bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–01–02
eighty-two papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. The Art of War: Ferroptosis and Pancreatic Cancer.
  2. Dual antisense oligonucleotide targeting miR-21/miR-155 synergize photodynamic therapy to treat triple-negative breast cancer and inhibit metastasis.
  3. Review of therapies using TiO2 nanomaterials for increased anticancer capability.
  4. Curcumin encapsulation in functional PLGA nanoparticles: A promising strategy for cancer therapies.
  5. Nanoformulations of α-Mangostin for Cancer Drug Delivery System.
  6. Curcumin combined with photodynamic therapy, promising therapies for the treatment of cancer.
  7. Polymeric Nanoparticles: Exploring the Current Drug Development and Therapeutic Insight of Breast Cancer Treatment and Recommendations.
  8. Biomedical Applications and Bioavailability of Curcumin-An Updated Overview.
  9. Renal Tubular Handling of Glucose and Fructose in Health and Disease.
  10. Persister cancer cells: Iron addiction and vulnerability to ferroptosis.
  11. Smart Tumor Microenvironment-Responsive Nano-Prodrug for Disulfiram Toxification In Situ and the Exploration of Lethal Mechanisms in Cells.
  12. Curcumin Synergizes with Cisplatin to Inhibit Colon Cancer through Targeting the MicroRNA-137-Glutaminase Axis.
  13. Reactive Oxygen Species-Responsive Miktoarm Amphiphile for Triggered Intracellular Release of Anti-Cancer Therapeutics.
  14. Effects of Syringic Acid on Apoptosis, Inflammation, and AKT/mTOR Signaling Pathway in Gastric Cancer Cells.
  15. Impact of cancer metabolism on therapy resistance - Clinical implications.
  16. Hypoxia responsive nano-drug delivery system based on angelica polysaccharide for liver cancer therapy.
  17. NIR Light-Triggered Chemo-Phototherapy by ICG Functionalized MWNTs for Synergistic Tumor-Targeted Delivery.
  18. Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment.
  19. Bioinspired synthesis of protein/polysaccharide-decorated folate as a nanocarrier of curcumin to potentiate cancer therapy.
  20. A pH-responsive complex based on supramolecular organic framework for drug-resistant breast cancer therapy.
  21. Signaling Pathway Inhibitors, miRNA, and Nanocarrier-Based Pharmacotherapeutics for the Treatment of Lung Cancer: A Review.
  22. Anticancer drug resistance: An update and perspective.
  23. A Multifunctional Layered Nickel Silicate Nanogenerator of Synchronous Oxygen Self-supply and Superoxide Radical Generation for Hypoxic Tumor Therapy.
  24. The Potential of Natural Products in the Treatment of Triple-Negative Breast Cancer.
  25. Delivery of small interfering RNAs by nanovesicles for cancer therapy.
  26. Self-assembled tocopherol-albumin nanoparticles with full biocompatibility for chemo-photothermal therapy against breast cancer.
  27. Receptor-Mediated Targeted Delivery of Surface-ModifiedNanomedicine in Breast Cancer: Recent Update and Challenges.
  28. Methodological Approaches for Assessing Metabolomic Changes in Glioblastomas.
  29. Co-delivery of paclitaxel and doxorubicin using polypeptide-engineered nanogels for combination therapy of tumor.
  30. Gallotannin-Enriched Fraction from Quercus infectoria Galls as an Antioxidant and Inhibitory Agent against Human Glioblastoma Multiforme.
  31. Growth Inhibitory Efficacy of Chinese Herbs in a Cellular Model for Triple-Negative Breast Cancer.
  32. Nanomedicine Targets Iron Metabolism for Cancer Therapy.
  33. Acidic microenvironment responsive polymeric MOF-based nanoparticles induce immunogenic cell death for combined cancer therapy.
  34. A Low-Glucose Eating Pattern Improves Biomarkers of Postmenopausal Breast Cancer Risk: An Exploratory Secondary Analysis of a Randomized Feasibility Trial.
  35. FTH promotes the proliferation and renders the HCC cells specifically resist to ferroptosis by maintaining iron homeostasis.
  36. Recent advances of nanotechnology in the diagnosis and therapy of triple-negative breast cancer (TNBC).
  37. Design and Application of Near-Infrared Nanomaterial-Liposome Hybrid Nanocarriers for Cancer Photothermal Therapy.
  38. Essential oils as anticancer agents: Potential role in malignancies, drug delivery mechanisms, and immune system enhancement.
  39. Singlet Oxygen Activatable Prodrugs of Paclitaxel, SN-38, MMC, and CA4: Non-mitochondria Targeted Prodrugs.
  40. IDH1/2 Mutations in Cancer Stem Cells and Their Implications for Differentiation Therapy.
  41. Engineering Supramolecular Nanomedicine for Targeted Near Infrared-triggered Mitochondrial Dysfunction to Potentiate Cisplatin for Efficient Chemophototherapy.
  42. Phthalocyanine and Its Formulations: A Promising Photosensitizer for Cervical Cancer Phototherapy.
  43. Camel Urine Promotes Sensitization to Doxorubicin by Inhibiting Epithelial-Mesenchymal Transition and Modulating NF-κB-Snail Signaling Pathway in Breast Cancer Cells.
  44. Dual Targeting of Cancer Cells and MMPs with Self-Assembly Hybrid Nanoparticles for Combination Therapy in Combating Cancer.
  45. Lipid Nanoparticles Containing Mixtures of Antioxidants to Improve Skin Care and Cancer Prevention.
  46. New Approaches on Japanese Knotweed (Fallopia japonica) Bioactive Compounds and Their Potential of Pharmacological and Beekeeping Activities: Challenges and Future Directions.
  47. Reshaping Tumor Immune Microenvironment Based on Light Activated Nano-Platform for Efficient Cancer Therapy.
  48. Sensitive and Precise Visually Guided Drug Delivery Nanoplatform with Dual Activation of pH and Light.
  49. Ultrasound Microbubbles Mediated Sonosensitizer and Antibody Co-delivery for Highly Efficient Synergistic Therapy on HER2-Positive Gastric Cancer.
  50. Glucose starvation suppresses gastric cancer through targeting miR-216a-5p/Farnesyl-Diphosphate Farnesyltransferase 1 axis.
  51. Baicalin; a promising chemopreventive agent, enhances the antitumor effect of 5-FU against breast cancer and inhibits tumor growth and angiogenesis in Ehrlich solid tumor.
  52. The Chemical Composition and Health-Promoting Effects of the Grewia Species-A Systematic Review and Meta-Analysis.
  53. Valproic Acid Prodrug Affects Selective Markers, Augments Doxorubicin Anticancer Activity and Attenuates Its Toxicity in a Murine Model of Aggressive Breast Cancer.
  54. Glycyrrhiza glabra (Licorice): A Comprehensive Review on Its Phytochemistry, Biological Activities, Clinical Evidence and Toxicology.
  55. Crosstalk between Statins and Cancer Prevention and Therapy: An Update.
  56. Protective Effects and Benefits of Olive Oil and Its Extracts on Women's Health.
  57. Fucoidan-Based Nanoparticles with Inherently Therapeutic Efficacy for Cancer Treatment.
  58. The association study of chemical compositions and their pharmacological effects of Cyperi Rhizoma (Xiangfu), a potential traditional Chinese medicine for treating depression.
  59. The Impact of Polyphenolic in The Management of Breast Cancer: Mechanistic Aspects and Recent Patents.
  60. Pharmacological Activity of Garcinia indica (Kokum): An Updated Review.
  61. Multistage Systemic and Cytosolic Protein Delivery for Effective Cancer Treatment.
  62. Immunometabolism modulation, a new trick of edible and medicinal plants in cancer treatment.
  63. Drug Delivery Strategies for Curcumin and Other Natural Nrf2 Modulators of Oxidative Stress-Related Diseases.
  64. Multifunctional phototheranostic nanoplatform based on polydopamine-manganese dioxide-IR780 iodide for effective magnetic resonance imaging-guided synergistic photodynamic/photothermal therapy.
  65. Anti-Inflammatory and Anticancer Properties of Birch Bark-Derived Betulin: Recent Developments.
  66. Screening of Hibiscus and Cinnamomum Plants and Identification of Major Phytometabolites in Potential Plant Extracts Responsible for Apoptosis Induction in Skin Melanoma and Lung Adenocarcinoma Cells.
  67. Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy.
  68. Arginine and Arginases Modulate Metabolism, Tumor Microenvironment and Prostate Cancer Progression.
  69. Small Molecule Based EGFR Targeting of Biodegradable Nanoparticles Containing Temozolomide and Cy5 Dye for Greatly Enhanced Image-Guided Glioblastoma Therapy.
  70. Tumor microenvironment-responsive Ag2S-PAsp(DOX)-cRGD nanoparticles-mediated photochemotherapy enhances the immune response to tumor therapy.
  71. Dendrimer-Based Nanogels for Cancer Nanomedicine Applications.
  72. Lichen-Derived Compounds and Extracts as Biologically Active Substances with Anticancer and Neuroprotective Properties.
  73. Advances in Use of Nanomaterials for Musculoskeletal Regeneration.
  74. Inhibiting TGF-[Formula: see text] 1-Mediated Cellular Processes as an Effective Strategy for the Treatment of Pulmonary Fibrosis with Chinese Herbal Medicines.
  75. The Synergistic Reducing Drug Resistance Effect of Cisplatin and Ursolic Acid on Osteosarcoma through a Multistep Mechanism Involving Ferritinophagy.
  76. The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers.
  77. Integrated Wearable Sensors for Sensing Physiological Pressure Signals and β-Hydroxybutyrate in Physiological Fluids.
  78. Effect of Doxorubicin on the Near-Infrared Optical Properties of Indocyanine Green.
  79. Dual enzyme-mimic nanozyme based on single-atom construction strategy for photothermal-augmented nanocatalytic therapy in the second near-infrared biowindow.
  80. Developmental Stages-Specific Response of Anise Plants to Laser-Induced Growth, Nutrients Accumulation, and Essential Oil Metabolism.
  81. Application of Nanoparticles in Drug Delivery for the Treatment of Osteosarcoma: Focusing on the Liposomes.
  82. One-Step Integration of Tumor Microenvironment-Responsive Calcium and Copper Peroxides Nanocomposite for Enhanced Chemodynamic/Ion-Interference Therapy.
  1. Front Pharmacol. 2021 ;12 773909
    The Art of War: Ferroptosis and Pancreatic Cancer.
    Jiao Liu, Rui Kang, Daolin Tang.
      Pancreatic cancer is a devastating gastrointestinal cancer, characterized by late diagnosis, low treatment success rate, and poor survival prognosis. The most common pathological type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which is mainly driven by the K-Ras oncogene. Ferroptosis was originally described as Ras-dependent cell death, but is now defined as lipid peroxidation-mediated regulated necrosis, accompanied by excessive activation of the autophagy degradation pathway and limited membrane repair capacity. The impaired ferroptotic pathway is involved in many types of cancer, including PDAC. On the one hand, the chronic inflammation caused by ferroptotic damage contributes to the formation of K-Ras-driven PDAC. On the other hand, drug-induced ferroptosis is an emerging strategy to suppress tumor growth in established PDAC. In this mini-review, we outline the core process of ferroptosis, discuss the regulatory mechanism of ferroptosis in PDAC, and highlight some of the challenges of targeting ferroptosis in PDAC therapy.
    Keywords:  autophagy; ferroptosis; pancreatic cancer; targeted therapy; tumorigenesis
    DOI:  https://doi.org/10.3389/fphar.2021.773909
  2. Biomed Pharmacother. 2021 Dec 23. pii: S0753-3322(21)01351-2. [Epub ahead of print]146 112564
    Dual antisense oligonucleotide targeting miR-21/miR-155 synergize photodynamic therapy to treat triple-negative breast cancer and inhibit metastasis.
    Mengdi Shang, Yiyang Wu, Yeyang Wang, Yanfei Cai, Jian Jin, Zhaoqi Yang.
      Triple negative breast cancer (TNBC) is a greatly aggressive subtype of breast cancer with high recurrence and mortality rates. Chemotherapy as a primary treatment for cancer is limited due to toxic side effects and drug resistance. Therefore, low toxicity and more effective breast cancer therapeutic approaches are greatly desired. In this study, a strategy which using ZIF-90 nanoparticles co-deliver Ce6-anti-miR-21 and Ce6-anti-miR-155 into the tumor cells was developed. Due to the pH responsive drug release of ZIF-90, antisense oligonucleotides (anti-miRNAs) and photosensitizers are able to be efficiently released inside tumor microenvironment. The nano delivery system captures overexpressed oncogenic miRNAs while the photosensitizer Ce6 generates ROS under light irradiation to effectively induce the apoptosis of tumor cell. This combinatorial effect was verified by results showing that the purposed therapic method could effectively inhibit tumor cell proliferation and metastasis. The concept of antisense oligonucleotide combined with photodynamic therapy has great potential in cancer treatment or adjuvant therapy.
    Keywords:  Photodynamic therapy; Synergistic therapy; Triple negative breast cancer; ZIF-90; miRNA
    DOI:  https://doi.org/10.1016/j.biopha.2021.112564
  3. Anticancer Agents Med Chem. 2021 Dec 28.
    Review of therapies using TiO2 nanomaterials for increased anticancer capability.
    Noé Rodríguez-Barajas, Luis Miguel Anaya-Esparza, Zuami Villagrán-de la Mora, Jorge Alberto Sánchez-Burgos, Alejandro Pérez-Larios.
      Recently, Titanium dioxide (TiO2) has been studied as an alternative to treat cancer diseases under different activation therapies. The aim of this review was to describe the effect of TiO2 nanoparticles (NPs) on some cancer cell lines and their interaction with phototherapies such as photodynamic therapy (PDT), photothermal therapy (PTT), sonodynamic therapy (SDT), and ultraviolet therapy (UV) for anticancer treatment. The use of TiO2 combined with PDT, PTT, SDT, or UV has shown a remarkable capacity to enhance the killing of cancer cells through reactive oxygen species formation. Thus, the combination of TiO2 and activation therapies exhibited great potential and could be a viable anticancer treatment strategy. However, more studies on phototherapies in combination with TiO2 and their effects at under different experimental conditions (TiO2 concentration, type of cancer cells, and intensity and frequency of therapies) are necessary to guarantee the safe use of this kind of therapy.
    Keywords:  Titanium dioxide; alternative therapies; antiproliferative effect; cancer treatment; photodynamic therapy (PDT); photothermal therapy (PTT); sonodynamic therapy (SDT); ultraviolet therapy (UV)
    DOI:  https://doi.org/10.2174/1871520622666211228112631
  4. Adv Colloid Interface Sci. 2021 Dec 14. pii: S0001-8686(21)00223-2. [Epub ahead of print]300 102582
    Curcumin encapsulation in functional PLGA nanoparticles: A promising strategy for cancer therapies.
    Felipe da Silva Feltrin, Tamara Agner, Claudia Sayer, Liliane Maria Ferrareso Lona.
      Nanoparticles have emerged as promising drug delivery systems for the treatment of several diseases. Novel cancer therapies have exploited these particles as alternative adjuvant therapies to overcome the traditional limitations of radio and chemotherapy. Curcumin is a natural bioactive compound found in turmeric, that has been reported to show anticancer activity against several types of tumors. Despite some biological limitations regarding its absorption in the human body, curcumin encapsulation in poly(lactic-co-glycolic acid) (PLGA), a non-toxic, biodegradable and biocompatible polymer, represents an effective strategy to deliver a drug to a tumor site. Furthermore, PLGA nanoparticles can be engineered with targeting moieties to reach specific cancer cells, thus enhancing the antitumor effects of curcumin. We herein aim to bring an up-to-date summary of the recently developed strategies for curcumin delivery to different types of cancer cells through encapsulation in PLGA nanoparticles, correlating their effects with those of curcumin on the biological capabilities acquired by cancer cells (cancer hallmarks). We discuss the targeting strategies proposed for advanced curcumin delivery and the respective improvements achieved for each cancer cell analyzed, in addition to exploring the encapsulation techniques employed. The conjugation of correct encapsulation techniques with tumor-oriented targeting design can result in curcumin-loaded PLGA nanoparticles that can successfully integrate the elaborate network of development of alternative cancer treatments along with traditional ones. Finally, the current challenges and future demands to launch these nanoparticles in oncology are comprehensively examined.
    Keywords:  Cancer nanomedicine; Colloidal nanosystems; Curcumin; Functional biomaterial; PLGA; Targeting strategy
    DOI:  https://doi.org/10.1016/j.cis.2021.102582
  5. Pharmaceutics. 2021 Nov 24. pii: 1993. [Epub ahead of print]13(12):
    Nanoformulations of α-Mangostin for Cancer Drug Delivery System.
    Lisna Meylina, Muchtaridi Muchtaridi, I Made Joni, Ahmed Fouad Abdelwahab Mohammed, Nasrul Wathoni.
      Natural compounds are emerging as effective agents for the treatment of malignant diseases. The active constituent of α-mangostin from the pericarp of Garcinia mangostana L. has earned significant interest as a plant base compound with anticancer properties. Despite α-mangostin's superior properties as an anticancer agent, its applications are limited due to its poor solubility and physicochemical stability, rapid systemic clearance, and low cellular uptake. Our review aimed to summarize and discuss the nanoparticle formulations of α-mangostin for cancer drug delivery systems from published papers recorded in Scopus, PubMed, and Google Scholar. We investigated various types of α-mangostin nanoformulations to improve its anticancer efficacy by improving bioavailability, cellular uptake, and localization to specific areas These nanoformulations include nanofibers, lipid carrier nanostructures, solid lipid nanoparticles, polymeric nanoparticles, nanomicelles, liposomes, and gold nanoparticles. Notably, polymeric nanoparticles and nanomicelles can increase the accumulation of α-mangostin into tumors and inhibit tumor growth in vivo. In addition, polymeric nanoparticles with the addition of target ligands can increase the cellular uptake of α-mangostin. In conclusion, nanoformulations of α-mangostin are a promising tool to enhance the cellular uptake, accumulation in cancer cells, and the efficacy of α-mangostin as a candidate for anticancer drugs.
    Keywords:  Garcinia mangostana L.; cancer therapy; drug delivery; nanotechnology
    DOI:  https://doi.org/10.3390/pharmaceutics13121993
  6. Biomed Pharmacother. 2021 Dec 22. pii: S0753-3322(21)01354-8. [Epub ahead of print]146 112567
    Curcumin combined with photodynamic therapy, promising therapies for the treatment of cancer.
    Liguo Xie, Xiuling Ji, Qi Zhang, Yunlin Wei.
      Curcumin, a phytochemical derived from the rhizome of turmeric (Curcuma longa L.), has a broad group of substances with antibacterial, anti-inflammatory, anti-oxidant, anticancer activities. The anticancer activity of curcumin and its derivatives are mainly related to its regulation of signal transduction pathways. However, due to the low oral availability of curcumin, fast metabolism and other pharmacokinetic properties limit the application of curcumin in the treatment of cancer. Evidence suggests that curcumin combined with photodynamic therapy can overcome the limitation of curcumin's low bioavailability by acting on apoptosis pathways, such as B-cell lymphoma 2 (Bcl-2) and caspase family, and affecting cell cycle. This paper reviews the structure and pharmacokinetics of curcumin, focusing on the anticancer activity of curcumin combined with photodynamic therapy and the effects on cancer-related signal pathways.
    Keywords:  Anticancer; Apoptosis; Cell cycle; Curcumin; Mitochondria; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.biopha.2021.112567
  7. Polymers (Basel). 2021 Dec 15. pii: 4400. [Epub ahead of print]13(24):
    Polymeric Nanoparticles: Exploring the Current Drug Development and Therapeutic Insight of Breast Cancer Treatment and Recommendations.
    Ali Sartaj, Zufika Qamar, Farheen Fatima Qizilbash, Annu, Shadab Md, Nabil A Alhakamy, Sanjula Baboota, Javed Ali.
      This manuscript aims to provide the latest update on polymeric nanoparticle drug delivery system for breast cancer treatment after 2015 and how research-oriented it is based on the available research data. Therefore, the authors have chosen breast cancer which is the most frequent and common reason for mortality in women worldwide. The first-line treatment for breast cancer treatment is chemotherapy, apart from surgery, radiation and hormonal therapy. Chemotherapy is associated with lesser therapeutics and undesirable side effects and hence. In addition, drug resistance affects the therapeutic dose to the target site. Although various nano-based formulations have been developed for effective treatment, the polymeric nanoparticles effectively avoid the lacunae of conventional chemotherapy. There has been an effort made to understand the chemotherapy drugs and their conventional formulation-related problems for better targeting and effective drug delivery for breast cancer treatment. Thus, the polymeric nanoparticles as a strategy overcome the associated problems with resulting dose reduction, enhanced bioavailability, reduced side effects, etc. This present review has compiled the research reports published from 2015 to 2021 from different databases, such as PubMed, Google Scholar, ScienceDirect, which are related to breast cancer treatment in which the drug delivery of numerous chemotherapeutic agents alone or in combination, including phytoconstituents formulated into various polymer-based nanoparticles.
    Keywords:  breast cancer; chemotherapy; multi-drug resistance; phytoconstituents; polymeric nanoparticles; side effects
    DOI:  https://doi.org/10.3390/polym13244400
  8. Pharmaceutics. 2021 Dec 07. pii: 2102. [Epub ahead of print]13(12):
    Biomedical Applications and Bioavailability of Curcumin-An Updated Overview.
    Soo-In Sohn, Arumugam Priya, Boopathi Balasubramaniam, Pandiyan Muthuramalingam, Chandran Sivasankar, Anthonymuthu Selvaraj, Alaguvel Valliammai, Ravi Jothi, Subramani Pandian.
      Curcumin, a yellow-colored molecule derived from the rhizome of Curcuma longa, has been identified as the bioactive compound responsible for numerous pharmacological activities of turmeric, including anticancer, antimicrobial, anti-inflammatory, antioxidant, antidiabetic, etc. Nevertheless, the clinical application of curcumin is inadequate due to its low solubility, poor absorption, rapid metabolism and elimination. Advancements in recent research have shown several components and techniques to increase the bioavailability of curcumin. Combining with adjuvants, encapsulating in carriers and formulating in nanoforms, in combination with other bioactive agents, synthetic derivatives and structural analogs of curcumin, have shown increased efficiency and bioavailability, thereby augmenting the range of applications of curcumin. The scope for incorporating biotechnology and nanotechnology in amending the current drawbacks would help in expanding the biomedical applications and clinical efficacy of curcumin. Therefore, in this review, we provide a comprehensive overview of the plethora of therapeutic potentials of curcumin, their drawbacks in efficient clinical applications and the recent advancements in improving curcumin's bioavailability for effective use in various biomedical applications.
    Keywords:  antibiotics; anticancer agents; bioavailability; curcumin; nanomedicine; pharmaceutical formulations
    DOI:  https://doi.org/10.3390/pharmaceutics13122102
  9. Compr Physiol. 2021 Dec 29. 12(1): 2995-3044
    Renal Tubular Handling of Glucose and Fructose in Health and Disease.
    Volker Vallon, Takahiko Nakagawa.
      The proximal tubule of the kidney is programmed to reabsorb all filtered glucose and fructose. Glucose is taken up by apical sodium-glucose cotransporters SGLT2 and SGLT1 whereas SGLT5 and potentially SGLT4 and GLUT5 have been implicated in apical fructose uptake. The glucose taken up by the proximal tubule is typically not metabolized but leaves via the basolateral facilitative glucose transporter GLUT2 and is returned to the systemic circulation or used as an energy source by distal tubular segments after basolateral uptake via GLUT1. The proximal tubule generates new glucose in metabolic acidosis and the postabsorptive phase, and fructose serves as an important substrate. In fact, under physiological conditions and intake, fructose taken up by proximal tubules is primarily utilized for gluconeogenesis. In the diabetic kidney, glucose is retained and gluconeogenesis enhanced, the latter in part driven by fructose. This is maladaptive as it sustains hyperglycemia. Moreover, renal glucose retention is coupled to sodium retention through SGLT2 and SGLT1, which induces secondary deleterious effects. SGLT2 inhibitors are new anti-hyperglycemic drugs that can protect the kidneys and heart from failing independent of kidney function and diabetes. Dietary excess of fructose also induces tubular injury. This can be magnified by kidney formation of fructose under pathological conditions. Fructose metabolism is linked to urate formation, which partially accounts for fructose-induced tubular injury, inflammation, and hemodynamic alterations. Fructose metabolism favors glycolysis over mitochondrial respiration as urate suppresses aconitase in the tricarboxylic acid cycle, and has been linked to potentially detrimental aerobic glycolysis (Warburg effect). © 2022 American Physiological Society. Compr Physiol 12:2995-3044, 2022.
    DOI:  https://doi.org/10.1002/cphy.c210030
  10. Mol Cell. 2021 Dec 20. pii: S1097-2765(21)01038-8. [Epub ahead of print]
    Persister cancer cells: Iron addiction and vulnerability to ferroptosis.
    Raphaël Rodriguez, Stuart L Schreiber, Marcus Conrad.
      Ferroptosis is a unique type of non-apoptotic cell death resulting from the unrestrained occurrence of peroxidized phospholipids, which are subject to iron-mediated production of lethal oxygen radicals. This cell death modality has been detected across many organisms, including in mammals, where it can be used as a defense mechanism against pathogens or even harnessed by T cells to sensitize tumor cells toward effective killing. Conversely, ferroptosis is considered one of the main cell death mechanisms promoting degenerative diseases. Emerging evidence suggests that ferroptosis represents a vulnerability in certain cancers. Here, we critically review recent advances linking ferroptosis vulnerabilities of dedifferentiating and persister cancer cells to the dependency of these cells on iron, a potential Achilles heel for small-molecule intervention. We provide a perspective on the mechanisms reliant on iron that contribute to the persister cancer cell state and how this dependency may be exploited for therapeutic benefits.
    DOI:  https://doi.org/10.1016/j.molcel.2021.12.001
  11. Langmuir. 2021 Dec 31.
    Smart Tumor Microenvironment-Responsive Nano-Prodrug for Disulfiram Toxification In Situ and the Exploration of Lethal Mechanisms in Cells.
    Ying Zhang, Guohua Qi, Xiaozhang Qu, Bo Wang, Kongshuo Ma, Yongdong Jin.
      Disulfiram (DSF) is a clinical antialcoholism drug that has been confirmed to show anticancer bioactivity after chelating with Cu2+. Therefore, how to co-deliver DSF and Cu2+ to tumor tissues and generate a smart response to the tumor microenvironment (TME) are the focus of repurposing DSF for the effective treatment of cancer. Herein, we fabricated facilely a smart nanosystem by coating tannic acid (TA) and Cu2+ network on DSF, denoted as DSF@TA-Cu, which responses well to TME and forms CuET complex in situ. In such a way, besides the chemotherapy effect of CuET, the anticancer efficacy of the resulting nano-prodrug can further be augmented by a continuous Fenton-like reaction. We then tested the cytotoxicity DSF@TA-Cu with normal and cancerous cell lines. Finally, by constructing mitochondria-targeted nanoprobes, we monitored the changes in mitochondrial metabolism and explored the lethal mechanisms in A549 cells. We found that DSF@TA-Cu showed higher toxicity to cancerous cells. By analyzing the fluorescence images and surface-enhanced Raman scattering (SERS) spectra of mitochondria, we found that the DNA damage and the decrease in mitochondrial membrane potential (MMP) were closely related to the generation and accumulation of reactive oxygen species (ROS). Although activated related pathways try to counteract the effects of elevation of ROS, excessive ROS inevitably leads to apoptosis of cancer cells.
    DOI:  https://doi.org/10.1021/acs.langmuir.1c03256
  12. Curr Med Sci. 2021 Dec 26.
    Curcumin Synergizes with Cisplatin to Inhibit Colon Cancer through Targeting the MicroRNA-137-Glutaminase Axis.
    Wen-Hui Fan, Feng-Chun Wang, Zhi Jin, Lin Zhu, Jian-Xin Zhang.
       OBJECTIVE: Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies world-wide. Currently, surgery, radiotherapy and chemotherapy are clinically applied as common approaches for CRC patients. Cisplatin is one of the most frequently used chemotherapy drugs for diverse cancers. Although chemotherapeutic strategies have improved the prognosis and survival of cancer patients, development of cisplatin resistance has led to cancer recurrence. Curcumin, isolated from turmeric, has been used as an effective anti-cancer agent. However, the molecular mechanisms for curcumin-mediated cisplatin sensitivity of CRC have not been elucidated. This study aimed to investigate the effects of curcumin treatment on cisplatin-resistant CRC cells.
    METHODS: Expression levels of miRNAs and mRNAs were determined by qRT-PCR. Protein expression levels were detected by Western blotting. Cell responses to curcumin treatments were evaluated by MTT assay, Clonogenic assay and Annexin V apoptosis assay. The glutamine metabolism of colon cancer cells was assessed by glutamine uptake and glutaminase (GLS) activity. The binding of miR-137 on 3' UTR of GLS was validated by Western blotting and luciferase assay.
    RESULTS: Results demonstrated that curcumin significantly synergized with cisplatin (combination index <1) to suppress proliferation of colon cancer cells compared with curcumin or cisplatin alone. Moreover, from the established cisplatin-resistant cell line (HT-29), glutamine metabolism was remarkedly elevated in cisplatin-resistant CRC cells that displayed a glutamine addictive phenotype. Furthermore, curcumin treatments attenuated glutamine metabolism in colon cancer cells. Under low glutamine supply, colon cancer cells showed less sensitivity to curcumin. Using a microRNA (miRNA) microArray assay, miR-137, a tumor suppressor in colon cancer, was significantly induced by curcumin treatments in CRC cells. Bioinformatics analysis and a luciferase assay illustrated miR-137 directly targeted the 3' UTR of GLS mRNA. Rescue experiments demonstrated that miR-137-induced cisplatin sensitization was through targeting of GLS. Finally, curcumin treatment overcame cisplatin resistance through miR-137-mediated glutamine inhibition.
    CONCLUSION: Collectively, these results indicate that curcumin could be clinically applied as an anti-chemoresistance approach against CRC by modulating miR-137-inhibited glutamine metabolism.
    Keywords:  cisplatin resistant; curcumin; glutaminase; glutamine metabolism; microRNA-137
    DOI:  https://doi.org/10.1007/s11596-021-2469-0
  13. Polymers (Basel). 2021 Dec 16. pii: 4418. [Epub ahead of print]13(24):
    Reactive Oxygen Species-Responsive Miktoarm Amphiphile for Triggered Intracellular Release of Anti-Cancer Therapeutics.
    Hyun-Chul Kim, Eunjoo Kim, Se Guen Lee, Sung Jun Lee, Sang Won Jeong, Young Jae Lee, Mi Kyung Kwon, Seong-Kyoon Choi, Jun Seong Hwang, Eunsook Choi.
      Reactive oxygen species (ROS)-responsive nanocarriers have received considerable research attention as putative cancer treatments because their tumor cell targets have high ROS levels. Here, we synthesized a miktoarm amphiphile of dithioketal-linked ditocopheryl polyethylene glycol (DTTP) by introducing ROS-cleavable thioketal groups as linkers between the hydrophilic and hydrophobic moieties. We used the product as a carrier for the controlled release of doxorubicin (DOX). DTTP has a critical micelle concentration (CMC) as low as 1.55 μg/mL (4.18 × 10-4 mM), encapsulation efficiency as high as 43.6 ± 0.23% and 14.6 nm particle size. The DTTP micelles were very responsive to ROS and released their DOX loads in a controlled manner. The tocopheryl derivates linked to DTTP generated ROS and added to the intracellular ROS in MCF-7 cancer cells but not in HEK-293 normal cells. In vitro cytotoxicity assays demonstrated that DOX-encapsulated DTTP micelles displayed strong antitumor activity but only slightly increased apoptosis in normal cells. This ROS-triggered, self-accelerating drug release device has high therapeutic efficacy and could be a practical new strategy for the clinical application of ROS-responsive drug delivery systems.
    Keywords:  ROS-responsive; drug delivery system; miktoarm amphiphile; tocopheryl derivate; tumor therapy
    DOI:  https://doi.org/10.3390/polym13244418
  14. Front Nutr. 2021 ;8 788929
    Effects of Syringic Acid on Apoptosis, Inflammation, and AKT/mTOR Signaling Pathway in Gastric Cancer Cells.
    Jinjin Pei, Periyannan Velu, Mohsen Zareian, Zili Feng, Annamalai Vijayalakshmi.
      Gastric cancer is one of the most common cancer and deadly disease worldwide. Despite substantial advances made in the treatment of gastric cancer, existing therapies still encounter bottlenecks. Chemotherapy, for instance, could lead to serious side effects, high drug resistance and treatment failure. Phytochemical-derived compounds from plants offer novel strategies as potent drug molecules in cancer therapy. Given the low toxicity and higher tolerance rate of naturally occurring compounds, the present study evaluated the effects of syringic acid on cytotoxicity, oxidative stress, mitochondrial membrane potential, apoptosis, and inflammatory responses in gastric cancer cell line (AGS). AGS cells were treated with various concentrations (5-40 μg/mL) of syringic acid for 24 h, after which cytotoxicity was analyzed. Reactive Oxygen Species (ROS), antioxidant enzyme activities, mitochondrial membrane potential (MMP, Δψ m), cell morphologies, the expression of apoptotic markers and protein expression patterns were also investigated. Results indicated that syringic acid-treated cells developed anti-cancer activities by losing MMP, cell viability, and enhancing intracellular ROS. Syringic acid selectively developed apoptosis in a dose-dependent manner via enhanced regulation of caspase-3, caspase-9 and Poly ADP-ribose Polymerase (PARP) whereas decreasing the expression levels of p53 and BCL-2. Syringic acid also lowered activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) whereas Thio Barbituric Acid Reactive Substances (TBARS) increased. Syringic acid suppressed gastric cancer cell proliferation, inflammation, and induced apoptosis by upregulating mTOR via AKT signaling pathway. The study suggests syringic acid may constitute a promising chemotherapeutic candidate for gastric cancer treatment. Our study is the first report on the anti-cancer effects of syringic acid against gastric cancer cells via apoptosis, inhibition of inflammation, and the suppression of the mTOR/AKT signaling pathway.
    Keywords:  antitumor activity; apoptosis; cancer cell lines; drug resistance; molecular mechanism; phytochemical therapy; plant-derived phytochemicals; therapeutic compounds
    DOI:  https://doi.org/10.3389/fnut.2021.788929
  15. Drug Resist Updat. 2021 Dec 16. pii: S1368-7646(21)00057-1. [Epub ahead of print] 100797
    Impact of cancer metabolism on therapy resistance - Clinical implications.
    Ana Cristina Gonçalves, Elena Richiardone, Joana Jorge, Bárbara Polónia, Cristina P R Xavier, Iris Chiara Salaroglio, Chiara Riganti, M Helena Vasconcelos, Cyril Corbet, Ana Bela Sarmento-Ribeiro.
      Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. Thus, there is an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options. Apart from mutation-driven resistance mechanisms, tumor microenvironment (TME) conditions generate an intratumoral phenotypic heterogeneity that supports disease progression and dismal outcomes. Tumor cell metabolism is a prototypical example of dynamic, heterogeneous, and adaptive phenotypic trait, resulting from the combination of intrinsic [(epi)genetic changes, tissue of origin and differentiation dependency] and extrinsic (oxygen and nutrient availability, metabolic interactions within the TME) factors, enabling cancer cells to survive, metastasize and develop resistance to anticancer therapies. In this review, we summarize the current knowledge regarding metabolism-based mechanisms conferring adaptive resistance to chemo-, radio-and immunotherapies as well as targeted therapies. Furthermore, we report the role of TME-mediated intratumoral metabolic heterogeneity in therapy resistance and how adaptations in amino acid, glucose, and lipid metabolism support the growth of therapy-resistant cancers and/or cellular subpopulations. We also report the intricate interplay between tumor signaling and metabolic pathways in cancer cells and discuss how manipulating key metabolic enzymes and/or providing dietary changes may help to eradicate relapse-sustaining cancer cells. Finally, in the current era of personalized medicine, we describe the strategies that may be applied to implement metabolic profiling for tumor imaging, biomarker identification, selection of tailored treatments and monitoring therapy response during the clinical management of cancer patients.
    Keywords:  Cancer metabolism; Glycolysis; Intratumor heterogeneity; Metabolic plasticity; Oxidative phosphorylation; Therapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.drup.2021.100797
  16. Drug Deliv. 2022 Dec;29(1): 138-148
    Hypoxia responsive nano-drug delivery system based on angelica polysaccharide for liver cancer therapy.
    Xue Liu, Zhenfeng Wu, Chunjing Guo, Huimin Guo, Yanguo Su, Qiang Chen, Changgang Sun, Qingming Liu, Daquan Chen, Hongjie Mu.
      Based on the tumor hypoxic microenvironment and the new programmed cell death mode of combined ferroptosis, an angelica polysaccharide-based nanocarrier material was synthesized. The polymer contains hydrophilic angelica polysaccharide (ASP) that is linked by azobenzene (AZO) linker with ferrocene (Fc), and then the side chain was covalently modified with arachidonic acid (AA). It was postulated that the polymer micelles could work as an instinctive liver targeting drug delivery carrier, owing to the existence of ASP with liver targeting. Moreover, the aim was to engineer hypoxia-responsive polymer micelles which was modified by AA, for selective enhancement of ferroptosis in solid tumor, via diminishing glutathione (GSH) under hypoxia. Finally, we synthesized the amphiphilic polymer micelles AA/ASP-AZO-Fc (AAAF) by self-assembling. The structure of AAAF was confirmed by 1H-NMR and FT-IR. Then, we exemplified the hydrophobic medication curcumin into polymer micelles AAAF@Cur, which has smooth and regular spheres. In vitro release test affirmed that AAAF@Cur can achieve hypoxia response to drug release. In addition, a series of cell experiments confirmed that hypoxia could enhance cell uptake and effectively improve the proliferation inhibitory activity of HepG2 cells. In conclusion, AAAF, as an effective cell carrier, is expected to develop in sensitizing ferroptosis and anti-tumor.
    Keywords:  Hypoxia responsive; angelica polysaccharide; ferroptosis; liver cancer; micelle
    DOI:  https://doi.org/10.1080/10717544.2021.2021324
  17. Pharmaceutics. 2021 Dec 13. pii: 2145. [Epub ahead of print]13(12):
    NIR Light-Triggered Chemo-Phototherapy by ICG Functionalized MWNTs for Synergistic Tumor-Targeted Delivery.
    Lu Tang, Aining Zhang, Yijun Mei, Qiaqia Xiao, Xiangting Xu, Wei Wang.
      The combinational application of photothermal therapy (PTT), chemotherapy, and nanotechnology is a booming therapeutic strategy for cancer treatment. Multi-walled carbon nanotube (MWNT) is often utilized as drug carrier in biomedical fields with excellent photothermal properties, and indocyanine green (ICG) is a near-infrared (NIR) dye approved by FDA. In addition, ICG is also a photothermal agent that can strongly absorb light energy for tumor ablation. Herein, we explored a synergistic strategy by connecting MWNT and a kind of ICG derivate ICG-NH2 through hyaluronic acid (HA) that possesses CD44 receptor targeting ability, which largely enhanced the PTT effect of both MWNT and ICG-NH2. To realize the synergistic therapeutic effect of chemotherapy and phototherapy, doxorubicin (DOX) was attached on the wall of MWNT via π-π interaction to obtain the final MWNT-HA-ICG/DOX nanocomplexes. Both in vitro and in vivo experiments verified the great therapeutic efficacy of MWNT-HA-ICG/DOX nanocomplexes, which was characterized by improved photothermal performance, strengthened cytotoxicity, and elevated tumor growth inhibition based on MCF-7 tumor models. Therefore, this synergistic strategy we report here might offer a new idea with promising application prospect for cancer treatment.
    Keywords:  cancer treatment; indocyanine green; multi-walled carbon nanotube; photothermal therapy; synergistic strategy; targeted drug delivery
    DOI:  https://doi.org/10.3390/pharmaceutics13122145
  18. Toxicol Res (Camb). 2021 Dec;10(6): 1077-1084
    Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment.
    Qiang Wang, Jing Wang, Jiayou Wang, Xiaoli Ju, Heng Zhang.
      Shikonin is one of the major bioactive components of Lithospermum erythrorhizon. It has a good killing effect in a variety of tumor cells. Its antitumor effect involves multiple targets and pathways and has received extensive attention and study in recent years. In this review, we systematically review recent progress in determining the antitumor mechanism of shikonin and its derivatives, specifically their induction of reactive oxygen species production, inhibition of EGFR and PI3K/AKT signaling pathway activation, inhibition of angiogenesis and induction of apoptosis and necroptosis. We also discuss the application of nanoparticles loaded with shikonin in the targeted therapy of various cancers. Finally, we suggest new strategies for the clinical application of shikonin and its derivatives.
    Keywords:  antitumor; apoptosis; nanoparticles; reactive oxygen species; shikonin
    DOI:  https://doi.org/10.1093/toxres/tfab107
  19. Int J Pharm. 2021 Dec 24. pii: S0378-5173(21)01226-6. [Epub ahead of print] 121420
    Bioinspired synthesis of protein/polysaccharide-decorated folate as a nanocarrier of curcumin to potentiate cancer therapy.
    Nihal S Elbialy, Samia F Aboushoushah, Noha M Sayed.
      Curcumin is a promising anticancer agent, but its clinical utilization has been hindered by its low solubility and bioaccessibility. To overcome these obstacles, we developed a natural protein-polysaccharide nanocomplex made from casein nanoparticles coated with a double layer of alginate and chitosan and decorated with folic acid (fCs-Alg@CCasNPs) for use as a nanocarrier for curcumin. The developed nanoformulation showed a drug encapsulation efficiency = 75%. The measured size distribution of fCs-Alg@CCasNPs was 333.8± 62.35nm with a polydispersity index (PDI) value of 0.179. The recorded zeta potential value of fCs-Alg@CCasNPs was 28.5mV. Morphologically, fCs-Alg@CCasNPs appeared spherical, as shown by transmission electron microscopy (TEM). The successful preparation of fCs-Alg@CCasNPs was confirmed by Fourier transform infrared (FTIR) spectroscopy of all the constituents forming the nanoformulation. Further in vitro investigations indicated the stability of fCs-Alg@CCasNPs as well as their controlled and sustained release of curcumin in the tumor microenvironment. Compared with free curcumin, fCs-Alg@CCasNPs induced a higher cytotoxic effect against a pancreatic cancer cell line. The in vivo pharmacokinetics of fCs-Alg@CCasNPs showed a significant AUC0-24 = 2307 ng.h/ml compared to 461 ng.h/ml of free curcumin; these results indicated high curcumin bioavailability in plasma. The in vivo results of tumor weight, the amount of DNA damage measured by comet assay and histopathological examination revealed that treating mice with fCs-Alg@CCasNPs (either intratumorally or intraperitonially) prompted higher therapeutic efficacy against Ehrlich carcinoma than treatment with free curcumin. Therefore, the incorporation of curcumin with protein/polysaccharide/folate is an innovative approach that can synergistically enhance curcumin bioavailability and potentiate cancer therapy with considerable biosafety.
    Keywords:  Curcumin; alginate-chitosan; cancer; casein nanocomplex; drug delivery; surface modification
    DOI:  https://doi.org/10.1016/j.ijpharm.2021.121420
  20. Drug Deliv. 2022 Dec;29(1): 128-137
    A pH-responsive complex based on supramolecular organic framework for drug-resistant breast cancer therapy.
    Yun-Chang Zhang, Pei-Yu Zeng, Zhi-Qiang Ma, Zi-Yue Xu, Ze-Kun Wang, Beibei Guo, Feng Yang, Zhan-Ting Li.
      Chemotherapy is one of the main ways to treat breast cancer clinically. However, the multidrug resistance to anti-tumor drugs limits their clinical use. To overcome these drawbacks, development of drug delivery systems (DDSs) has attracted more and more attention in cancer therapy. At present, the preparation and purification process are complicated for many reported DDSs, while clinic calls for new DDSs that are more convenient for preparation. Here, a new pH-responsive supramolecular organic framework drug delivery complex loading doxorubicin (DOX) is fabricated. Anti-tumor activity of the system in vitro was investigated by cell cytotoxicity, uptake assay, and cell apoptosis analysis. The anti-tumor activity in vivo was investigated by inspecting nude mice body weight, tumor volume, and weight, also a preliminary mechanism probe was conducted by HE and TUNEL staining. The DOX@SOF displayed high stability, good biocompatibility, and pH regulated drug release. At acid condition, the hydrazone bonds would be broken, which result in the dissociation of SOF, and then the drugs would be released from the system. Furthermore, DOX@SOF enhanced cellular internalization. Both in vitro and in vivo experiments reflected that DOX@SOF could enhance the anti-tumor activity of DOX for the MCF-7/ADR tumor cells and tumors. This study provides a highly efficient strategy to prepare stimulus-responsive supramolecular drug delivery complex for treatment of drug-resistant cancer, the results presented inspiring scientific interests in exploring new drug delivery strategy and reversing multi-drug resistance for clinical chemotherapy.
    Keywords:  Supramolecular organic framework; breast cancer; doxorubicin; drug delivery system; drug resistance
    DOI:  https://doi.org/10.1080/10717544.2021.2021325
  21. Pharmaceutics. 2021 Dec 08. pii: 2120. [Epub ahead of print]13(12):
    Signaling Pathway Inhibitors, miRNA, and Nanocarrier-Based Pharmacotherapeutics for the Treatment of Lung Cancer: A Review.
    Shadab Md, Nabil A Alhakamy, Shahid Karim, Gamal A Gabr, Mohammad Kashif Iqubal, Samar S A Murshid.
      Lung cancer is one of the most commonly diagnosed cancers and is responsible for a large number of deaths worldwide. The pathogenic mechanism of lung cancer is complex and multifactorial in origin. Thus, various signaling pathways as targets for therapy are being examined, and many new drugs are in the pipeline. However, both conventional and target-based drugs have been reported to present significant adverse effects, and both types of drugs can affect the clinical outcome in addition to patient quality of life. Recently, miRNA has been identified as a promising target for lung cancer treatment. Therefore, miRNA mimics, oncomiRs, or miRNA suppressors have been developed and studied for possible anticancer effects. However, these miRNAs also suffer from the limitations of low stability, biodegradation, thermal instability, and other issues. Thus, nanocarrier-based drug delivery for the chemotherapeutic drug delivery in addition to miRNA-based systems have been developed so that existing limitations can be resolved, and enhanced therapeutic outcomes can be achieved. Thus, this review discusses lung cancer's molecular mechanism, currently approved drugs, and their adverse effects. We also discuss miRNA biosynthesis and pathogenetic role, highlight pre-clinical and clinical evidence for use of miRNA in cancer therapy, and discussed limitations of this therapy. Furthermore, nanocarrier-based drug delivery systems to deliver chemotherapeutic drugs and miRNAs are described in detail. In brief, the present review describes the mechanism and up-to-date possible therapeutic approaches for lung cancer treatment and emphasizes future prospects to bring these novel approaches from bench to bedside.
    Keywords:  angiogenesis; apoptosis; lung cancer; miRNA; oncomiRs
    DOI:  https://doi.org/10.3390/pharmaceutics13122120
  22. Drug Resist Updat. 2021 Dec 16. pii: S1368-7646(21)00056-X. [Epub ahead of print] 100796
    Anticancer drug resistance: An update and perspective.
    Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang.
      Driver mutations promote initiation and progression of cancer. Pharmacological treatment can inhibit the action of the mutant protein; however, drug resistance almost invariably emerges. Multiple studies revealed that cancer drug resistance is based upon a plethora of distinct mechanisms. Drug resistance mutations can occur in the same protein or in different proteins; as well as in the same pathway or in parallel pathways, bypassing the intercepted signaling. The dilemma that the clinical oncologist is facing is that not all the genomic alterations as well as alterations in the tumor microenvironment that facilitate cancer cell proliferation are known, and neither are the alterations that are likely to promote metastasis. For example, the common KRasG12C driver mutation emerges in different cancers. Most occur in NSCLC, but some occur, albeit to a lower extent, in colorectal cancer and pancreatic ductal carcinoma. The responses to KRasG12C inhibitors are variable and fall into three categories, (i) new point mutations in KRas, or multiple copies of KRAS G12C which lead to higher expression level of the mutant protein; (ii) mutations in genes other than KRAS; (iii) original cancer transitioning to other cancer(s). Resistance to adagrasib, an experimental antitumor agent exerting its cytotoxic effect as a covalent inhibitor of the G12C KRas, indicated that half of the cases present multiple KRas mutations as well as allele amplification. Redundant or parallel pathways included MET amplification; emerging driver mutations in NRAS, BRAF, MAP2K1, and RET; gene fusion events in ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN tumor suppressors. In the current review we discuss the molecular mechanisms underlying drug resistance while focusing on those emerging to common targeted cancer drivers. We also address questions of why cancers with a common driver mutation are unlikely to evolve a common drug resistance mechanism, and whether one can predict the likely mechanisms that the tumor cell may develop. These vastly important and tantalizing questions in drug discovery, and broadly in precision medicine, are the focus of our present review. We end with our perspective, which calls for target combinations to be selected and prioritized with the help of the emerging massive compute power which enables artificial intelligence, and the increased gathering of data to overcome its insatiable needs.
    Keywords:  Cancer; Chemotherapy; Chromatin accessibility; Drug discovery; Drug resistance; Epigenetics; Interactome; MAPK; Precision medicine; Single cell; Transcriptomics
    DOI:  https://doi.org/10.1016/j.drup.2021.100796
  23. ACS Nano. 2021 Dec 28.
    A Multifunctional Layered Nickel Silicate Nanogenerator of Synchronous Oxygen Self-supply and Superoxide Radical Generation for Hypoxic Tumor Therapy.
    Xiaoyu Huang, Wei Zhang, Yaowei Peng, Lu Gao, Fu Wang, Lan Wang, Xunbin Wei.
      Oxygen consumption but hypoxic tumor environment has been considered as the major obstacle in photodynamic therapy. Although oxygen-supplied strategies have been reported extensively, they still suffer from the complicated system and unsatisfied PDT efficiency. Herein, one-component layered nickel silicate nanoplatforms (LNS NPs) are successfully synthesized using natural vermiculite as the silica source, which can simultaneously supply oxygen (O2) and generate superoxide radicals (O2-•) under near-infrared irradiation. The appropriate electron band structure endows LNS NPs with attractive optical properties, where the bandgap edges determine the performance of redox activity and spectral response characteristic. Evidenced by both in vitro and in vivo investigations, LNS NPs can generate sufficient superoxide radicals under 660 nm laser irradiation to induce tumor cell apoptosis even in a severe hypoxic environment, which benefits from self-supplied oxygen. Besides, the photoacoustic oxy-hem imaging and histologic assay further demonstrated that the generated oxygen can relieve the inherent intratumoral hypoxia. Therefore, LNS NPs not only serve as superoxide radical generator but also produce oxygen to modulate hypoxia, suggesting that it can be used for superoxide radical-mediated photodynamic therapy with enhanced antitumor effect.
    Keywords:  hypoxic tumor; layered nickel silicate; oxygen self-supply; photodynamic therapy; superoxide radical generation
    DOI:  https://doi.org/10.1021/acsnano.1c08580
  24. Curr Cancer Drug Targets. 2021 Dec 31.
    The Potential of Natural Products in the Treatment of Triple-Negative Breast Cancer.
    Danny Yu Jia Ke, Sara El-Sahli, Lisheng Wang.
      Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks receptors for targeted therapy. Consequently, chemotherapy is currently the mainstay of systemic treatment options. However, the enrichment of cancer stem cells (CSC, a subpopulation with stem-cell characteristics and tumor-initiating propensity) promotes chemo-resistance and tumorigenesis, resulting in cancer recurrence and relapse. Furthermore, toxic side effects of chemotherapeutics reduce patient wellbeing. Natural products, specifically compounds derived from plants, have the potential to treat TNBC and target CSCs by inhibiting CSC signaling pathways. Literature evidence from six promising compounds were reviewed, including sulforaphane, curcumin, genistein, resveratrol, lycopene, and epigallocatechin-3-gallate. These compounds have been shown to promote cell cycle arrest and apoptosis in TNBC cells. They also could inhibit the epithelial-mesenchymal transition (EMT) that plays an important role in metastasis. In addition, those natural compounds have been found to inhibit pathways important for CSCs, such as NF-κB, PI3K/Akt/mTOR, Notch 1, Wnt/β-catenin, and YAP. Clinicals trials conducted on these compounds have shown varying degrees of effectiveness. Epidemiological case-control studies for the compounds commonly consumed in certain human populations have also been summarized. While in vivo and in vitro data are promising, further basic and clinical investigations are required. Likely, natural products in combination with other drugs may hold great potential to improve TNBC treatment efficacy and patient outcomes.
    Keywords:  Breast cancer; apoptosis; cancer stem cell; metastasis; natural compounds; triple-negative breast cancer
    DOI:  https://doi.org/10.2174/1568009622666211231140623
  25. Drug Metab Pharmacokinet. 2021 Oct 15. pii: S1347-4367(21)00046-X. [Epub ahead of print]42 100425
    Delivery of small interfering RNAs by nanovesicles for cancer therapy.
    Supusson Pengnam, Samarwadee Plianwong, Boon-Ek Yingyongnarongkul, Prasopchai Patrojanasophon, Praneet Opanasopit.
      Small interfering ribonucleic acids (siRNAs) are originally recognized as an intermediate of the RNA interference (RNAi) pathway. They can inhibit or silence various cellular pathways by knocking down specific messenger RNA molecules. In cancer cells, siRNAs can suppress the expression of several multidrug-resistant genes, leading to the increased deposition of chemotherapeutic drugs at the tumor site. siRNA therapy can be used to selectively increase apoptosis of cancer cells or activate an immune response to the cancer. However, delivering siRNAs to the targeted location is the main limitation in achieving safe and effective delivery of siRNAs. This review highlights some representative examples of nonviral delivery systems, especially nanovesicles such as exosomes, liposomes, and niosomes. Nanovesicles can improve the delivery of siRNAs by increasing their intracellular delivery, and they have demonstrated excellent potential for cancer therapy. This review focuses on recent discoveries of siRNA targets for cancer therapy and the use of siRNAs to successfully silence these targets. In addition, this review summarizes the recent progress in designing nanovesicles (liposomes or niosomes) for siRNA delivery to cancer cells and the effects of a combination of anticancer drugs and siRNA therapy in cancer therapy.
    Keywords:  Anti-apoptotic siRNA; Cancer therapy; Nanovesicles; Niosomes; siRNA delivery
    DOI:  https://doi.org/10.1016/j.dmpk.2021.100425
  26. Curr Drug Deliv. 2021 Dec 29.
    Self-assembled tocopherol-albumin nanoparticles with full biocompatibility for chemo-photothermal therapy against breast cancer.
    Haijun Shen, Qianqian Gao, Tingting Liu, Haoran Wang, Ran Zhang, Jie Zhou, Sihui Ding, Yang Ye, Zhenhua Sun.
       BACKGROUND: The combination of photothermal therapy (PTT) and chemotherapy has proven to be a promising strategy for cancer treatment. Various nanomaterials have shown great potential in combination therapy, including gold, graphene oxide, iron oxide, and other nanoparticles. However, their undefinable toxicity in vivo greatly slowed down their development for clinical applications.
    OBJECTIVE: The present work aimed to develop a multifunctional nanoparticle for chemo-photothermal therapy composed of acknowledged biocompatible materials.
    METHODS: A novel biocompatible nanoparticle (HIT-NPs) was self-assembled through the intrinsic interaction between D-α-tocopherol Succinate (TOS), human serum albumin (HSA) and indocyanine green (ICG). Doxorubicin (DOX) was then loaded due to the ion pairing between DOX and TOS. The feasibility of combined chemo-photothermal therapy induced by DOX-loaded HIT-NPs was carefully evaluated.
    RESULTS: In vitro, HIT-NPs showed no cytotoxicity on human normal liver cells (HL-7702 cells) but obvious killing effects murine breast cancer cells (4T1 cells). The combined chemo-photothermal therapeutic effect on 4T1 cells was successfully obtained. DOX-loaded HIT-NPs could effectively accumulate in 4T1 subcutaneous tumors after intravenous injection, and the tumor temperature rapidly increased under laser exposure, indicating the feasibility of PTT in vivo.
    CONCLUSION: The self-assembled HIT-NPs could provide a promising platform for combined chemo-photothermal cancer therapy with full biocompatibility.
    Keywords:  Combination therapy; albumin nanoparticles; biocompatibility; chemotherapy; photothermal therapy; tocopherol
    DOI:  https://doi.org/10.2174/1567201819666211229120611
  27. Pharmaceutics. 2021 Nov 29. pii: 2039. [Epub ahead of print]13(12):
    Receptor-Mediated Targeted Delivery of Surface-ModifiedNanomedicine in Breast Cancer: Recent Update and Challenges.
    Md Rizwanullah, Mohammad Zaki Ahmad, Mohammed M Ghoneim, Sultan Alshehri, Syed Sarim Imam, Shadab Md, Nabil A Alhakamy, Keerti Jain, Javed Ahmad.
      Breast cancer therapeutic intervention continues to be ambiguous owing to the lack of strategies for targeted transport and receptor-mediated uptake of drugs by cancer cells. In addition to this, sporadic tumor microenvironment, prominent restrictions with conventional chemotherapy, and multidrug-resistant mechanisms of breast cancer cells possess a big challenge to even otherwise optimal and efficacious breast cancer treatment strategies. Surface-modified nanomedicines can expedite the cellular uptake and delivery of drug-loaded nanoparticulate constructs through binding with specific receptors overexpressed aberrantly on the tumor cell. The present review elucidates the interesting yet challenging concept of targeted delivery approaches by exploiting different types of nanoparticulate systems with multiple targeting ligands to target overexpressed receptors of breast cancer cells. The therapeutic efficacy of these novel approaches in preclinical models is also comprehensively discussed in this review. It is concluded from critical analysis of related literature that insight into the translational gap between laboratories and clinical settings would provide the possible future directions to plug the loopholes in the process of development of these receptor-targeted nanomedicines for the treatment of breast cancer.
    Keywords:  breast cancer; multidrug resistance; nanoparticle; receptor-mediated; surface-modification; targeted delivery
    DOI:  https://doi.org/10.3390/pharmaceutics13122039
  28. Methods Mol Biol. 2022 ;2445 305-328
    Methodological Approaches for Assessing Metabolomic Changes in Glioblastomas.
    Trang T T Nguyen, Enyuan Shang, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.
      Glioblastoma (GBM), a highly malignant primary brain tumor, inevitably leads to death. In the last decade, a variety of novel molecular characteristics of GBMs were unraveled. The identification of the mutation in the IDH1 and less commonly IDH2 gene was surprising and ever since has nurtured research in the field of GBM metabolism. While initially thought that mutated IDH1 were to act as a loss of function mutation it became clear that it conferred the production of an oncometabolite that in turn substantially reprograms GBM metabolism. While mutated IDH1 represents truly the tip of the iceberg, there are numerous other related observations in GBM that are of significant interest to the field, including the notion that oxidative metabolism appears to play a more critical role than believed earlier. Metabolic zoning is another important hallmark of GBM since it was found that the infiltrative margin that drives GBM progression reveals enrichment of fatty acid derivatives. Consistently, fatty acid metabolism appears to be a novel therapeutic target for GBM. How metabolism in GBM intersects is another pivotal issue that appears to be important for its progression and response and resistance to therapies. In this review, we will summarize some of the most relevant findings related to GBM metabolism and cell death and how these observations are influencing the field. We will provide current approaches that are applied in the field to measure metabolomic changes in GBM models, including the detection of unlabeled and labeled metabolites as well as extracellular flux analysis.
    Keywords:  Cell death; Glioblastoma; IDH1; Metabolic reprogramming; Metabolism
    DOI:  https://doi.org/10.1007/978-1-0716-2071-7_19
  29. Nanotechnology. 2021 Dec 28.
    Co-delivery of paclitaxel and doxorubicin using polypeptide-engineered nanogels for combination therapy of tumor.
    Jie Yang, Rui-Mei Jin, Shen-Yan Wang, Xiao-Ting Xie, Wei Hu, Hong-Feng Tang, Bo Liu.
      Loading of chemotherapeutic agents into nanoparticles has been demonstrated to be an effective strategy for cancer therapy. However, simultaneous delivery of different functional drugs to tumor sites for chemotherapy still remains challenging. In this study, nanogels formed by an engineered coiled-coil polypeptide PC10A were designed and prepared as a carrier for co-delivery of paclitaxel (PTX) and doxorubicin (DOX) through ultrasonic treatment and electrostatic adsorption. The drug loading content and encapsulation efficiency of PTX and DOX in the PC10A/PTX/DOX nanogels were 5.98 wt.%, 70 wt.%, and 8.55 wt.%, 83 wt.%, respectively. Because the polypeptide PC10A was non-toxic and biodegradable, the PC10A/PTX/DOX nanogels exhibited good biocompatibility. The in vitro and in vivo antitumor experiments showed that the PC10A/PTX/DOX nanogels possessed obviously synergistic therapy effect of tumors and lower side effects compared with free PTX/DOX. Therefore, the PC10A/PTX/DOX nanogels are promising to provide a new strategy for combination therapy of different functional drugs.
    Keywords:  chemotherapy; co-delivery; engineered polypeptide; nanogel; synergistic therapy
    DOI:  https://doi.org/10.1088/1361-6528/ac46b4
  30. Plants (Basel). 2021 Nov 25. pii: 2581. [Epub ahead of print]10(12):
    Gallotannin-Enriched Fraction from Quercus infectoria Galls as an Antioxidant and Inhibitory Agent against Human Glioblastoma Multiforme.
    Nur Alisa Kamarudin, Nik Nur Hakimah Nik Salleh, Suat Cheng Tan.
      In recent years, herbal medicine has experienced rapid development in the search for alternative anticancer compounds. Various phytochemicals present in Quercus infectoria (QI) galls have been reported to trigger cytotoxic effects on many types of cancer cells. However, a specific active constituent of QI galls with the potential to inhibit highly invasive stage IV malignant brain tumor, glioblastoma multiforme (GBM), is yet to be discovered. In this study, a two-phase system composed of aqueous soxhlet extraction and methanolic enrichment fractionation was employed to extract an anticancer compound, gallotannin, from the QI galls. This optimized two-phase system successfully generated a fraction (F4) with ~71% gallotannin, verified by the TLC and HPLC assays. Astoundingly, this fraction showed significantly higher (~1.15-fold) antioxidant activities compared to its crude extract, as well as to a commercial synthetic pure gallotannin. The F4 was also found to significantly suppress GBM cell growth, better than the synthetic pure gallotannin and the QI gall crude extract, probably related to its significantly higher antioxidant property. Moreover, the inhibitory effects exerted by the F4 treatment on GBM cells were comparable to the effects of two clinically used chemo-drugs (Temozolomide and Tamoxifen), indicating its high efficiency in combating human cancer. In conclusion, this study pioneered the development of an optimized extraction procedure for enriched yield of the natural gallotannin metabolite from the galls of the QI medicinal plant with high antioxidant potential and inhibitory effects on human GBM cells.
    Keywords:  Quercus infectoria galls; anticancer; antioxidant; gallotannin; glioblastoma multiforme; medicinal plant
    DOI:  https://doi.org/10.3390/plants10122581
  31. Pharmaceuticals (Basel). 2021 Dec 17. pii: 1318. [Epub ahead of print]14(12):
    Growth Inhibitory Efficacy of Chinese Herbs in a Cellular Model for Triple-Negative Breast Cancer.
    Nitin T Telang, Hareesh B Nair, George Y C Wong.
      Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor-α progesterone receptor and human epidermal growth factor receptor-2. Treatment for this breast cancer subtype is restricted to multidrug chemotherapy and survival pathway-based molecularly targeted therapy. The long-term treatment options are associated with systemic toxicity, spontaneous and/or acquired tumor resistance and the emergence a of drug-resistant stem cell population. These limitations lead to advanced stage metastatic cancer. Current emphasis is on research directions that identify efficacious, naturally occurring agents representing an unmet need for testable therapeutic alternatives for therapy resistant breast cancer. Chinese herbs are widely used in traditional Chinese medicine in women for estrogen related health issues and also for integrative support for cancer treatment. This review discusses published evidence on a TNBC model for growth inhibitory effects of several mechanistically distinct nontoxic Chinese herbs, most of them nutritional in nature, and identifies susceptible pathways and potential molecular targets for their efficacy. Documented anti-proliferative and pro-apoptotic effects of these herbs are associated with downregulation of RB, RAS, PI3K, and AKT signaling, modulation of Bcl-2/BAX protein expressions and increased caspase activity. This review provides a proof of concept for Chinese herbs as testable alternatives for prevention/therapy of TNBC.
    Keywords:  Chinese herbs; breast cancer; growth inhibition
    DOI:  https://doi.org/10.3390/ph14121318
  32. Cancer Sci. 2021 Dec 28.
    Nanomedicine Targets Iron Metabolism for Cancer Therapy.
    Liangru Lin, Hanqing Chen, Ruifang Zhao, Motao Zhu, Guangjun Nie.
      Iron is an essential element for cell proliferation and homeostasis via engaging in cell metabolism including DNA synthesis, cell cycle, and redox cycling, while iron overload may contribute to tumor initiation, proliferation, metastasis, and angiogenesis. Therefore, manipulating iron metabolisms, such as using iron chelators, transferrin receptor 1 (TFR1) antibodies, and cytotoxic ligands conjugated to transferrin, has become a considera.
    Keywords:  cancer therapy; ferroptosis; iron metabolism; iron reductive therapy; nano-drug delivery systems
    DOI:  https://doi.org/10.1111/cas.15250
  33. J Nanobiotechnology. 2021 Dec 28. 19(1): 455
    Acidic microenvironment responsive polymeric MOF-based nanoparticles induce immunogenic cell death for combined cancer therapy.
    Xiaoli Zhang, Yi Lu, Die Jia, Wei Qiu, Xianbin Ma, Xingliang Zhang, Zhigang Xu, Feiqiu Wen.
       BACKGROUND: The complex tumor microenvironment and non-targeting drugs limit the efficacy of clinical tumor therapy. For ensuring the accurate delivery and maximal effects of anticancer drugs, it is important to develop innovative drug delivery system based on nano-strategies.
    RESULT: In this study, an intracellular acidity-responsive polymeric metal organic framework nanoparticle (denoted as DIMP) has been constructed, which can co-deliver the chemotherapy agent of doxorubicin (DOX) and phototherapy agent of indocyanine green (ICG) for breast carcinoma theranostics. Specifically, DIMP possesses a suitable and stable nanometer size and can respond to the acidic microenvironment in cells, thus precisely delivering drugs into target tumor sites and igniting the biological reactions towards cell apoptosis. Following in vivo and in vitro results showed that DIMP could be effectively accumulated in tumor sites and induced powerful immunogenic cell death (ICD) effect.
    CONCLUSION: The designed DIMP displayed its effectiveness in combined photo-chemotherapy with auxiliary of ICD effect under a multimodal imaging monitor. Thus, the present MOF-based strategy may offer a potential paradigm for designing drug-delivery system for image-guided synergistic tumor therapy.
    Keywords:  Immunogenic cell death; Multi-modal imaging; Nanoreactor; Synergistic therapy; Tumor-specific activatable
    DOI:  https://doi.org/10.1186/s12951-021-01217-4
  34. Nutrients. 2021 Dec 16. pii: 4508. [Epub ahead of print]13(12):
    A Low-Glucose Eating Pattern Improves Biomarkers of Postmenopausal Breast Cancer Risk: An Exploratory Secondary Analysis of a Randomized Feasibility Trial.
    Susan M Schembre, Michelle R Jospe, Erin D Giles, Dorothy D Sears, Yue Liao, Karen M Basen-Engquist, Cynthia A Thomson.
      Postmenopausal breast cancer is the most common obesity-related cancer death among women in the U.S. Insulin resistance, which worsens in the setting of obesity, is associated with higher breast cancer incidence and mortality. Maladaptive eating patterns driving insulin resistance represent a key modifiable risk factor for breast cancer. Emerging evidence suggests that time-restricted feeding paradigms (TRF) improve cancer-related metabolic risk factors; however, more flexible approaches could be more feasible and effective. In this exploratory, secondary analysis, we identified participants following a low-glucose eating pattern (LGEP), defined as consuming energy when glucose levels are at or below average fasting levels, as an alternative to TRF. Results show that following an LGEP regimen for at least 40% of reported eating events improves insulin resistance (HOMA-IR) and other cancer-related serum biomarkers. The magnitude of serum biomarkers changes observed here has previously been shown to favorably modulate benign breast tissue in women with overweight and obesity who are at risk for postmenopausal breast cancer. By comparison, the observed effects of LGEP were similar to results from previously published TRF studies in similar populations. These preliminary findings support further testing of LGEP as an alternative to TRF and a postmenopausal breast cancer prevention strategy. However, results should be interpreted with caution, given the exploratory nature of analyses.
    Keywords:  adherence; blood glucose; eating physiology; food intake regulation; metabolism; obesity; weight management
    DOI:  https://doi.org/10.3390/nu13124508
  35. Cancer Cell Int. 2021 Dec 29. 21(1): 709
    FTH promotes the proliferation and renders the HCC cells specifically resist to ferroptosis by maintaining iron homeostasis.
    Wanye Hu, Chaoting Zhou, Qiangan Jing, Yancun Li, Jing Yang, Chen Yang, Luyang Wang, Jiayu Hu, Huanjuan Li, Hairui Wang, Chen Yuan, Yi Zhou, Xueying Ren, Xiangmin Tong, Jing Du, Ying Wang.
       BACKGROUND: Ferroptosis is a newly identified type of programmed cell death, which preferentially targets iron-rich cancer cells such as hepatocellular carcinoma (HCC). Ferritin heavy chain (FTH) is a major iron storing nanocage to store redox-inactive iron, and harbors ferroxidase activity to prevent the iron-mediated production of ROS. Our previous studies have demonstrated that FTH acts as a protective role to increase the cellular resistance to ferroptosis. However, the specific role of FTH in the development of HCC and ferroptosis resistance remains unclear.
    METHODS: The indicated databases were used for bioinformatics analysis. The abilities of cell proliferation, migration were measured by cell proliferation assay, transwell assay and wound healing assay. The levels of reactive oxygen species (ROS), lipid peroxide, free iron, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were determined by DCF-DA, C11-BODIPY, mitoSOX, mitoTracker, JC-10 and TMRM staining, respectively. The mitochondrial oxygen consumption rate was monitored by the Seahorse XF24 Analyzer.
    RESULTS: The pan-cancer analysis was performed and showed that FTH expression is upregulated in multiple cancers, such as LIHC, CHOL, HNSC, compared to corresponding normal tissues. In addition, the level of serum ferritin is positively associated with the progression of hepatitis, cirrhosis liver and hepatocellular carcinoma. Further investigation shed light on the strong correlation between FTH expression and tumor grades, cancer stages and prognosis of HCC. Importantly, the proteins interaction network elucidated that FTH is involved in iron homeostasis maintenance and lysosomal-dependent degradation. Enforced expression of FTH accelerates proliferation, migration and endows HCC cells specifically resistant to ferroptosis, but does not protect against cell death caused by cytotoxic compounds like oxaliplatin, irinotecan, and adriamycin. Mechanically, FTH reconstituted cells exhibit diminished peroxides accumulation, reduce mitochondrial ROS level, attenuate the impaired mitochondrial respiratory and rescue the mitochondrial homeostasis. Notably, FTH expression boosts tumorigenic potential in vivo with increased PCNA staining and lesser lipid peroxides generation.
    CONCLUSION: These results provide new insights that FTH acts as an oncogene in the carcinogenesis and progression of HCC, and is hopeful to be a potential target for therapeutic intervention through ferroptosis.
    Keywords:  FTH; Ferroptosis; Hepatocellular carcinoma; Iron homeostasis; Mitochondria
    DOI:  https://doi.org/10.1186/s12935-021-02420-x
  36. Curr Pharm Biotechnol. 2021 Dec 30.
    Recent advances of nanotechnology in the diagnosis and therapy of triple-negative breast cancer (TNBC).
    Abhishek Kanugo, Rupesh K Gautam, Mohammad Amjad Kamal.
       BACKGROUND: The development of advanced treatment of triple-negative breast cancer (TNBC) is the utmost need of an era. TNBC is recognized as the most aggressive, metastatic cancer and the leading cause of mortality in females worldwide. The lack of expression of triple receptors namely, estrogen, progesterone, and human epidermal receptor2 defined TNBC.
    OBJECTIVE: The current review introduced the novel biomarkers such as miRNA and family, PD1, EGFR, VEGF, TILs, P53, AR and PI3K, etc. contributed significantly to the prognosis and diagnosis of TNBC. Once diagnosed the utilization advanced approaches available for TNBC because of the limitations of chemotherapy. Novel approaches include lipid-based (liposomes, SLN, NLC, and SNEDDS), polymer-based (micelle, nanoparticles, dendrimers, and quantum dots), advanced nanocarriers such as (exosomes, antibody and peptide-drug conjugates), carbon-based nanocarriers (Carbon nanotubes, and graphene oxide). Lipid-based delivery is used for excellent carriers for hydrophobic drugs, biocompatibility, and lesser systemic toxicities than chemotherapeutic agents. Polymer-based approaches are preferred over lipids for providing longer circulation time, nanosize, high loading efficiency, high linking; avoiding the expulsion of drugs, targeted action, diagnostic and biosensing abilities. Advanced approaches like exosomes, conjugated moieties are preferred over polymeric for possessing potency, high penetrability, biomarkers, and avoiding the toxicity of tissues. Carbon-based gained wide applicability for their unique properties like a versatile carrier, prognostic, diagnostic, sensing, photodynamic, and photothermal characteristics.
    CONCLUSION: The survival rate can be increased by utilizing several kinds of biomarkers. The advanced approaches can also be significantly useful in the prognosis and theranostic of triple-negative breast cancer. One of the biggest successes in treating with nanotechnology-based approaches is the marked reduction of systemic toxicity with high therapeutic effectiveness compared with chemotherapy, surgery, etc. The requirements such as prompt diagnosis, longer circulation time, high efficiency, and high potency, can be fulfilled with these nanocarriers.
    Keywords:  Biomarkers; Carbon nanotubes. Photodynamic; Liposomes; Nanoparticles; Polymeric micelle; TNBC
    DOI:  https://doi.org/10.2174/1389201023666211230113658
  37. Pharmaceutics. 2021 Dec 03. pii: 2070. [Epub ahead of print]13(12):
    Design and Application of Near-Infrared Nanomaterial-Liposome Hybrid Nanocarriers for Cancer Photothermal Therapy.
    Pan Liang, Linshen Mao, Yanli Dong, Zhenwen Zhao, Qin Sun, Maryam Mazhar, Yining Ma, Sijin Yang, Wei Ren.
      Liposomes are attractive carriers for targeted and controlled drug delivery receiving increasing attention in cancer photothermal therapy. However, the field of creating near-infrared nanomaterial-liposome hybrid nanocarriers (NIRN-Lips) is relatively little understood. The hybrid nanocarriers combine the dual superiority of nanomaterials and liposomes, with more stable particles, enhanced photoluminescence, higher tumor permeability, better tumor-targeted drug delivery, stimulus-responsive drug release, and thus exhibiting better anti-tumor efficacy. Herein, this review covers the liposomes supported various types of near-infrared nanomaterials, including gold-based nanomaterials, carbon-based nanomaterials, and semiconductor quantum dots. Specifically, the NIRN-Lips are described in terms of their feature, synthesis, and drug-release mechanism. The design considerations of NIRN-Lips are highlighted. Further, we briefly introduced the photothermal conversion mechanism of NIRNs and the cell death mechanism induced by photothermal therapy. Subsequently, we provided a brief conclusion of NIRNs-Lips applied in cancer photothermal therapy. Finally, we discussed a synopsis of associated challenges and future perspectives for the applications of NIRN-Lips in cancer photothermal therapy.
    Keywords:  hybrid nanocarriers; liposomes; near-infrared nanomaterials; photothermal therapy; targeted drug delivery
    DOI:  https://doi.org/10.3390/pharmaceutics13122070
  38. Biomed Pharmacother. 2021 Dec 25. pii: S0753-3322(21)01301-9. [Epub ahead of print]146 112514
    Essential oils as anticancer agents: Potential role in malignancies, drug delivery mechanisms, and immune system enhancement.
    Mansi Sharma, Kamaljit Grewal, Rupali Jandrotia, Daizy Rani Batish, Harminder Pal Singh, Ravinder Kumar Kohli.
      Cancer retains a central place in fatality rates among the wide variety of diseases known world over, and the conventional synthetic medicaments, albeit used until now, produce numerous side effects. As a result, newer, better, and safer alternatives such as natural plant products, are gravely required. Essential oils (EOs) offer a plethora of bioactivities including antibacterial, antiviral, antioxidant, and anticancer properties, therefore, the use of EOs in combination with synthetic drugs or aromatherapy continues to be popular in many settings. In view of the paramount importance of EOs and their potential bioactivities, this review summarizes the current knowledge on the interconnection between EOs and cancer treatment. In particular, the current review presents an updated summary of the chemical composition of EOs, their current applications in cancer treatments based on clinical studies, and the mechanism of action against the cancer cell lines. Similarly, an overview of using EOs in aromatherapy and enhancing immunity during cancer treatment is provided. Further, this review focuses on the recent technological advancements such as the loading of EOs using protein microspheres, ligands, or nanoemulsions/nanoencapsulation, which offer multiple benefits in cancer treatment via site-specific and target-oriented delivery of drugs. The continuing clinical studies of EOs implicate that their pharmacological applications are a rewarding research area.
    Keywords:  Anti-mutagenic activity; Anti-proliferative activity; Anticancer activity; Aromatherapy; Drug delivery systems; Essential oils
    DOI:  https://doi.org/10.1016/j.biopha.2021.112514
  39. Photochem Photobiol. 2021 Dec 31.
    Singlet Oxygen Activatable Prodrugs of Paclitaxel, SN-38, MMC, and CA4: Non-mitochondria Targeted Prodrugs.
    Kazi Md Mahabubur Rahman, Pritam Thapa, Robert Hurst, Sukyung Woo, Youngjae You.
      We established a light-activatable prodrug strategy that produces the combination effect of photodynamic therapy (PDT) and site-specific chemotherapy. Prodrugs are activated by singlet oxygen (SO), generated from PS and visible or near IR light, in either intra- or inter-molecular manner. The goal of this study is to evaluate cytotoxic effects of non-mitochondria targeted prodrugs of a number of anticancer drugs with different mechanisms of action. They were tested in both 2D and 3D in vitro conditions via inter-molecular activation of prodrugs by SO generated in mitochondria by protoporphyrin IX-PDT (PpIX-PDT). Prodrugs of anticancer drugs (paclitaxel, SN-38, combrestatin A4, and mitomycin C) were synthesized using facile and high yielding reactions. Non-mitochondria targeted prodrugs showed limited dark toxicity while all of them showed greatly enhanced phototoxicity compared to PpIX-PDT in the 2D culture model. Prodrugs generated up to about 95% cell killing at 2.5 μM when administered with hexyl-aminolevulinate (HAL) to produce Protoporphyrin IX in cancer cells in both 2D monolayer and 3D spheroids model. The data demonstrate that mitochondria-targeting of prodrugs is not fully essential for our inter-molecular activation prodrug strategy. The prodrug strategy also worked for anticancer drugs with diverse MOAs.
    Keywords:  NMIBC; mitochondria targeting; photodynamic therapy; prodrugs; protoporphyrin IX
    DOI:  https://doi.org/10.1111/php.13589
  40. J Histochem Cytochem. 2022 Jan;70(1): 83-97
    IDH1/2 Mutations in Cancer Stem Cells and Their Implications for Differentiation Therapy.
    Remco J Molenaar, Johanna W Wilmink.
      Isocitrate dehydrogenase 1 and 2 (IDH1/2) are enzymes recurrently mutated in various types of cancer, including glioma, cholangiocarcinoma, chondrosarcoma, and acute myeloid leukemia. Mutant IDH1/2 induce a block in differentiation and thereby contribute to the stemness and oncogenesis of their cells of origin. Recently, small-molecule inhibitors of mutant IDH1/2 have been Food and Drug Administration-approved for the treatment of IDH1/2-mutated acute myeloid leukemia. These inhibitors decrease the stemness of the targeted IDH1/2-mutated cancer cells and induce their differentiation to more mature cells. In this review, we elucidate the mechanisms by which mutant IDH1/2 induce a block in differentiation and the biological and clinical effects of the release into differentiation by mutant-IDH1/2 inhibitors. (J Histochem Cytochem 70:83-97, 2022).
    Keywords:  2-hydroxyglutarate; cancer stem cells; chemotherapy; differentiation; enasidenib; isocitrate dehydrogenase; ivosidenib; targeted therapy; therapy responses
    DOI:  https://doi.org/10.1369/00221554211062499
  41. ACS Nano. 2021 Dec 28.
    Engineering Supramolecular Nanomedicine for Targeted Near Infrared-triggered Mitochondrial Dysfunction to Potentiate Cisplatin for Efficient Chemophototherapy.
    Wei Zhang, Xiang-Fu Du, Ben Liu, Cairong Li, Jing Long, Mei-Xia Zhao, Zhenyu Yao, Xing-Jie Liang, Yuxiao Lai.
      Combinatorial cancer therapies based on nanomedicine have emerged as a promising strategy to achieve potentiated treatment efficiency. Herein, cisplatin (CDDP) prodrug (Pt-CD) and a mitochondria-targeted near-infrared (NIR) photosensitizer IR780 were combined to construct a multifunctional nanomedicine IR780@Pt NPs through a supramolecular self-assembly strategy. Targeted mitochondrial dysfunction of cancer cells was sufficiently induced under NIR laser irradiation through both photothermal and photodynamic effects, inhibiting the overactive mitochondrial energy pathways of cancer cells. The mitochondrial dysfunction significantly attenuated the crosstalk between mitochondria and nucleus via the cellular ATP energy chain, leading to obvious down-regulation of the key proteins of the nucleotide excision repair (NER) pathway. Thereby, the chemotherapeutic effect of CDDP could be significantly potentiated because of reduced DNA lesion repair capacity by ERCC1-XPF nuclease system. Moreover, IR780@Pt NPs exhibited excellent NIR fluorescence and photoacoustic (PA) imaging capacity for in vivo imaging-guided NIR laser treatment. Ultimately, the IR780@Pt NPs mediated combinatorial chemophototherapy achieved potentiated anticancer efficacy against cancer cells in vitro and tumor inhibition performance in vivo. Overall, this study highlighted the significance of nanomedicine mediated targeted induction of mitochondrial dysfunction to potentiate chemotherapy for efficient combinatorial cancer therapy.
    Keywords:  cisplatin; combinatorial therapy; mitochondrial dysfunction; nanomedicine; supramolecular self-assembly
    DOI:  https://doi.org/10.1021/acsnano.1c09555
  42. Pharmaceutics. 2021 Dec 02. pii: 2057. [Epub ahead of print]13(12):
    Phthalocyanine and Its Formulations: A Promising Photosensitizer for Cervical Cancer Phototherapy.
    Lucimara R Carobeli, Lyvia E de F Meirelles, Gabrielle M Z F Damke, Edilson Damke, Maria V F de Souza, Natália L Mari, Kayane H Mashiba, Cristiane S Shinobu-Mesquita, Raquel P Souza, Vânia R S da Silva, Renato S Gonçalves, Wilker Caetano, Márcia E L Consolaro.
      Cervical cancer is one of the most common causes of cancer-related deaths in women worldwide. Despite advances in current therapies, women with advanced or recurrent disease present poor prognosis. Photodynamic therapy (PDT) has emerged as an effective therapeutic alternative to treat oncological diseases such as cervical cancer. Phthalocyanines (Pcs) are considered good photosensitizers (PS) for PDT, although most of them present high levels of aggregation and are lipophilic. Despite many investigations and encouraging results, Pcs have not been approved as PS for PDT of invasive cervical cancer yet. This review presents an overview on the pathophysiology of cervical cancer and summarizes the most recent developments on the physicochemical properties of Pcs and biological results obtained both in vitro in tumor-bearing mice and in clinical tests reported in the last five years. Current evidence indicates that Pcs have potential as pharmaceutical agents for anti-cervical cancer therapy. The authors firmly believe that Pc-based formulations could emerge as a privileged scaffold for the establishment of lead compounds for PDT against different types of cervical cancer.
    Keywords:  in vitro; in vivo; photochemotherapy; phthalocyanine; uterine cervical neoplasms
    DOI:  https://doi.org/10.3390/pharmaceutics13122057
  43. Asian Pac J Cancer Prev. 2021 Dec 01. pii: 89907. [Epub ahead of print]22(12): 4017-4029
    Camel Urine Promotes Sensitization to Doxorubicin by Inhibiting Epithelial-Mesenchymal Transition and Modulating NF-κB-Snail Signaling Pathway in Breast Cancer Cells.
    Mashael Saqer Al-Mutairi, Ibtehal Kamal Matar, Suad Alfadli, Awated Al-Mutairi.
       BACKGROUND: Camel urine (CU) has been used as traditional treatment in the Arabian Peninsula for centuries. Although, researchers have reported CU anti-cancer effects, the exact mechanism(s) of action involved has not been fully elucidated. The epithelial-mesenchymal transition EMT is a phenotypic switch that promotes the acquisition of a fibroblastoid-like morphology by epithelial tumor cells, resulting in enhanced tumor cell motility and invasiveness. EMT has been shown to contribute to metastasis and chemoresistance of carcinomas. For that, in the present study, we have assessed the potential mechanism (s) by which CU exert its anti-cancer effects and its possible synergistic therapeutic effect with Doxorubicin (DOX) in breast cancer cells.
    METHODS: Determination of anti-proliferative and apoptosis validation of CU was performed by 3-(4,5-Dimethylthiazol-2-yl)-2,5,-diphenyltetrazolium bromide (MTT), annexin-V-fluorescein isothiocyanate assays, and Western blot. EMT protein markers, migration and invasion of cells were determined by Western blot or immunofluorescent staining, Scratch assay, Transwell invasion assay, respectively.
    RESULTS: CU applied a significant anti-cancer effect on breast cancer cells via induction of DNA damage and apoptosis in a concentration- and time-dependent manner. Also, CU remarkably reversed the EMT by downregulating N-cadherin and Vimentin expression and upregulating E-cadherin expression. As a result, the stemness, migration and invasion of breast cancer cells were also inhibited, which was likely mediated by NF-κB-Snail signalling pathway and its downstream inflammatory effectors. CU successfully enhanced DOX cytotoxicity by reversing EMT which possibly through inhibition of NF-κB-Snail signalling and subsequently inflammation.  Thus, our study provides new mechanistic bases for the therapeutic application of CU that may improve the outcomes of anti-cancer chemotherapy.
    Keywords:  Chemoresistance; EMT; NF-KB; breast cancer; camel urine
    DOI:  https://doi.org/10.31557/APJCP.2021.22.12.4017
  44. Pharmaceutics. 2021 Nov 23. pii: 1990. [Epub ahead of print]13(12):
    Dual Targeting of Cancer Cells and MMPs with Self-Assembly Hybrid Nanoparticles for Combination Therapy in Combating Cancer.
    Kai Zhang, Jingjing Li, Xiaofei Xin, Xiaoqing Du, Di Zhao, Chao Qin, Xiaopeng Han, Meirong Huo, Lei Yang, Lifang Yin.
      The co-delivery of chemotherapeutic agents and immune modulators to their targets remains to be a great challenge for nanocarriers. Here, we developed a hybrid thermosensitive nanoparticle (TMNP) which could co-deliver paclitaxel-loaded transferrin (PTX@TF) and marimastat-loaded thermosensitive liposomes (MMST/LTSLs) for the dual targeting of cancer cells and the microenvironment. TMNPs could rapidly release the two payloads triggered by the hyperthermia treatment at the site of tumor. The released PTX@TF entered cancer cells via transferrin-receptor-mediated endocytosis and inhibited the survival of tumor cells. MMST was intelligently employed as an immunomodulator to improve immunotherapy by inhibiting matrix metalloproteinases to reduce chemokine degradation and recruit T cells. The TMNPs promoted the tumor infiltration of CD3+ T cells by 2-fold, including memory/effector CD8+ T cells (4.2-fold) and CD4+ (1.7-fold), but not regulatory T cells. Our in vivo anti-tumor experiment suggested that TMNPs possessed the highest tumor growth inhibitory rate (80.86%) compared with the control group. We demonstrated that the nanoplatform could effectively inhibit the growth of tumors and enhance T cell recruitment through the co-delivery of paclitaxel and marimastat, which could be a promising strategy for the combination of chemotherapy and immunotherapy for cancer treatment.
    Keywords:  chemoimmunotherapy; hybrid nanoparticles; immunomodulator; matrix metalloproteinases; transferrin
    DOI:  https://doi.org/10.3390/pharmaceutics13121990
  45. Pharmaceutics. 2021 Nov 30. pii: 2042. [Epub ahead of print]13(12):
    Lipid Nanoparticles Containing Mixtures of Antioxidants to Improve Skin Care and Cancer Prevention.
    Catarina Gonçalves, Maria João Ramalho, Renata Silva, Vera Silva, Rita Marques-Oliveira, Ana Catarina Silva, Maria Carmo Pereira, Joana A Loureiro.
      Oxidative stress, triggered by UV radiation, is one of the major causes of free radical-associated disorders, such as skin cancer. The application of natural compounds (NCs) with antioxidant effects can attenuate free radicals' accumulation and, therefore, provide a strategy for skin care and cancer prevention. In this work, three natural compounds, naringenin, nordihydroguaiaretic acid (NDGA), and kaempferol, were encapsulated into nanostructured lipid carriers (NLCs) aiming for the development of a formulation for cutaneous application with antioxidant properties. For the experiments, different formulation parameters were evaluated to optimize the NLCs that showed a diameter around 200 nm, which is an adequate particle size for incorporation in cosmetics. Transmission electron microscopy (TEM) analysis confirmed the NLCs' typical spherical morphology. Encapsulation efficiency (EE) and loading capacity (LC) values revealed an effective production process, with EEs over 90% and LCs near the maximum value. The developed NLCs revealed a prolonged in vitro release of the natural compounds. The NLCs were stable under storage conditions, maintaining their psychochemical characteristics for 30 days. Additionally, they did not show any physical instability in accelerated stability studies, which also suggests long-term stability. Finally, the NCs antioxidant activity was evaluated. Interestingly, the NDGA and kaempferol mixture provided an antioxidant synergic effect. The NLC formulations' cytotoxicity was tested in vitro in immortalized human keratinocytes (HaCaT). In addition, putative antioxidant effects of the developed NLC formulations against tert-butyl hydroperoxide (t-BHP)-induced oxidative stress were studied, and the NDGA-loaded NLC was revealed to be the one with the most protective effect. Therefore, we concluded that the naringenin, NDGA, and kaempferol incorporation into NLCs constitutes a promising strategy to increase their bioavailability and delivery to the skin.
    Keywords:  bioactive compounds; drug delivery systems; nanostructured lipid carriers; oxidative stress; solid lipid nanoparticles
    DOI:  https://doi.org/10.3390/pharmaceutics13122042
  46. Plants (Basel). 2021 Nov 29. pii: 2621. [Epub ahead of print]10(12):
    New Approaches on Japanese Knotweed (Fallopia japonica) Bioactive Compounds and Their Potential of Pharmacological and Beekeeping Activities: Challenges and Future Directions.
    Alexandra-Antonia Cucu, Gabriela-Maria Baci, Ştefan Dezsi, Mircea-Emil Nap, Florin Ioan Beteg, Victoriţa Bonta, Otilia Bobiş, Emilio Caprio, Daniel Severus Dezmirean.
      Known especially for its negative ecological impact, Fallopia japonica (Japanese knotweed) is now considered one of the most invasive species. Nevertheless, its chemical composition has shown, beyond doubt, some high biological active compounds that can be a source of valuable pharmacological potential for the enhancement of human health. In this direction, resveratrol, emodin or polydatin, to name a few, have been extensively studied to demonstrate the beneficial effects on animals and humans. Thus, by taking into consideration the recent advances in the study of Japanese knotweed and its phytochemical constituents, the aim of this article is to provide an overview on the high therapeutic potential, underlining its antioxidant, antimicrobial, anti-inflammatory and anticancer effects, among the most important ones. Moreover, we describe some future directions for reducing the negative impact of Fallopia japonica by using the plant for its beekeeping properties in providing a distinct honey type that incorporates most of its bioactive compounds, with the same health-promoting properties.
    Keywords:  Fallopia japonica; Japanese knotweed; antimicrobial activity; antioxidant effect; bioactive compounds; honey; invasive species; phytopharmaceuticals
    DOI:  https://doi.org/10.3390/plants10122621
  47. Adv Mater. 2021 Dec 29. e2108908
    Reshaping Tumor Immune Microenvironment Based on Light Activated Nano-Platform for Efficient Cancer Therapy.
    Zebin Yang, Yu Luo, Huizhu Yu, Kaicheng Liang, Miao Wang, Qigang Wang, Bo Yin, Hangrong Chen.
      Immunosuppressive tumor microenvironment (TME) always cause poor antitumor immune efficacy, prone to relapse and metastasis. Herein, a novel polyvinyl pyrrolidone (PVP) modified BiFeO3 /Bi2 WO6 (BFO/BWO) with p-n type heterojunction was constructed for reshaping immunosuppressive TME. Reactive oxygen species could be generated under light activation by the well separation of hole (h+ )-electron (e- ) pairs owing to the heterojunction in BFO/BWO-PVP NPs. Interestingly, the h+ can trigger the decomposition of H2 O2 to generate O2 for alleviating tumor hypoxia, which not only sensitizes photodynamic therapy (PDT) and radiotherapy (RT), but also promotes the tumor-associated macrophages (TAMs) polarization from M2 to M1 phenotype, beneficial to decrease the expression of HIF-1α. Importantly, such a light activated nano-platform combing with RT could efficiently activate and recruit cytotoxic T lymphocytes to infiltrate in tumor tissues, as well as stimulate TAMs to M1 phenotype, dramatically reverse the immunosuppressive TME into the immunoactive one and further boost immune memory responses. Moreover, BFO/BWO-PVP NPs also present high performance of computed tomography imaging contrast. Taken together, this work offers a novel paradigm for achieving O2 self-supplement of inorganic nano-agent and reshaping tumor immune microenvironment to effective inhibition of cancer as well as metastasis and recurrence. This article is protected by copyright. All rights reserved.
    Keywords:  hypoxia; metastasis; photodynamic therapy; recurrence; tumor immune microenvironment
    DOI:  https://doi.org/10.1002/adma.202108908
  48. Acta Biomater. 2021 Dec 28. pii: S1742-7061(21)00843-6. [Epub ahead of print]
    Sensitive and Precise Visually Guided Drug Delivery Nanoplatform with Dual Activation of pH and Light.
    Chenyu Liu, Hengjun Zhou, Simiao Yu, Hailiang Chen, Ning Wang, Weihe Yao, An-Hui Lu, Weihong Qiao.
      Controlled-release drug carriers in cancer therapy are the most ideal way to reduce toxicity and improve drug efficacy. Since light stimulation is precise and operable, most multi-stimulation response carriers utilize phototherapy to enhance release efficiency. However, phototoxicity severely limits the application of phototherapy. Herein, we designed and synthesized a Cou-ONB lipid with sensitive fluorescence feedback and multi-stimulus response. COBL liposomes prepared from Cou-ONB lipids will passively aggregate at the tumor and guide phototherapy by fluorescence. More importantly, it can reflect the drug release effect in vivo through its own sensitive fluorescence changes, further enabling precise phototherapy and reducing phototoxicity. In this paper, the multi-stimulus superimposed response and precise fluorescence-guided performance of COBL liposomes were investigated at the molecular, liposome, cellular, and animal levels. Finally, tumor treatment experiments showed that the D-COBL-UV group had the best tumor suppression effect (5.3-fold). This paper highlights a real-time fluorescence-guided multi-stimulus superposition strategy and provides a design idea to precisely implement exogenous stimuli by displaying the degree of drug release, aiming to achieve less toxic and more efficient cancer therapy through timely and precise multi-stimulation. STATEMENT OF SIGNIFICANCE: Multi-stimulus responsive drug carriers have been extensively developed in the last decade. Visual guidance is an important tool to achieve precision medicine and precise control of drug release. However, the available visualization materials are more aimed at directing stimulation at the optimal moment. There is little discussion on when to stop exogenous stimulation and how to minimize the damage of stimulation to the patient. Here, we provide a Cou-ONB lipid that not only responds to multiple stimuli, but also provides sensitive feedback on its own dissociation with a fluorescent signal so that physicians can adjust exogenous stimuli in a timely manner. This paper provides insights to facilitate precision drug delivery systems, providing viable design ideas for precise, efficient, and less toxic cancer therapies.
    Keywords:  Cancer Therapy; Coumarin; Fluorescent Indicator; Liposomes; Multi-stimulus response
    DOI:  https://doi.org/10.1016/j.actbio.2021.12.029
  49. ACS Appl Mater Interfaces. 2021 Dec 27.
    Ultrasound Microbubbles Mediated Sonosensitizer and Antibody Co-delivery for Highly Efficient Synergistic Therapy on HER2-Positive Gastric Cancer.
    Lihong Sun, Jinxia Zhang, Menghong Xu, Lulu Zhang, Qingshuang Tang, Jing Chen, Ming Gong, Suhui Sun, Huiyu Ge, Shumin Wang, Xiaolong Liang, Ligang Cui.
      Trastuzumab combined with chemotherapy is the first-line treatment for advanced HER2-positive gastric cancer, but it still suffers from limited therapeutic efficiency and serious side effects, which are usually due to the poor delivery efficiency and the drug resistance of tumor cells to the chemotherapeutic drugs. Herein, a type of ultrasound microbubble for simultaneous delivery of sonosensitizers and therapeutic antibodies to achieve targeting combination of sonodynamic therapy and antibody therapy of HER2-positive gastric cancer was constructed from pyropheophorbide-lipid followed by trastuzumab conjugation (TP MBs). In vitro and in vivo studies showed that TP MBs had good biological safety, and their in vivo delivery can be monitored by ultrasound/fluorescence bimodal imaging. With ultrasound (US) located at the tumor area, TP MBs can be converted into nanoparticles (TP NPs) in situ by US-targeted microbubble destruction; plus the enhanced permeability and retention effects and the targeting effects of trastuzumab, the enrichment of sonosensitizers and antibodies in the tumor tissue can be greatly enhanced (∼2.1 times). When combined with ultrasound, TP MBs can not only increase the uptake of sonosensitizers in HER2-positive gastric cancer NCI-N87 cells but also efficiently generate singlet oxygen to greatly increase the killing effect on cells, obviously inhibiting the tumor growth in HER2-positive gastric cancer NCI-N87 cell models with a tumor inhibition rate up to 79.3%. Overall, TP MBs combined with US provided an efficient way for co-delivery of sonosensitizers and antibodies, greatly enhancing the synergistic therapeutic effect on HER2-positive gastric cancer while effectively reducing the side effects.
    Keywords:  HER2-positive gastric cancer; microbubbles; sonodynamic therapy; targeted therapy; trastuzumab
    DOI:  https://doi.org/10.1021/acsami.1c21924
  50. Cancer Cell Int. 2021 Dec 25. 21(1): 704
    Glucose starvation suppresses gastric cancer through targeting miR-216a-5p/Farnesyl-Diphosphate Farnesyltransferase 1 axis.
    Ruiyang Zhao, Bo Cao, Hanghang Li, Tian Li, Xingming Xu, Hao Cui, Huan Deng, Bo Wei.
       BACKGROUND: Fasting mimic diet is an effect approach for gastric cancer (GC) treatment. Exploring mechanisms of glucose deprivation-mediated GC suppression is required to develop novel therapeutic regimens. Farnesyltransferase 1 (FDFT1), as a novel target in basic research, has been reported to regulate malignant progression in some types of cancer. However, biological functions of FDFT1 in GC are still unclear. This study focused on biological functions of FDFT1 in GC and the association between glucose starvation (GS) and FDFT1.
    METHODS: The data derived from the Kaplan-Meier Plotter database were collected to identify the relationship between survival time and FDFT1 expression levels of GC patients. Bioinformatic analysis was performed to explore the biological functions of FDFT1. The expression levels of targeted genes and microRNAs (miRNAs) were detected with immunohistochemistry, quantitative real-time PCR and western blot. Malignant behaviors were measured using cell counting, cell counting kit-8, 5-ethynyl-2-deoxyuridine, wound healing, invasion transwell assays in vitro and constructions of subcutaneous and lung-metastatic tumors in vivo. The glycolysis of GC cells was determined by a series of metabolites, including lactate acid, pyruvic acid, ATP production, rates of glucose uptake, extracellular acidification rate and oxygen consumption rate.
    RESULTS: FDFT1 was downregulated in GC and negatively correlated with pathological T stage, pathological TNM stage and cancer differentiation. High expression of FDFT1 also indicated better prognosis of GC patients. FDFT1 upregulation attenuated proliferation, migration and invasion of GC. miR-216a-5p was identified as a critical suppressor of FDFT1 expression and miR-216a-5p/FDFT1 axis regulated malignant behaviors and glycolysis of GC cells. GS suppressed malignant behaviors of GC by targeting miR-216a-5p/FDFT1 axis both in vitro and in vivo.
    CONCLUSION: This study illustrated novel mechanisms by which GS effectively suppresses GC. FDFT1 may become a potential prognostic indicator and novel target of GC therapy.
    Keywords:  FDFT1; Gastric cancer; Glucose starvation; Glycolysis; Malignant progression; miR-216a-5p
    DOI:  https://doi.org/10.1186/s12935-021-02416-7
  51. Biomed Pharmacother. 2021 Dec 27. pii: S0753-3322(21)01386-X. [Epub ahead of print]146 112599
    Baicalin; a promising chemopreventive agent, enhances the antitumor effect of 5-FU against breast cancer and inhibits tumor growth and angiogenesis in Ehrlich solid tumor.
    Nisreen H Shehatta, Tarek M Okda, Gamal A Omran, Mohammad M Abd-Alhaseeb.
      Despite considerable advances in cancer treatment, chemotherapy remains a cornerstone in breast cancer therapy. Therefore, reducing chemoresistance and adverse effects of chemotherapy is a priority. In this regard, Baicalin (BA) is the dominant natural flavonoid extracted from the roots of Scutellaria baicalensis showed fascinating antitumor activity in many types of cancers, including breast cancer. The present study aimed to explore the chemopreventive and antitumor action of baicalin alone and in combination with 5-FU in addition to its ability to enhance the antitumor effect of 5-FU on breast cancer using the Ehrlich solid tumor-mice model.
    MATERIALS AND METHODS: A total of 70 female mice were divided into seven groups (1st group, saline group; 2nd group, DMSO group; 3rd group, BA+EST group; 4th group, EST group; 5th group, EST+5-FU; 6th group, EST+BA group; 7th group, EST+5-FU+BA).tumors were assessed by weight and histopathological examination. Inflammation, angiogenesis, and apoptosis were examined by ELISA, qRT-PCR, and immunohistochemical examinations.
    RESULTS: showed that pre-treatment with baicalin and treatment with baicalin and/or 5-FU significantly reduced inflammation and angiogenesis indicated by suppression of NF-kB/ IL-1β and VEGF amplification loop with marked elevation in apoptosis indicated by up-regulation of apoptotic caspase-3, pro-apoptotic p53, Bax and downregulation of anti-apoptotic Bcl-2.
    CONCLUSION: BA is a promising preventive or adjuvant therapy in breast cancer treatment with 5-FU mainly via cooperative inhibition of inflammation, angiogenesis, and triggering apoptotic cell death.
    Keywords:  5-Fluorouracil; Angiogenesis; Apoptosis; Baicalin; Breast cancer; Ehrlich solid tumor
    DOI:  https://doi.org/10.1016/j.biopha.2021.112599
  52. Nutrients. 2021 Dec 20. pii: 4565. [Epub ahead of print]13(12):
    The Chemical Composition and Health-Promoting Effects of the Grewia Species-A Systematic Review and Meta-Analysis.
    Muhammad Qamar, Saeed Akhtar, Tariq Ismail, Muqeet Wahid, Ross T Barnard, Tuba Esatbeyoglu, Zyta M Ziora.
      Globally grown and organoleptically appreciated Grewia species are known as sources of bioactive compounds that avert the risk of communicable and non-communicable diseases. Therefore, in recent years, the genus Grewia has attracted increasing scientific attention. This is the first systematic review which focusses primarily on the nutritional composition, phytochemical profile, pharmacological properties, and disease preventative role of Grewia species. The literature published from 1975 to 2021 was searched to retrieve relevant articles from databases such as Google Scholar, Scopus, PubMed, and Web of Science. Two independent reviewers carried out the screening, selection of articles, and data extraction. Of 815 references, 56 met our inclusion criteria. G. asiatica and G. optiva were the most frequently studied species. We found 167 chemical compounds from 12 Grewia species, allocated to 21 categories. Flavonoids represented 41.31% of the reported bioactive compounds, followed by protein and amino acids (10.7%), fats and fatty acids (9.58%), ash and minerals (6.58%), and non-flavonoid polyphenols (5.96%). Crude extracts, enriched with bioactive compounds, and isolated compounds from the Grewia species show antioxidant, anticancer, anti-inflammatory, antidiabetic, hepatoprotective/radioprotective, immunomodulatory, and sedative hypnotic potential. Moreover, antimicrobial properties, improvement in learning and memory deficits, and effectiveness against neurodegenerative ailments are also described within the reviewed article. Nowadays, the side effects of some synthetic drugs and therapies, and bottlenecks in the drug development pathway have directed the attention of researchers and pharmaceutical industries towards the development of new products that are safe, cost-effective, and readily available. However, the application of the Grewia species in pharmaceutical industries is still limited.
    Keywords:  antimicrobial; antioxidant; cancer; diabetes; inflammation; phytochemicals
    DOI:  https://doi.org/10.3390/nu13124565
  53. Pharmaceuticals (Basel). 2021 Nov 30. pii: 1244. [Epub ahead of print]14(12):
    Valproic Acid Prodrug Affects Selective Markers, Augments Doxorubicin Anticancer Activity and Attenuates Its Toxicity in a Murine Model of Aggressive Breast Cancer.
    Nataly Tarasenko, Harel Josef Wilner, Abraham Nudelman, Gania Kessler-Icekson, Ada Rephaeli.
      We studied the unique inhibitor of the histone deacetylases (HDAC) valproate-valpromide of acyclovir (AN446) that upon metabolic degradation release the HDAC inhibitor (HDACI) valproic acid (VPA). Among the HDAC inhibitors that we have tested, only AN446, and to a lesser extent VPA, synergized with doxorubicin (Dox) anti-cancer activity. Romidepsin (Rom) was additive and the other HDACIs tested were antagonistic. These findings led us to test and compare the anticancer activities of AN446, VPA, and Rom with and without Dox in the 4T1 triple-negative breast cancer murine model. A dose of 4 mg/kg once a week of Dox had no significant effect on tumor growth. Rom was toxic, and when added to Dox the toxicity intensified. AN446, AN446 + Dox, and VPA + Dox suppressed tumor growth. AN446 and AN446 + Dox were the best inhibitory treatments for tumor fibrosis, which promotes tumor growth and metastasis. Dox increased fibrosis in the heart and kidneys, disrupting their function. AN446 most effectively suppressed Dox-induced fibrosis in these organs and protected their function. AN446 and AN446 + Dox treatments were the most effective inhibitors of metastasis to the lungs, as measured by the gap area. Genes that control and regulate tumor growth, DNA damage and repair, reactive oxygen production, and generation of inflammation were examined as potential therapeutic targets. AN446 affected their expression in a tissue-dependent manner, resulting in augmenting the anticancer effect of Dox while reducing its toxicity. The specific therapeutic targets that emerged from this study are discussed.
    Keywords:  DNA damage; doxorubicin; fibrosis; triple-negative breast cancer; valproic acid prodrug
    DOI:  https://doi.org/10.3390/ph14121244
  54. Plants (Basel). 2021 Dec 14. pii: 2751. [Epub ahead of print]10(12):
    Glycyrrhiza glabra (Licorice): A Comprehensive Review on Its Phytochemistry, Biological Activities, Clinical Evidence and Toxicology.
    Shadma Wahab, Sivakumar Annadurai, Shahabe Saquib Abullais, Gotam Das, Wasim Ahmad, Md Faruque Ahmad, Geetha Kandasamy, Rajalakshimi Vasudevan, Md Sajid Ali, Mohd Amir.
      There are more than 30 species of Glycyrrhiza genus extensively spread worldwide. It was the most prescribed herb in Ancient Egyptian, Roman, Greek, East China, and the West from the Former Han era. There are various beneficial effects of licorice root extracts, such as treating throat infections, tuberculosis, respiratory, liver diseases, antibacterial, anti-inflammatory, and immunodeficiency. On the other hand, traditional medicines are getting the attraction to treat many diseases. Therefore, it is vital to screen the medicinal plants to find the potential of new compounds to treat chronic diseases such as respiratory, cardiovascular, anticancer, hepatoprotective, etc. This work comprehensively reviews ethnopharmacological uses, phytochemistry, biological activities, clinical evidence, and the toxicology of licorice, which will serve as a resource for future clinical and fundamental studies. An attempt has been made to establish the pharmacological effect of licorice in different diseases. In addition, the focus of this review article is on the molecular mechanism of licorice extracts and their four flavonoids (isoliquiritigenin, liquiritigenin, lichalocone, and glabridin) pharmacologic activities. Licorice could be a natural alternative for current therapy to exterminate new emerging disorders with mild side effects. This review will provide systematic insights into this ancient drug for further development and clinical use.
    Keywords:  Glycyrrhiza glabra; anticancer; cardiovascular; hepatoprotective; phytochemistry; respiratory infection
    DOI:  https://doi.org/10.3390/plants10122751
  55. Pharmaceuticals (Basel). 2021 Nov 25. pii: 1220. [Epub ahead of print]14(12):
    Crosstalk between Statins and Cancer Prevention and Therapy: An Update.
    Beniamin Oskar Grabarek, Dariusz Boroń, Emilia Morawiec, Piotr Michalski, Veronica Palazzo-Michalska, Łukasz Pach, Barbara Dziuk, Magdalena Świder, Nikola Zmarzły.
      The importance of statins in cancer has been discussed in many studies. They are known for their anticancer properties against solid tumors of the liver or lung, as well as diffuse cancers, such as multiple myeloma or leukemia. Currently, the most commonly used statins are simvastatin, rosuvastatin and atorvastatin. The anti-tumor activity of statins is largely related to their ability to induce apoptosis by targeting cancer cells with high selectivity. Statins are also involved in the regulation of the histone acetylation level, the disturbance of which can lead to abnormal activity of genes involved in the regulation of proliferation, differentiation and apoptosis. As a result, tumor growth and its invasion may be promoted, which is associated with a poor prognosis. High levels of histone deacetylases are observed in many cancers; therefore, one of the therapeutic strategies is to use their inhibitors. Combining statins with histone deacetylase inhibitors can induce a synergistic anticancer effect.
    Keywords:  anticancer therapy; cancer; cancer prevention; statins
    DOI:  https://doi.org/10.3390/ph14121220
  56. Nutrients. 2021 Nov 27. pii: 4279. [Epub ahead of print]13(12):
    Protective Effects and Benefits of Olive Oil and Its Extracts on Women's Health.
    Thanh Truong Giang Ly, Jisoo Yun, Dong-Hyung Lee, Joo-Seop Chung, Sang-Mo Kwon.
      Women and men share similar diseases; however, women have unique issues, including gynecologic diseases and diseases related to menstruation, menopause, and post menopause. In recent decades, scientists paid more attention to natural products and their derivatives because of their good tolerability and effectiveness in disease prevention and treatment. Olive oil is an essential component in the Mediterranean diet, a diet well known for its protective impact on human well-being. Investigation of the active components in olive oil, such as oleuropein and hydroxytyrosol, showed positive effects in various diseases. Their effects have been clarified in many suggested mechanisms and have shown promising results in animal and human studies, especially in breast cancer, ovarian cancer, postmenopausal osteoporosis, and other disorders. This review summarizes the current evidence of the role of olives and olive polyphenols in women's health issues and their potential implications in the treatment and prevention of health problems in women.
    Keywords:  breast cancer; gynecologic cancer; hydroxytyrosol; mediterranean diet; oleuropein; olive oil; osteoporosis; postmenopausal disorders
    DOI:  https://doi.org/10.3390/nu13124279
  57. Pharmaceutics. 2021 Nov 23. pii: 1986. [Epub ahead of print]13(12):
    Fucoidan-Based Nanoparticles with Inherently Therapeutic Efficacy for Cancer Treatment.
    Chih-Sheng Chiang, Bo-Jie Huang, Jui-Yu Chen, Wee Wei Chieng, Seh Hong Lim, Wei Lee, Weoi-Cherng Shyu, Long-Bin Jeng.
      The anticancer properties of fucoidan have been widely studied in cancer research. However, the lack of safety information on the parenteral administration of fucoidan and its rapid clearance from the system have limited its application. Herein, we assessed the therapeutic efficacy and safety of fucoidan and developed fucoidan nanoparticles (FuNPs) to enhance their therapeutic effect in the mouse model of breast cancer. FuNPs were synthesized through the emulsion method, and the stable colloid has an average size of 216.3 nm. FuNPs were efficiently internalized into breast cancer cells in vitro, demonstrating an enhanced antitumor activity in comparison with free form fucoidan. After the treatment of FuNPs, the tumor progression was significantly inhibited in viv. The tumor volume was reduced by 2.49-fold compared with the control group. Moreover, the inhibition of the invasion of tumor cells into the lungs revealed the antimetastatic properties of the FuNPs. FuNPs, as naturally marine polysaccharide-based nanoparticles, have shown their broader therapeutic window and enhanced antimetastatic ability, opening an avenue to the development of the inherently therapeutic nanomedicines.
    Keywords:  anti-metastasis; antitumor effect; fucoidan nanoparticle; marine polysaccharide; parenteral administration; safety
    DOI:  https://doi.org/10.3390/pharmaceutics13121986
  58. J Ethnopharmacol. 2021 Dec 27. pii: S0378-8741(21)01192-2. [Epub ahead of print] 114962
    The association study of chemical compositions and their pharmacological effects of Cyperi Rhizoma (Xiangfu), a potential traditional Chinese medicine for treating depression.
    Junrong Lu, Wenbing Li, Tianhui Gao, Shengpeng Wang, Chaomei Fu, Shu Wang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Cyperi Rhizoma (CR) derives from the rhizome or tuber of Cyperus rotundus L. of Cyperaceae. It is an herbal medicine which has been widely used in different healthcare systems like in China, India, Iran, and Japan. In Chinese medicine, CR could promote the flow of Qi in the Liver and Sanjiao channels, regulate menstruation and alleviate pain. Clinically, CR is used for depression, flatulence, hypochondriac pain, and dysmenorrhea. Thus, it has a long history and significant curative effect for the treatment of various Qi stagnation symptoms.
    AIM OF THIS REVIEW: This review focuses on explaining the major antidepressant mechanisms of CR, and assessing the shortcomings of existing work. Besides, clinical applications, pharmacological effects and their corresponding chemical compositions and quality control of CR have been researched.
    MATERIALS AND METHODS: The search terms "Cyperus rotundus L." was used to obtain the literatures from electronic databases such as Web of Science, ScienceDirect, PubMed, and China National Knowledge Infrastructure (CNKI). The information provided in this review to illustrate material basis of CR were only limited to papers which reported on the chemical compositions and pharmacological effects simultaneously.
    RESULT: The study showed that CR has significant application in Qi stagnation, like depressed liver, stomach, and bowel disorders, etc. in different countries or districts. Aqueous extract, EtOH extract, essential oil, total oligomeric flavonoids and five other extracts were effective constituents displaying pharmacological activities such as antibacterial, antioxidant, neuroprotective, antihemolytic, and anti-inflammatory effect. 41 kinds of specific components like α-cyperone, nootkatone exhibited corresponding pharmacological activities mentioned above. Different concentrations of ethanol extract, essential oil, decoction of CR and monomer composition like α-cyperone, rotunduside G had anti-depressant effects.
    CONCLUSIONS: In the present study, we have provided scientific information and research developments on traditional uses, phytochemical compositions and corresponding pharmacological activities, and quality control status on CR. The antidepression effect and its corresponding chemical compositions were generalized separately. The pharmacological activities studies should be more focused on the reflection of traditional clinical values. CR could be a significant potential herbal medicine to develop antidepressant drugs with lower side effects.
    Keywords:  Chemical compositions; Cyperi rhizoma; Depression; Pharmacological effects
    DOI:  https://doi.org/10.1016/j.jep.2021.114962
  59. Recent Pat Anticancer Drug Discov. 2021 Dec 12.
    The Impact of Polyphenolic in The Management of Breast Cancer: Mechanistic Aspects and Recent Patents.
    Heba A S El-Nashar, Shaza H Aly, Amirhossein Ahmadi, Mohamed El-Shazly.
       BACKGROUND: Breast cancer is the most frequently diagnosed type of cancer in women (2.1 million) and stands as the fifth leading cause of death. Several treatment strategies are available such as surgical resection, radiation, hormonal therapy, and conventional chemotherapy that are associated with severe adverse effects on the patients.
    OBJECTIVE: This review aims to summarize the different studies (in vitro, in vivo, and new patents) concerning the therapeutic potential of plant polyphenolics in the management of breast cancer published in the period from January 2016 to January 2021. Moreover, this review will focus on the underlying mechanism of action and molecular characteristics of these compounds.
    METHODS: The data of this review were collected from different scientific databases such as PubMed, Science Direct, Google Scholarship, sci-finder, and Egyptian Knowledge bank (EKB).
    RESULTS: During the last period (2016-2021), the in vitro studies investigated about 52 natural compounds of polyphenolic nature with promising anti-breast cancer, while fourteen compounds were reported via in vivo studies. Besides, there were about fifteen compounds registered as patent drugs. Different mechanisms of action and molecular targets were reported to provide a great clarified base and precise reflection for the anticancer properties of these compounds against breast cancer.
    CONCLUSION: Polyphenolics represent a plentiful sources of anticancer lead compounds that stand against the progression of breast cancer invasion and metastasis.
    Keywords:  anticancer; breast cancer; chemotherapy; metastasis; patents; polyphenolics
    DOI:  https://doi.org/10.2174/1574892816666211213090623
  60. Pharmaceuticals (Basel). 2021 Dec 20. pii: 1338. [Epub ahead of print]14(12):
    Pharmacological Activity of Garcinia indica (Kokum): An Updated Review.
    Sung Ho Lim, Ho Seon Lee, Chang Hoon Lee, Chang-Ik Choi.
      Garcinia indica (commonly known as kokum), belonging to the Clusiaceae family (mangosteen family), is a tropical evergreen tree distributed in certain regions of India. It has been used in culinary and industrial applications for a variety of purposes, including acidulant in curries, pickles, health drinks, wine, and butter. In particular, G. indica has been used in traditional medicine to treat inflammation, dermatitis, and diarrhea, and to promote digestion. According to several studies, various phytochemicals such as garcinol, hydroxycitric acid (HCA), cyanidin-3-sambubioside, and cyanidin-3-glucoside were isolated from G. indica, and their pharmacological activities were published. This review highlights recent updates on the various pharmacological activities of G. indica. These studies reported that G. indica has antioxidant, anti-obesity, anti-arthritic, anti-inflammatory, antibacterial, hepatoprotective, cardioprotective, antidepressant and anxiolytic effects both in vitro and in vivo. These findings, together with previously published reports of pharmacological activity of various components isolated from G. indica, suggest its potential as a promising therapeutic agent to prevent various diseases.
    Keywords:  Garcinia indica; kokum; pharmacological activity; wild mangosteen
    DOI:  https://doi.org/10.3390/ph14121338
  61. Nano Lett. 2021 Dec 28.
    Multistage Systemic and Cytosolic Protein Delivery for Effective Cancer Treatment.
    Liyi Fu, Xianwu Hua, Xingya Jiang, Jinjun Shi.
      Current clinical applications of protein therapy are largely limited to systemically accessible targets in vascular or extracellular areas. Major obstacles to the widespread application of protein therapeutics in cancer treatment include low membrane permeability and endosomal entrapment. Herein, we report a multistage nanoparticle (NP) strategy for systemic and cytosolic protein delivery to tumor cells, by encapsulating a protein conjugate, tetra-guanidinium (TG)-modified saporin, into tumor microenvironment (TME) pH-responsive polymeric NPs. Upon reaching the tumor site after systemic circulation, the polymeric NPs respond rapidly to the acidic tumor microenvironment and release the TG-saporin conjugates, which penetrate the tumor tissue and enter into tumor cells via TG-mediated cytosolic transportation. The TG-saproin NPs showed potent inhibition of lung cancer cell growth in vitro and in vivo. We expect that this multistage NP delivery strategy with long blood circulation, deep tumor penetration, and efficient cytosolic transport may be applicable to various therapeutic proteins for effective cancer treatment.
    Keywords:  TME pH-responsive nanoparticle; cytosolic transport; multistage delivery; protein conjugate; tumor penetration
    DOI:  https://doi.org/10.1021/acs.nanolett.1c03293
  62. Food Chem. 2021 Dec 15. pii: S0308-8146(21)02866-1. [Epub ahead of print]376 131860
    Immunometabolism modulation, a new trick of edible and medicinal plants in cancer treatment.
    Wen Tan, Tingrui Pan, Shengpeng Wang, Peng Li, Yongfan Men, Rui Tan, Zhangfeng Zhong, Yitao Wang.
      The edible and medicinal plants (EMPs) are becoming an abundant source for cancer prevention and treatment since the natural and healthy trend for modern human beings. Currently, there are more than one hundred species of EMPs widely used and listed by the national health commission of China, and most of them indicate immune or metabolic regulation potential in cancer treatment with numerous studies over the past two decades. In the present review, we focused on the metabolic influence in immunocytes and tumor microenvironment, including immune response, immunosuppressive factors and cancer cells, discussing the immunometabolic potential of EMPs in cancer treatment. There are more than five hundred references collected and analyzed through retrieving pharmacological studies deposited in PubMed by medical subject headings and the corresponding names derived from pharmacopoeia of China as a sole criterion. Finally, the immunometabolism modulation of EMPs was sketch out implying an immunometabolic control in cancer treatment.
    Keywords:  Cancer; Edible and medicinal plants; Immunometabolism; Traditional Chinese medicinal herb
    DOI:  https://doi.org/10.1016/j.foodchem.2021.131860
  63. Pharmaceutics. 2021 Dec 12. pii: 2137. [Epub ahead of print]13(12):
    Drug Delivery Strategies for Curcumin and Other Natural Nrf2 Modulators of Oxidative Stress-Related Diseases.
    Nina Katarina Grilc, Matej Sova, Julijana Kristl.
      Oxidative stress is associated with a wide range of diseases characterised by oxidant-mediated disturbances of various signalling pathways and cellular damage. The only effective strategy for the prevention of cellular damage is to limit the production of oxidants and support their efficient removal. The implication of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the cellular redox status has spurred new interest in the use of its natural modulators (e.g., curcumin, resveratrol). Unfortunately, most natural Nrf2 modulators are poorly soluble and show extensive pre-systemic metabolism, low oral bioavailability, and rapid elimination, which necessitates formulation strategies to circumvent these limitations. This paper provides a brief introduction on the cellular and molecular mechanisms involved in Nrf2 modulation and an overview of commonly studied formulations for the improvement of oral bioavailability and in vivo pharmacokinetics of Nrf2 modulators. Some formulations that have also been studied in vivo are discussed, including solid dispersions, self-microemulsifying drug delivery systems, and nanotechnology approaches, such as polymeric and solid lipid nanoparticles, nanocrystals, and micelles. Lastly, brief considerations of nano drug delivery systems for the delivery of Nrf2 modulators to the brain, are provided. The literature reviewed shows that the formulations discussed can provide various improvements to the bioavailability and pharmacokinetics of natural Nrf2 modulators. This has been demonstrated in animal models and clinical studies, thereby increasing the potential for the translation of natural Nrf2 modulators into clinical practice.
    Keywords:  Nrf2 modulator; SMEDDS; curcumin; micelles; nanoparticles; oral bioavailability; oxidative stress; poor solubility; resveratrol; solid dispersions
    DOI:  https://doi.org/10.3390/pharmaceutics13122137
  64. J Colloid Interface Sci. 2021 Dec 13. pii: S0021-9797(21)02208-6. [Epub ahead of print]611 193-204
    Multifunctional phototheranostic nanoplatform based on polydopamine-manganese dioxide-IR780 iodide for effective magnetic resonance imaging-guided synergistic photodynamic/photothermal therapy.
    Zhimin Mo, Mengjun Qiu, Kan Zhao, Han Hu, Qi Xu, Jinguo Cao, Yuxuan Luo, Liping Liu, Zushun Xu, Changfeng Yi, Zhifan Xiong, Guangfu Liao, Shengli Yang.
      Multifunctional phototheranostics combining diagnostic and therapeutic modalities may provide a revolutionary opportunity for cancer treatment. As a promising tumor phototheranostic molecule, IR780 iodide (IR780) shows excellent photodynamic and photothermal performance under near-infrared laser irradiation; however, its hydrophobicity and instability limit its further use in organisms. This work demonstrates the design and development of a multifunctional nanoplatform (PMIDA, referring to polydopamine (PDA)-manganese dioxide (MnO2)-IR780) for imaging-guided phototherapy. The good biocompatibility of PDA greatly improves the water solubility and photostability of IR780, and its excellent photothermal properties make PMIDA a dual photothermal therapy (PTT). MnO2-induced generation of oxygen in the tumor microenvironment improves the hypoxia effect and photodynamic therapy (PDT) of IR780. Moreover, Mn2+ serves as a decent T1-weighted magnetic resonance imaging (MRI) probe to guide treatment. Notably, in relevant cellular assays, PMIDA shows high photodynamic and photothermal effects contributing to the final therapeutic effect. The MRI-guided PDT/PTT synergistic therapy effect in vivo is demonstrated by precise tumor diagnosis and complete tumor elimination outcomes. Based on these experiments, PMIDA nanoparticles display promising effects in facilitating intravenous injection of IR780 and achieving magnetic resonance imaging (MRI)-guided phototheranostic efficacy for tumor treatment.
    Keywords:  Magnetic resonance imaging (MRI); Phototheranostics; Stimulus response; Synergistic therapy
    DOI:  https://doi.org/10.1016/j.jcis.2021.12.071
  65. Plants (Basel). 2021 Dec 03. pii: 2663. [Epub ahead of print]10(12):
    Anti-Inflammatory and Anticancer Properties of Birch Bark-Derived Betulin: Recent Developments.
    Hardeep Singh Tuli, Katrin Sak, Dhruv Sanjay Gupta, Ginpreet Kaur, Diwakar Aggarwal, Nidarshana Chaturvedi Parashar, Renuka Choudhary, Mukerrem Betul Yerer, Jagjit Kaur, Manoj Kumar, Vivek Kumar Garg, Gautam Sethi.
      Birch tree bark-derived betulin has attracted scientific interest already for several centuries, being one of the first natural products identified from plants. However, the cellular events regulated by betulin and precise molecular mechanisms under these processes have been begun to be understood only recently. Today, we know that betulin can exert important anticancer activities through modulation of diverse cellular pathways. In this review article, betulin-regulated molecular signaling is unraveled and presented with a special focus on its participation in anti-inflammatory processes, especially by modulating nuclear factor-κB (NF-κB), prostaglandin/COX, and nuclear factor erythroid2-related factor 2 (Nrf2)-mediated cascades. By regulating these diverse pathways, betulin can not only affect the development and progression of different cancers, but also enhance the antitumor action of traditional therapeutic modalities. It is expected that by overcoming the low bioavailability of betulin by encapsulating it into nanocarriers, this promising natural compound may provide novel possibilities for targeting inflammation-related cancers.
    Keywords:  NF-κB; Nrf2; betulin; birch bark; cancer; inflammation; nanocarriers
    DOI:  https://doi.org/10.3390/plants10122663
  66. Front Bioeng Biotechnol. 2021 ;9 779393
    Screening of Hibiscus and Cinnamomum Plants and Identification of Major Phytometabolites in Potential Plant Extracts Responsible for Apoptosis Induction in Skin Melanoma and Lung Adenocarcinoma Cells.
    Neha Kaushik, Hyunji Oh, Yeasol Lim, Nagendra Kumar Kaushik, Linh Nhat Nguyen, Eun Ha Choi, June Hyun Kim.
      Carcinogenesis is a major concern that severely affects the human population. Owing to persistent demand for novel therapies to treat and prohibit this lethal disease, research interest among scientists is drawing its huge focus toward natural products, as they have minimum toxicity comparable with existing treatment methods. The plants produce secondary metabolites, which are known to have the anticancer potential for clinical drug development. Furthermore, the use of nanocarriers could boost the solubility and stability of phytocompounds to obtain site-targeting delivery. The identification of potential phytochemicals in natural compounds would be beneficial for the synthesis of biocompatible nanoemulsions. The present study aimed to investigate the potential cytotoxicity of ethanol extracts of Hibiscus syriacus and Cinnamomum loureirii Nees plant parts on human skin melanoma (G361) and lung adenocarcinoma (A549) cells. Importantly, biochemical analysis results showed the presence of high phenol (50-55 µgGAE/mg) and flavonoids [42-45 µg quercetin equivalents (QE)/mg] contents with good antioxidant activity (40-58%) in C. loureirii Nees plants extracts. This plant possesses potent antiproliferative activity (60-90%) on the malignant G361 and A549 and cell lines correlated with the production of nitric oxide. Especially, C. loureirii plant extracts have major metabolites that exhibit cancer cell death associated with cell cycle arrest. These findings support the potential application of Cinnamomum for the development of therapeutic nanoemulsion in future cancer therapy.
    Keywords:  cinnamomum loureirii nees; growth inhibition; hibiscus syriacus; lung adenocarcinoma; nanoemulsions; skin melanoma cell line
    DOI:  https://doi.org/10.3389/fbioe.2021.779393
  67. Drug Deliv. 2022 Dec;29(1): 75-88
    Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy.
    Bo Li, Tingfei Tan, Weiwei Chu, Ying Zhang, Yuanzi Ye, Shanshan Wang, Yan Qin, Jihui Tang, Xi Cao.
      Breast cancer is one of the most common types of cancer in female patients with high morbidity and mortality. Multi-drug chemotherapy has significant advantages in the treatment of malignant tumors, especially in reducing drug toxicity, increasing drug sensitivity and reducing drug resistance. The objective of this research is to fabricate lipid nanoemulsions (LNs) for the co-delivery of PTX and docosahexaenoic acid (DHA) with folic acid (FA) decorating (PTX/DHA-FA-LNs), and investigate the anti-tumor activity of the PTX/DHA-FA-LNs against breast cancer both in vitro and in vivo. PTX/DHA-FA-LNs showed a steady release of PTX and DHA from the drug delivery system (DDS) without any burst effect. Furthermore, the PTX/DHA-FA-LNs exhibited a dose-dependent cytotoxicity and a higher rate of apoptosis as compared with the other groups in MCF-7 cells. The cellular uptake study revealed that this LNs were more readily uptaken by MCF-7 cells and M2 macrophages in vitro. Additionally, the targeted effect of PTX/DHA-FA-LNs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. The anti-tumor efficiency results showed that PTX/DHA-FA-LNs significant inhibited tumor volume growth, prolonged survival time, and reduced toxicity when compared with the other groups. These results indicated that DHA increases the sensitivity of tumor cells and tumor-associated macrophages (ATM2) to PTX, and synergistic effects of folate modification in breast cancer treatment, thus PTX/DHA-FA-LNs may be a promising nanocarrier for breast cancer treatment.
    Keywords:  Paclitaxel (PTX); breast cancer; docosahexaenoic acid (DHA); folic acid (FA); lipid nanoemulsions (LNs); multi-drug chemotherapy
    DOI:  https://doi.org/10.1080/10717544.2021.2018523
  68. Nutrients. 2021 Dec 16. pii: 4503. [Epub ahead of print]13(12):
    Arginine and Arginases Modulate Metabolism, Tumor Microenvironment and Prostate Cancer Progression.
    Andreia Matos, Marcos Carvalho, Manuel Bicho, Ricardo Ribeiro.
      Arginine availability and activation of arginine-related pathways at cancer sites have profound effects on the tumor microenvironment, far beyond their well-known role in the hepatic urea cycle. Arginine metabolism impacts not only malignant cells but also the surrounding immune cells behavior, modulating growth, survival, and immunosurveillance mechanisms, either through an arginase-mediated effect on polyamines and proline synthesis, or by the arginine/nitric oxide pathway in tumor cells, antitumor T-cells, myeloid-derived suppressor cells, and macrophages. This review presents evidence concerning the impact of arginine metabolism and arginase activity in the prostate cancer microenvironment, highlighting the recent advances in immunotherapy, which might be relevant for prostate cancer. Even though further research is required, arginine deprivation may represent a novel antimetabolite strategy for the treatment of arginine-dependent prostate cancer.
    Keywords:  arginase; arginine; metabolism; nitric oxide; prostate cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/nu13124503
  69. Nanomedicine. 2021 Dec 23. pii: S1549-9634(21)00156-8. [Epub ahead of print] 102513
    Small Molecule Based EGFR Targeting of Biodegradable Nanoparticles Containing Temozolomide and Cy5 Dye for Greatly Enhanced Image-Guided Glioblastoma Therapy.
    Rebecca R Schmitt, Supriya D Mahajan, Artem Pliss, Paras N Prasad.
      Current glioblastoma multiform (GBM) treatment is insufficient, facing obstacles like poor tumor accumulation and dose limiting side effects of chemotherapeutic agents. Targeted nanomaterials offer breakthrough potential in GBM treatment; however, traditional antibody-based targeting poses challenges for live brain application. To overcome current obstacles, we introduce here the development of a small molecule targeting agent, CFMQ, coupled to biocompatible chitosan coated poly(lactic-co-glycolic) acid nanoparticles. These targeted nanoparticles enhance cellular uptake and show rapid blood-brain barrier (BBB) permeability in-vitro, demonstrating the ability to effectively deliver their load to tumor cells. Encapsulation of the chemotherapeutic agent, temozolomide (TMZ), decreases the IC50~34-fold compared to free-drug. Also, CFMQ synergistically suppresses tumor cell progression, reducing colony formation (98%), cell migration (84%), and cell invasion (77%). Co-encapsulation of Cy5 enables optical image guided therapy. This biocompatible theranostic nanoformulation shows early promise in significantly enhancing the efficacy of TMZ, while providing potential for image-guided therapy for GBM.
    Keywords:  Image guided therapy; Nanoparticle; Polymeric drug carrier; Small molecule targeting; cancer chemotherapy
    DOI:  https://doi.org/10.1016/j.nano.2021.102513
  70. Biomaterials. 2021 Dec 20. pii: S0142-9612(21)00684-0. [Epub ahead of print]281 121328
    Tumor microenvironment-responsive Ag2S-PAsp(DOX)-cRGD nanoparticles-mediated photochemotherapy enhances the immune response to tumor therapy.
    Ruxia Han, Qingya Liu, Yi Lu, Jinrong Peng, Meng Pan, GuiHua Wang, Wen Chen, Yao Xiao, ChengLi Yang, Zhiyong Qian.
      Chemotherapy drugs play important roles in clinical treatment, and most first-line regimens of cancer therapy contain chemotherapy drugs. In particular, some chemotherapeutic drugs can also produce ICD effect and enhance the immune response of the body. However, most chemotherapy drugs do not specifically target tumors or the complex tumor microenvironment, which renders their curative effect insufficient. Therefore, we constructed a tumor microenvironment-responsive drug delivery system (Ag2S-PAsp-cRGD) combined with doxorubicin (DOX) for tumor therapy. Firstly, Ag2S nanoparticles (NPs) were modified with polymer aspartic acid (PAsp) to construct the drug-loading platform. Then, an active targeting ligand (cRGD) was coupled through an amide reaction to enhance the functional targeting ability of the drug delivery system. In vivo imaging of the system showed that the nanoparticles accumulated in the tumor site, which facilitated the delivery of the chemotherapy drug DOX to the targeted tumor site. Furthermore, the photothermal effect of Ag2S NPs can effectively killed tumor cells, and also helped the release of DOX from nanoparticles into tumor tissue, thus enhancing the chemotherapeutic effect. Moreover, combined with the ICD effect jointly induced by photothermal therapy (PTT) and DOX, the treatment further activated the host immune response against tumors by enhancing the presentation of antigens and promoting the differentiation of T cells. This strategy of photo-chemo-immunotherapy showed excellent antitumor effect, not only eliminating the primary tumor but also preventing recurrence and inhibiting metastasis.
    Keywords:  Eliminate tumor; ICD effect; Immunotherapy; Photochemotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biomaterials.2021.121328
  71. Bioconjug Chem. 2021 Dec 30.
    Dendrimer-Based Nanogels for Cancer Nanomedicine Applications.
    Shewaye Lakew Mekuria, Zhijun Ouyang, Cong Song, João Rodrigues, Mingwu Shen, Xiangyang Shi.
      Recent advances in the field of nanotechnology bring an alternative approach to personalized medicine in cancer treatment. Nanogels (NGs) are among the nanosized superconstructs composed of amphiphilic or hydrophilic polymer networks. The design of different types of biodegradable polymer-based NGs in various biomedical applications has received extensive attention, due to their unique physicochemical properties such as highly porous structure, stimuli-responsiveness, and mimicking of some biological properties. In this review, we concisely surveyed the synthesis of dendrimer-based NGs synthesized via different methods including covalent conjugation, inverse nanoprecipitation, physical cross-linking, or self-assembly for various cancer nanomedicine applications, particularly for drug delivery, gene delivery, photothermal therapy, and combination therapy, as well as for biological imaging-guided chemotherapy. Additionally, we provide herein future perspective toward the new design of dendrimer-based NGs for different cancer nanomedicine uses.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.1c00587
  72. Pharmaceuticals (Basel). 2021 Dec 10. pii: 1293. [Epub ahead of print]14(12):
    Lichen-Derived Compounds and Extracts as Biologically Active Substances with Anticancer and Neuroprotective Properties.
    Elżbieta Studzińska-Sroka, Aleksandra Majchrzak-Celińska, Przemysław Zalewski, Dominik Szwajgier, Ewa Baranowska-Wójcik, Barbara Kaproń, Tomasz Plech, Marcin Żarowski, Judyta Cielecka-Piontek.
      Lichens are a source of chemical compounds with valuable biological properties, structurally predisposed to penetration into the central nervous system (CNS). Hence, our research aimed to examine the biological potential of lipophilic extracts of Parmelia sulcata, Evernia prunastri, Cladonia uncialis, and their major secondary metabolites, in the context of searching for new therapies for CNS diseases, mainly glioblastoma multiforme (GBM). The extracts selected for the study were standardized for their content of salazinic acid, evernic acid, and (-)-usnic acid, respectively. The extracts and lichen metabolites were evaluated in terms of their anti-tumor activity, i.e., cytotoxicity against A-172 and T98G cell lines and anti-IDO1, IDO2, TDO activity, their anti-inflammatory properties exerted by anti-COX-2 and anti-hyaluronidase activity, antioxidant activity, and anti-acetylcholinesterase and anti-butyrylcholinesterase activity. The results of this study indicate that lichen-derived compounds and extracts exert significant cytotoxicity against GBM cells, inhibit the kynurenine pathway enzymes, and have anti-inflammatory properties and weak antioxidant and anti-cholinesterase properties. Moreover, evernic acid and (-)-usnic acid were shown to be able to cross the blood-brain barrier. These results demonstrate that lichen-derived extracts and compounds, especially (-)-usnic acid, can be regarded as prototypes of pharmacologically active compounds within the CNS, especially suitable for the treatment of GBM.
    Keywords:  (−)-usnic acid; biological activity; evernic acid; lichen extracts; salazinic acid; secondary metabolites
    DOI:  https://doi.org/10.3390/ph14121293
  73. Pharmaceutics. 2021 Nov 24. pii: 1994. [Epub ahead of print]13(12):
    Advances in Use of Nanomaterials for Musculoskeletal Regeneration.
    Josef Jampilek, Daniela Placha.
      Since the worldwide incidence of bone disorders and cartilage damage has been increasing and traditional therapy has reached its limits, nanomaterials can provide a new strategy in the regeneration of bones and cartilage. The nanoscale modifies the properties of materials, and many of the recently prepared nanocomposites can be used in tissue engineering as scaffolds for the development of biomimetic materials involved in the repair and healing of damaged tissues and organs. In addition, some nanomaterials represent a noteworthy alternative for treatment and alleviating inflammation or infections caused by microbial pathogens. On the other hand, some nanomaterials induce inflammation processes, especially by the generation of reactive oxygen species. Therefore, it is necessary to know and understand their effects in living systems and use surface modifications to prevent these negative effects. This contribution is focused on nanostructured scaffolds, providing a closer structural support approximation to native tissue architecture for cells and regulating cell proliferation, differentiation, and migration, which results in cartilage and bone healing and regeneration.
    Keywords:  bones; cartilage; healing; implants; musculoskeletal disorders; nanocomposites; nanomaterials
    DOI:  https://doi.org/10.3390/pharmaceutics13121994
  74. Am J Chin Med. 2021 ;49(8): 1965-1999
    Inhibiting TGF-[Formula: see text] 1-Mediated Cellular Processes as an Effective Strategy for the Treatment of Pulmonary Fibrosis with Chinese Herbal Medicines.
    Jing Wang, Xingtao Zhao, Wuwen Feng, Yunxia Li, Cheng Peng.
      Pulmonary fibrosis (PF) is a chronic and irreversible interstitial lung disease that even threatens the lives of some patients infected with COVID-19. PF is a multicellular pathological process, including the initial injuries of epithelial cells, recruitment of inflammatory cells, epithelial-mesenchymal transition, activation and differentiation of fibroblasts, etc. TGF-[Formula: see text]1 acts as a key effect factor that participates in these cellular processes of PF. Recently, much attention was paid to inhibiting TGF-[Formula: see text]1 mediated cell processes in the treatment of PF with Chinese herbal medicines (CHM), an important part of traditional Chinese medicine. Here, this review first summarized the effects of TGF-[Formula: see text]1 in different cellular processes of PF. Then, this review summarized the recent research on CHM (compounds, multi-components, single medicines and prescriptions) to directly and/or indirectly inhibit TGF-[Formula: see text]1 signaling (TLRs, PPARs, micrRNA, etc.) in PF. Most of the research focused on CHM natural compounds, including but not limited to alkaloids, flavonoids, phenols and terpenes. After review, the research perspectives of CHM on TGF-[Formula: see text]1 inhibition in PF were further discussed. This review hopes that revealing the inhibiting effects of CHM on TGF-[Formula: see text]1-mediated cellular processes of PF can promote CHM to be better understood and utilized, thus transforming the therapeutic activities of CHM into practice.
    Keywords:  Cellular Processes; Pulmonary Fibrosis; Review; TGF-[Formula: see text]1; Traditional Chinese Medicine
    DOI:  https://doi.org/10.1142/S0192415X21500932
  75. Oxid Med Cell Longev. 2021 ;2021 5192271
    The Synergistic Reducing Drug Resistance Effect of Cisplatin and Ursolic Acid on Osteosarcoma through a Multistep Mechanism Involving Ferritinophagy.
    Zhen Tang, Hui Dong, Tian Li, Ning Wang, Xinghui Wei, Hao Wu, Yichao Liu, Wei Wang, Zheng Guo, Xin Xiao.
      Increasing evidence suggests that traditional Chinese medicine strategies are obviously beneficial for cancer treatment, but scientific research on the underlying molecular mechanisms is lacking. We report that ursolic acid, a bioactive ingredient isolated from Radix Actinidiae chinensis, has strong antitumour effects on osteosarcoma cells. Functional studies showed that ursolic acid inhibited tumour cell proliferation and promoted the apoptosis of a variety of osteosarcoma cells. Ursolic acid had a synergistic cytotoxic effect with cisplatin on osteosarcoma cells. In a mouse osteosarcoma xenograft model, low-dose cisplatin combined with ursolic acid significantly reduced tumour growth. Notably, ursolic acid reversed weight loss in mice treated with cisplatin. Mechanistic studies showed that ursolic acid degraded ferritin by activating autophagy and induced intracellular overload of ferrous ions, leading to ferroptosis. In addition, ursolic acid enhanced the DNA-damaging effect of cisplatin on osteosarcoma cells. Taken together, these findings suggest that ursolic acid is a nontoxic adjuvant that may enhance the effectiveness of chemotherapy in osteosarcoma.
    DOI:  https://doi.org/10.1155/2021/5192271
  76. Pharmaceutics. 2021 Dec 16. pii: 2167. [Epub ahead of print]13(12):
    The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers.
    Thomas C Chen, Clovis O da Fonseca, Daniel Levin, Axel H Schönthal.
      Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity. Clinical trials with an oral POH formulation administered to cancer patients failed to realize therapeutic expectations, although an intra-nasal POH formulation yielded encouraging results in malignant glioma patients. Based on its amphipathic nature, POH revealed the ability to overcome biological barriers, primarily the blood-brain barrier (BBB), but also the cytoplasmic membrane and the skin, which appear to be characteristics that critically contribute to POH's value for drug development and delivery. In this review, we present the physicochemical properties of POH that underlie its ability to overcome the obstacles placed by different types of biological barriers and consequently shape its multifaceted promise for cancer therapy and applications in drug development. We summarized and appraised the great variety of preclinical and clinical studies that investigated the use of POH for intranasal delivery and nose-to-brain drug transport, its intra-arterial delivery for BBB opening, and its permeation-enhancing function in hybrid molecules, where POH is combined with or conjugated to other therapeutic pharmacologic agents, yielding new chemical entities with novel mechanisms of action and applications.
    Keywords:  NEO100; blood–brain barrier; drug formulation; drug hybrids; intra-arterial delivery; intracranial malignancies; intranasal delivery; monoterpene; monoterpenoid
    DOI:  https://doi.org/10.3390/pharmaceutics13122167
  77. Anal Chem. 2021 Dec 27.
    Integrated Wearable Sensors for Sensing Physiological Pressure Signals and β-Hydroxybutyrate in Physiological Fluids.
    Xieli Zhang, Yong Xia, Yang Liu, Samuel M Mugo, Qiang Zhang.
      Flexible and wearable sensors have attracted much attention for their applications in health monitoring and the human-machine interaction. The most studied wearable sensors have been demonstrated for sensing a limited range of metabolites such as ions, glucose, uric acid, lactate, etc. Both sweat and urine contain numerous other physiologically relevant metabolites indicative of health and wellness. This work demonstrates the use of the wearable sensor for the detection of β-hydroxybutyrate (HB) in sweat. HB is an important biomarker for diabetic ketoacidosis, a condition caused by the accumulation of ketone bodies in hyperglycemia or metabolic acidosis patients. Herein, we fabricated an integrated sensing system coupling an HB detection chamber with a serpentine electrode for sensing physiological signals such as pulse beat, vocal cord vibration, etc. The real-time HB detection was based on a β-hydroxybutyrate dehydrogenase enzymatic reaction. The stability of the enzyme and the cofactor couple was achieved by cross-linking networks and a redox mediator, thereby achieving high selectivity and low detection limits to HB in urine and sweat. The dual-functional sensor was integrated with a signal processing circuitry for signal transduction, conditioning, processing, wireless transmission, and real-time convenient health monitoring display to a smartphone via home-developed software.
    DOI:  https://doi.org/10.1021/acs.analchem.1c03884
  78. ACS Omega. 2021 Dec 21. 6(50): 34842-34849
    Effect of Doxorubicin on the Near-Infrared Optical Properties of Indocyanine Green.
    Saumya Jaiswal, Surjendu Bikash Dutta, Debasis Nayak, Sharad Gupta.
      In recent years, chemo-photothermal therapy (chemo-PTT) has been extensively studied for the upgradation of cancer treatment. The combined therapeutic approach reduces the overall cytotoxicity and enhances the therapeutic effect against the cancerous cells. In chemo-PTT, Indocyanine green (ICG) dye, a near-infrared chromophore, is used for PTT in combination with doxorubicin (DOX), a chemotherapeutic drug. ICG and DOX work very efficiently in synergy against cancer. However, the effect of DOX on the optical properties of ICG has not been studied yet. Here, for the first time, we report the effect of DOX on the optical properties of ICG in detail. DOX interacts with ICG and induces the aggregation of ICG even at a low concentration. The coincubation of both the molecules causes H and J aggregations in ICG. However, the J aggregation becomes more prominent with an increasing DOX concentration. These findings suggest that the optical properties of ICG change upon incubation with the DOX, which might affect the efficacy of PTT.
    DOI:  https://doi.org/10.1021/acsomega.1c05500
  79. Biomaterials. 2021 Dec 16. pii: S0142-9612(21)00681-5. [Epub ahead of print]281 121325
    Dual enzyme-mimic nanozyme based on single-atom construction strategy for photothermal-augmented nanocatalytic therapy in the second near-infrared biowindow.
    Yutian Su, Fan Wu, Qiuxian Song, Mengjie Wu, Mohsen Mohammadniaei, Taiwei Zhang, Baolei Liu, Shishan Wu, Ming Zhang, Ao Li, Jian Shen.
      Nanozyme-based catalytic therapy, an emerging therapeutic pattern, has significantly incorporated in the advancement of tumor therapy by generating lethal reactive oxygen species. Nevertheless, most of the nanozymes have mono catalytic performances with H2O2 in the tumor microenvironment (TME), which lowers their therapeutic efficiency. Herein, we design a newly-developed single-atom Fe dispersed N-doped mesoporous carbon nanospheres (SAFe-NMCNs) nanozyme with high H2O2 affinity for photothermal-augmented nanocatalytic therapy. The SAFe-NMCNs nanozyme possesses dual enzyme-mimic catalytic activity which not only acts as a catalase-mimic role to achieve ultrasonic imaging in tumor site by O2 generation, but also exhibits the superior peroxidase-mimic catalytic performance to generate •OH for nanocatalytic therapy. Besides, the SAFe-NMCNs nanozyme with strong optical absorption in the second near-infrared (NIR-II) region shows excellent photothermal conversion performance. The peroxidase-mimic catalytic process of SAFe-NMCNs nanozyme is realized using density functional theory (DFT). Both in vitro and in vivo results indicate that the SAFe-NMCNs nanozyme can efficiently suppress tumor cells growth by a synergistic therapy effect with photothermal-augmented nanocatalytic therapy. The work developed a single-atom-coordinated nanozyme with dual-enzyme catalytic performance and achieve hyperthermia-augmented nanocatalytic therapy effect, can open a window for potential biological applications.
    Keywords:  Dual enzyme-mimic; NIR-II region; Nanocatalytic therapy; Nanozyme; Single-atom
    DOI:  https://doi.org/10.1016/j.biomaterials.2021.121325
  80. Plants (Basel). 2021 Nov 26. pii: 2591. [Epub ahead of print]10(12):
    Developmental Stages-Specific Response of Anise Plants to Laser-Induced Growth, Nutrients Accumulation, and Essential Oil Metabolism.
    Mohammad K Okla, Mohamed Abdel-Mawgoud, Saud A Alamri, Zahid Khorshid Abbas, Wahidah H Al-Qahtani, Salem Mesfir Al-Qahtani, Nadi Awad Al-Harbi, Abdelrahim H A Hassan, Samy Selim, Mohammed H Alruhaili, Hamada AbdElgawad.
      Compared to seeds and mature tissues, sprouts are well known for their higher nutritive and biological values. Fruits of Pimpinella anisum (anise) are extensively consumed as food additives; however, the sprouting-induced changes in their nutritious metabolites are hardly studied. Herein, we investigated the bioactive metabolites, phytochemicals, and antioxidant properties of fruits, sprouts (9-day-old), and mature tissue (5-week-old) of anise under laser irradiation treatment (He-Ne laser, 632 nm). Laser treatment increased biomass accumulation of both anise sprouts and mature plants. Bioactive primary (e.g., proteins and sugars) and secondary metabolites (e.g., phenolic compounds), as well as mineral levels, were significantly enhanced by sprouting and/or laser light treatment. Meanwhile, laser light has improved the levels of essential oils and their related precursors (e.g., phenylalanine), as well as enzyme activities [e.g., O-methyltransferase and 3-Deoxy-D-arabino-heptulosonate-7-phosphate synthase (DAHPS)] in mature tissues. Moreover, laser light induced higher levels of antioxidant and anti-lipidemic activities in sprouts as compared to fruits and mature tissues. Particularly at the sprouting stage, anise was more responsive to laser light treatment than mature plants.
    Keywords:  He–Ne laser; anise sprouts; antioxidant; mature plants; nutritious metabolites
    DOI:  https://doi.org/10.3390/plants10122591
  81. J Drug Target. 2021 Dec 28. 1-39
    Application of Nanoparticles in Drug Delivery for the Treatment of Osteosarcoma: Focusing on the Liposomes.
    Wenqing Liang, Yongqiang Dong, Ruyi Shao, Songou Zhang, Xudong Wu, Xiaogang Huang, Bin Sun, Bin Zeng, Jiayi Zhao.
      Osteosarcoma (OS) is one of the most common primary bone malignancies in children and adolescents. The toxicity to healthy tissues from conventional therapeutic strategies, including chemotherapy and radiotherapy, and drug resistance, severely affect OS patients' quality of life and cancer-specific outcomes. Many efforts have been made to develop various nanomaterial-based drug delivery systems with specific properties to overcome these limitations. Among the developed nanocarriers, liposomes are the most successful and promising candidates for providing targeted tumor therapy and enhancing the safety and therapeutic effect of encapsulated agents. Liposomes have low immunogenicity, high biocompatibility, prolonged half-life, active group protection, cell-like membrane structure, safety, and effectiveness. This review will discuss various nanomaterial-based carriers in cancer therapy and then the characteristics and design of liposomes with a particular focus on the targeting feature. We will also summarize the recent advances in the liposomal drug delivery system for OS treatment in preclinical and clinical studies.
    Keywords:  Drug delivery system; Liposome; Nanocarrier; Nanomaterial; Osteosarcoma
    DOI:  https://doi.org/10.1080/1061186X.2021.2023160
  82. ACS Nano. 2021 Dec 27.
    One-Step Integration of Tumor Microenvironment-Responsive Calcium and Copper Peroxides Nanocomposite for Enhanced Chemodynamic/Ion-Interference Therapy.
    Bin Liu, Yulong Bian, Shuang Liang, Meng Yuan, Shuming Dong, Fei He, Shili Gai, Piaoping Yang, Ziyong Cheng, Jun Lin.
      Recently, various metal peroxide nanomaterials have drawn increasing attention as an efficient hydrogen peroxide (H2O2) self-supplying agent for enhanced tumor therapy. However, a single kind of metal peroxide is insufficient to achieve more effective antitumor performance. Here, a hyaluronic acid modified calcium and copper peroxides nanocomposite has been synthesized by a simple one-step strategy. After effective accumulation at the tumor site due to the enhanced permeability and retention (EPR) effect and specific recognition of hyaluronate acid with CD44 protein on the surface of tumor cells, plenty of Ca2+, Cu2+, and H2O2 can be simultaneously released in acid and hyaluronidase overexpressed tumor microenvironment (TME), generating abundant hydroxyl radical through enhanced Fenton-type reaction between Cu2+ and self-supplying H2O2 with the assistance of glutathione depletion. Overloaded Ca2+ can lead to mitochondria injury and thus enhance the oxidative stress in tumor cells. Moreover, an unbalanced calcium transport channel caused by oxidative stress can further promote tumor calcification and necrosis, which is generally defined as ion-interference therapy. As a result, the synergistic effect of Fenton-like reaction by Cu2+ and mitochondria dysfunction by Ca2+ in ROS generation is performed. Therefore, a TME-responsive calcium and copper peroxides nanocomposite based on one-step integration has been successfully established and exhibits a more satisfactory antitumor efficiency than any single kind of metal peroxide.
    Keywords:  calcium peroxide; chemodynamic therapy; copper peroxide; ion-interference therapy; one-step integration
    DOI:  https://doi.org/10.1021/acsnano.1c07893
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