials. 2021 Dec 06. pii: S0142-9612(21)00668-2. [Epub ahead of print]280 121312
    Polymeric PD-L1 blockade nanoparticles for cancer photothermal-immunotherapy.
    Yunjian Yu, Jie Li, Boyi Song, Zhuang Ma, Yufei Zhang, Haonan Sun, Xiaosong Wei, Yayun Bai, Xueguang Lu, Peng Zhang, Xinge Zhang.
      Checkpoint inhibitors, such as antibodies blocking the PD-1/PD-L1 pathway, are among the most promising immunotherapies to treat metastatic cancers, but their response rate remains low. In addition, the usage of monoclonal antibodies as checkpoint inhibitors is associated with a series of drawbacks. Herein, an all synthetic nanoparticle with PD-L1 blockade capability is developed for cancer photothermal-immunotherapy. The polymeric nanoparticle integrates photothermal treatment, antitumor vaccination, and PD-1/PD-L1 blockade in a single system to augment the antitumor efficacy. In a CT26 bilateral tumor model, intravenously injected nanoparticles accumulate in tumor sites and mediate strong photothermal effects, eradicate the NIR treated primary tumors and elicit strong antitumor immunity by inducing immunogenic cell death (ICD). Growth of the untreated distant tumors is also suppressed due to the synergies of systemic antitumor immune activation and PD-L1 blockade. Our strategy offers a simple but promising approach for the treatment of metastatic cancer.
    Keywords:  Antitumor immunity; Metastatic cancer; PD-L1 blockade; Photothermal treatment; Polymeric nanoparticle
    DOI:  https://doi.org/10.1016/j.biomaterials.2021.121312
  89. J Nanobiotechnology. 2021 Dec 14. 19(1): 421
    Irinotecan/scFv co-loaded liposomes coaction on tumor cells and CAFs for enhanced colorectal cancer therapy.
    Zhaohuan Li, Chunxi Liu, Chenglei Li, Fangqing Wang, Jianhao Liu, Zengjuan Zheng, Jingliang Wu, Bo Zhang.
       BACKGROUND: Cancer-associated fibroblasts (CAFs), as an important component of stroma, not only supply the "soils" to promote tumor invasion and metastasis, but also form a physical barrier to hinder the penetration of therapeutic agents. Based on this, the combinational strategy that action on both tumor cells and CAFs simultaneously would be a promising approach for improving the antitumor effect.
    RESULTS: In this study, the novel multifunctional liposomes (IRI-RGD/R9-sLip) were designed, which integrated the advantages including IRI and scFv co-loading, different targets, RGD mediated active targeting, R9 promoting cell efficient permeation and lysosomal escape. As expected, IRI-RGD/R9-sLip showed enhanced cytotoxicity in different cell models, effectively increased the accumulation in tumor sites, as well as exhibited deep permeation ability both in vitro and in vivo. Notably, IRI-RGD/R9-sLip not only exhibited superior in vivo anti-tumor effect in both CAFs-free and CAFs-abundant bearing mice models, but also presented excellent anti-metastasis efficiency in lung metastasis model.
    CONCLUSION: In a word, the novel combinational strategy by coaction on both "seeds" and "soils" of the tumor provides a new approach for cancer therapy, and the prepared liposomes could efficiently improve the antitumor effect with promising clinical application prospects.
    Keywords:  Cancer-associated fibroblasts; Co-cultured cells; Colorectal cancer; Liposomes; Single chain fragment variable
    DOI:  https://doi.org/10.1186/s12951-021-01172-0
  90. Drug Metab Dispos. 2021 Dec 13. pii: DMD-MR-2021-000455. [Epub ahead of print]
    Withaferin A in the treatment of liver diseases: progress and pharmacokinetic insights.
    Yangliu Xia, Mingrui Yan, Ping Wang, Keisuke Hamada, Nana Yan, Haiping Hao, Frank J Gonzalez, Tingting Yan.
      Withaferin A (WA) is a natural steroidal compound used in Ayurvedic medicine in India and elsewhere. While WA was used as an anti-cancer reagent for decades, its role in the treatment of liver diseases has only recently been experimentally explored. Here, the effects of WA in the treatment of liver injury, systematic inflammation, and liver cancer are reviewed, and the toxicity and metabolism of WA as well as pharmacological potentials of other extracts from W. somnifera discussed. The pharmacokinetic behaviors of WA are summarized and pharmacokinetic insights into current progress and future opportunities are highlighted. Significance Statement This review outlines the current experimental progress of WA hepatoprotective activities and highlights gaps in the field. This work also discusses the pharmacokinetics of WA that can be used to guide future studies for the possible treatment of liver diseases with this compound.
    Keywords:  Liver; drug delivery; liver disease; liver injury/toxicity (DILI); pharmacokinetic
    DOI:  https://doi.org/10.1124/dmd.121.000455
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