bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2023–01–01
forty-two papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Effects of metabolic cancer therapy on tumor microenvironment.
  2. Nanotherapeutic Intervention in Photodynamic Therapy for Cancer.
  3. Glucose metabolism and tumour microenvironment in pancreatic cancer: A key link in cancer progression.
  4. Targeting KRAS in Pancreatic Cancer.
  5. Importance of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) in cancer cells.
  6. Metabolic reprograming of cancer as a therapeutic target.
  7. Recent Advances on Natural and Non-natural Xanthones as Potential Anticancer agents: A review.
  8. Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer.
  9. Development of PEGylated PLGA Nanoparticles Co-Loaded with Bioactive Compounds: Potential Anticancer Effect on Breast Cancer Cell Lines.
  10. Apocynin and its chitosan nanoparticles attenuated cisplatin-induced multiorgan failure: Synthesis, characterization, and biological evaluation.
  11. Role of the tumor microenvironment in cancer hallmarks and targeted therapy (Review).
  12. Nanoengineered sonosensitive platelets for synergistically augmented sonodynamic tumor therapy by glutamine deprivation and cascading thrombosis.
  13. Editorial: Induced cell senescence as a therapeutic strategy for cancer treatment.
  14. Apocynin-loaded PLGA nanomedicine tailored with galactosylated chitosan intrigue asialoglycoprotein receptor in hepatic carcinoma: Prospective targeted therapy.
  15. Preparation and Optimization of Liposome Containing Thermosensitive In Situ Nasal Hydrogel System for Brain Delivery of Sumatriptan Succinate.
  16. Indocyanine green as a near-infrared theranostic agent for ferroptosis and apoptosis-based, photothermal, and photodynamic cancer therapy.
  17. Induction mechanism of ferroptosis: A novel therapeutic target in lung disease.
  18. Polysaccharide-based nanocarriers for efficient transvascular drug delivery.
  19. Traditional Herbal Medicine: A Potential Therapeutic Approach for Adjuvant Treatment of Non-small Cell Lung Cancer in the Future.
  20. Autophagy induction sensitizes cancer cells to anti-cancer drugs.
  21. Regulation and function of the mammalian tricarboxylic acid cycle.
  22. Nanoenabled Tumor Energy Metabolism Disorder via Sonodynamic Therapy for Multidrug Resistance Reversal and Metastasis Inhibition.
  23. Application of nanomaterials in diagnosis and treatment of glioblastoma.
  24. Cucurbitacins as potential anticancer agents: new insights on molecular mechanisms.
  25. Advanced diagnostic and therapeutic strategies in nanotechnology for lung cancer.
  26. Endothelial GLUTs and vascular biology.
  27. Methionine-Restricted Diet: A Feasible Strategy Against Chronic or Aging-Related Diseases.
  28. Nanomedicine-based commercial formulations: current developments and future prospects.
  29. Harnessing immunotherapy to enhance the systemic anti-tumor effects of thermosensitive liposomes.
  30. Combined time-restricted feeding and cisplatin enhance the anti-tumor effects in cisplatin-resistant and -sensitive lung cancer cells.
  31. Bisphenols S and F drive ovarian granulosa cell tumor invasion via a metabolic switch.
  32. Cancer Plasticity: Investigating the causes for this agility.
  33. Nonclinical Testing Evaluation of Liposomes as Drug Delivery Systems.
  34. Turbulence of glutamine metabolism in pan-cancer prognosis and immune microenvironment.
  35. Withania somnifera (L.) Dunal (Ashwagandha); current understanding and future prospect as a potential drug candidate.
  36. Dicoumarol: from chemistry to antitumor benefits.
  37. Plant metabolite diosmin as the therapeutic agent in human diseases.
  38. The Influences and Mechanisms of High-altitude Hypoxia Exposure on Drug Metabolism.
  39. Suppressive effects of bioactive herbal polysaccharides against different cancers: From mechanisms to translational advancements.
  40. Chitosan - dextran phosphate carbamate hydrogels for locally controlled co-delivery of doxorubicin and indomethacin: From computation study to in vivo pharmacokinetics.
  41. Exploring the possibility of drug repurposing for cancer therapy targeting human lactate dehydrogenase A: a computational approach.
  42. Molecular hydrogen therapy for neurological diseases: a review of current evidence.
  1. Front Oncol. 2022 ;12 1046630
    Effects of metabolic cancer therapy on tumor microenvironment.
    Petra Hyroššová, Mirko Milošević, Josef Škoda, Jiří Vachtenheim, Jakub Rohlena, Kateřina Rohlenová.
      Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly - clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.
    Keywords:  cancer; endothelial cells; fatty acid metabolism; glycolysis; metabolism; nucleotide metabolism; oxidative phoshorylation; tumor micro environment (TME)
    DOI:  https://doi.org/10.3389/fonc.2022.1046630
  2. ACS Omega. 2022 Dec 20. 7(50): 45882-45909
    Nanotherapeutic Intervention in Photodynamic Therapy for Cancer.
    Asif Mohd Itoo, Milan Paul, Sri Ganga Padaga, Balaram Ghosh, Swati Biswas.
      The clinical need for photodynamic therapy (PDT) has been growing for several decades. Notably, PDT is often used in oncology to treat a variety of tumors since it is a low-risk therapy with excellent selectivity, does not conflict with other therapies, and may be repeated as necessary. The mechanism of action of PDT is the photoactivation of a particular photosensitizer (PS) in a tumor microenvironment in the presence of oxygen. During PDT, cancer cells produce singlet oxygen (1O2) and reactive oxygen species (ROS) upon activation of PSs by irradiation, which efficiently kills the tumor. However, PDT's effectiveness in curing a deep-seated malignancy is constrained by three key reasons: a tumor's inadequate PS accumulation in tumor tissues, a hypoxic core with low oxygen content in solid tumors, and limited depth of light penetration. PDTs are therefore restricted to the management of thin and superficial cancers. With the development of nanotechnology, PDT's ability to penetrate deep tumor tissues and exert desired therapeutic effects has become a reality. However, further advancement in this field of research is necessary to address the challenges with PDT and ameliorate the therapeutic outcome. This review presents an overview of PSs, the mechanism of loading of PSs, nanomedicine-based solutions for enhancing PDT, and their biological applications including chemodynamic therapy, chemo-photodynamic therapy, PDT-electroporation, photodynamic-photothermal (PDT-PTT) therapy, and PDT-immunotherapy. Furthermore, the review discusses the mechanism of ROS generation in PDT advantages and challenges of PSs in PDT.
    DOI:  https://doi.org/10.1021/acsomega.2c05852
  3. Front Immunol. 2022 ;13 1038650
    Glucose metabolism and tumour microenvironment in pancreatic cancer: A key link in cancer progression.
    Shi Dong, Wancheng Li, Xin Li, Zhengfeng Wang, Zhou Chen, Huaqing Shi, Ru He, Chen Chen, Wence Zhou.
      Early and accurate diagnosis and treatment of pancreatic cancer (PC) remain challenging endeavors globally. Late diagnosis lag, high invasiveness, chemical resistance, and poor prognosis are unresolved issues of PC. The concept of metabolic reprogramming is a hallmark of cancer cells. Increasing evidence shows that PC cells alter metabolic processes such as glucose, amino acids, and lipids metabolism and require continuous nutrition for survival, proliferation, and invasion. Glucose metabolism, in particular, regulates the tumour microenvironment (TME). Furthermore, the link between glucose metabolism and TME also plays an important role in the targeted therapy, chemoresistance, radiotherapy ineffectiveness, and immunosuppression of PC. Altered metabolism with the TME has emerged as a key mechanism regulating PC progression. This review shed light on the relationship between TME, glucose metabolism, and various aspects of PC. The findings of this study provide a new direction in the development of PC therapy targeting the metabolism of cancer cells.
    Keywords:  glucose metabolism; pancreatic cancer; prognosis; treatment; tumour microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.1038650
  4. J Pers Med. 2022 Nov 08. pii: 1870. [Epub ahead of print]12(11):
    Targeting KRAS in Pancreatic Cancer.
    Darren Cowzer, Mohammed Zameer, Michael Conroy, Walter Kolch, Austin G Duffy.
      Pancreatic cancer is mainly driven by mutations in the KRAS oncogene. While this cancer has shown remarkable therapy resistance, new approaches to inhibit mutated KRAS, KRAS activators and effectors show promise in breaking this therapeutic deadlock. Here, we review these innovations in therapies that target RAS signaling in pancreatic cancer from a clinical point of view. A number of promising approaches are currently in clinical trials or in clinical development. We focus on small-molecule drugs but also discuss immunotherapies and tumor vaccines.
    Keywords:  KRAS; pancreas cancer; targeted therapy
    DOI:  https://doi.org/10.3390/jpm12111870
  5. Health Sci Rep. 2023 Jan;6(1): e996
    Importance of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) in cancer cells.
    Hamed Hatami, Atefe Sajedi, Seyed Mostafa Mir, Mohammad Yousef Memar.
       Background: In most regions, cancer ranks the second most frequent cause of death following cardiovascular disorders.
    Aim: In this article, we review the various aspects of glycolysis with a focus on types of MCTs and the importance of lactate in cancer cells.
    Results and Discussion: Metabolic changes are one of the first and most important alterations in cancer cells. Cancer cells use different pathways to survive, energy generation, growth, and proliferation compared to normal cells. The increase in glycolysis, which produces substances such as lactate and pyruvate, has an important role in metastases and invasion of cancer cells. Two important cellular proteins that play a role in the production and transport of lactate include lactate dehydrogenase and monocarboxylate transporters (MCTs). These molecules by their various isoforms and different tissue distribution help to escape the immune system and expansion of cancer cells under different conditions.
    Keywords:  cancer metabolism; lactate; monocarboxylate transporters
    DOI:  https://doi.org/10.1002/hsr2.996
  6. Biochim Biophys Acta Gen Subj. 2022 Dec 23. pii: S0304-4165(22)00219-7. [Epub ahead of print] 130301
    Metabolic reprograming of cancer as a therapeutic target.
    Tatsuhiko Furukawa, Sho Tabata, Kentaro Minami, Masatatsu Yamamoto, Kohichi Kawahara, Akihide Tanimoto.
      Our understanding of metabolic reprogramming in cancer has tremendously improved along with the technical progression of metabolomic analysis. Metabolic changes in cancer cells proved much more complicated than the classical Warburg effect. Previous studies have approached metabolic changes as therapeutic and/or chemopreventive targets. Recently, several clinical trials have reported anti-cancer agents associated with metabolism. However, whether cancer cells are dependent on metabolic reprogramming or favor suitable conditions remains nebulous. Both scenarios are possibly intertwined. Identification of downstream molecules and the understanding of mechanisms underlying reprogrammed metabolism can improve the effectiveness of cancer therapy. Here, we review several examples of the metabolic reprogramming of cancer cells and the therapies targeting the metabolism-related molecules as well as discuss practical approaches to improve the next generation of cancer therapies focused on the metabolic reprogramming of cancer.
    Keywords:  Anticancer agent; Clinical trial; Drug discovery; Metabolic reprograming; Therapeutic target
    DOI:  https://doi.org/10.1016/j.bbagen.2022.130301
  7. Med Chem. 2022 Dec 26.
    Recent Advances on Natural and Non-natural Xanthones as Potential Anticancer agents: A review.
    Urvashee Gogoi, Kalyani Pathak, Riya Saikia, Manash Pratim Pathak, Tirna Paul, Shah Alam Khan, Aparoop Das.
       BACKGROUND: Xanthones, natural or synthetic, due to their wide range of biological activities, have become an interesting subject of investigation for many researchers. Xanthonic scaffold has proven to have a vital role in anticancer drug development since many of its derivatives have shown anticancer activities on various cell lines. In addition, targeting epigenetic markers in cancer has yielded promising results. There have also been reports on the impact of xanthone and related polyphenolic compounds on epigenetics markers in cancer prevention and therapy.
    OBJECTIVE: The objective of this review is to comprehensively highlight the main natural and non-natural sources of xanthones having potential anti-cancer effects along with their key structural elements, structure-activity relationships (SARs), mechanisms of action, and epigenetic profile of xanthone-based anti-cancer compounds. The challenges and future directions of xanthone-based therapies are also discussed briefly.
    METHOD: The methods involved in the preparation of the present review included the collection of all recent information up to November 2021 from various scientific databases, indexed periodicals, and search engines such as Medline Scopus, Google Scholar, PubMed, PubMed Central, Web of Science, and Science Direct.
    RESULTS: Exploration of the diversity of the xanthone scaffold led to the identification of several derivatives having prominent anti-cancer activity. Their unique structural diversity and synthetic modifications showed the ongoing endeavour of enriching the chemical diversity of the xanthone molecular framework to discover pharmacologically interesting compounds. However, studies regarding their modes of action, pharmacokinetic properties, clinical data, epigenetics, and safety are limited.
    CONCLUSION: Elucidation of the exact biological mechanisms and the associated targets of xanthones will yield better opportunities for these compounds to be developed as potential anticancer drugs. Further clinical studies with conclusive results are required to implement xanthones as treatment modalities in cancer.
    Keywords:  Cancer; Cytotoxicity; Epigenetics; Natural products; Synthetic analogs; Xanthones
    DOI:  https://doi.org/10.2174/1573406419666221226093311
  8. iScience. 2023 Jan 20. 26(1): 105719
    Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer.
    Madeline Galbraith, Herbert Levine, José N Onuchic, Dongya Jia.
      Cancer metastasis relies on an orchestration of traits driven by different interacting functional modules, including metabolism and epithelial-mesenchymal transition (EMT). During metastasis, cancer cells can acquire a hybrid metabolic phenotype (W/O) by increasing oxidative phosphorylation without compromising glycolysis and they can acquire a hybrid epithelial/mesenchymal (E/M) phenotype by engaging EMT. Both the W/O and E/M states are associated with high metastatic potentials, and many regulatory links coupling metabolism and EMT have been identified. Here, we investigate the coupled decision-making networks of metabolism and EMT. Their crosstalk can exhibit synergistic or antagonistic effects on the acquisition and stability of different coupled metabolism-EMT states. Strikingly, the aggressive E/M-W/O state can be enabled and stabilized by the crosstalk irrespective of these hybrid states' availability in individual metabolism or EMT modules. Our work emphasizes the mutual activation between metabolism and EMT, providing an important step toward understanding the multifaceted nature of cancer metastasis.
    Keywords:  Cancer systems biology; Metabolic flux analysis
    DOI:  https://doi.org/10.1016/j.isci.2022.105719
  9. Asian Pac J Cancer Prev. 2022 Dec 01. pii: 90396. [Epub ahead of print]23(12): 4063-4072
    Development of PEGylated PLGA Nanoparticles Co-Loaded with Bioactive Compounds: Potential Anticancer Effect on Breast Cancer Cell Lines.
    Sina Mohammadinejad, Davoud Jafari-Gharabaghlou, Nosratollah Zarghami.
       OBJECTIVE: The incidence of breast cancer continues to rise despite decades of laboratory, epidemiological and clinical research. Breast cancer is still the leading cause of cancer death in women. Cyclin D1 is one of the most important oncoproteins associated with cancer cell proliferation and is overexpressed in more than 50% of cases. Curcumin and chrysin are plant-derived components that are believed to assist in inhibiting the viability of breast cancer cells. These agents are involved in cancer cells' growth and reducing cyclin D1 expression. In this study, the hypothesis of combining curcumin and chrysin is applied to analyze the potential synergistic effect in inhibiting cancer cell proliferation and down-regulation of cyclin D1. Furthermore, applying PLGA-PEG NPs could improve the bioavailability of free curcumin and chrysin components and at the same time increases the anti-cancer potential of this compound.
    METHODS: PLGA-PEG NPs were synthesized via the ring-opening polymerization technique and characterized with FT-IR and FE-SEM for chemical structure and morphological characteristics, respectively. Next, curcumin and chrysin were loaded in PLGA-PEG NPs and MTT assay was performed to assess the cytotoxic effect of these agents. T-47D cells were treated with appropriate concentrations of these agents and cyclin D1 expression level was evaluated by real-time PCR.
    RESULTS: The obtained results from FT-IR and FE-SEM techniques illustrated that curcumin and chrysin were efficiently encapsulated into PLGA-PEG NPs. Curcumin, chrysin, and curcumin-chrysin in free and nano-encapsulated forms exhibited an anti-cancer effect on T-47D cells in a time- and dose-dependent manner, especially in a combination of free and encapsulated forms demonstrated synergistic anti-cancer effects. Compared to free form, Nano-curcumin, Nano-chrysin, and Nano-combination remarkably down-regulated cyclin D1 gene expression. (p-value < 0.05).
    CONCLUSION: Our results revealed that the curcumin-chrysin combination has a synergistic effect and the encapsulated form of this nano-component has more inhibition on cyclin D1 expression.<br />.
    Keywords:  Chrysin; PLGA-PEG Nano-particles; and cyclin D1; breast cancer; curcumin
    DOI:  https://doi.org/10.31557/APJCP.2022.23.12.4063
  10. Life Sci. 2022 Dec 22. pii: S0024-3205(22)01013-X. [Epub ahead of print]314 121313
    Apocynin and its chitosan nanoparticles attenuated cisplatin-induced multiorgan failure: Synthesis, characterization, and biological evaluation.
    Nahed A Mahmoud, Emad H M Hassanein, Etify A Bakhite, Eman S Shaltout, Ahmed M Sayed.
      Cisplatin (CDDP) is an effective chemotherapeutic drug that has been used successfully in treating various tumors. Although its higher antineoplastic agent activity, CDDP exhibited severe side effects that limit its use. CDDP-induced toxicity is attributed to oxidative stress and inflammation. Apocynin (APO) is a bioactive phytochemical with potent antioxidant and anti-inflammatory properties. However, pharmaceutical experts face significant hurdles due to the limited bioavailability and quick elimination of APO. Therefore, we synthesized a chitosan (CTS)-based nano delivery system using the ionic gelation method to enhance APO bioactivity. CTS-APO-NPs were characterized using different physical and chemical approaches, including FTIR, XRD, TGA, Zeta-sizer, SEM, and TEM. In addition, the protective effect of CTS-APO-NPs against CDDP-induced nephrotoxicity, hepatotoxicity, and cardiotoxicity in rats was evaluated. CTS-APO-NPs restored serum biomarkers and antioxidants to their normal levels. Also, histopathological examination was used to assess the recovery of heart, kidney, and liver tissues. CTS-APO-NPs attenuated the oxidative stress mediated by Nrf2 activation while it dampened inflammation mediated by NF-κB suppression. CTS-APO-NPs is a potentially attractive target for more therapeutic trials.
    Keywords:  Apocynin; Chitosan; Cisplatin; Drug delivery; Nrf2 and NF-κB
    DOI:  https://doi.org/10.1016/j.lfs.2022.121313
  11. Int J Oncol. 2023 Feb;pii: 23. [Epub ahead of print]62(2):
    Role of the tumor microenvironment in cancer hallmarks and targeted therapy (Review).
    Rayan Naser, Isabelle Fakhoury, Adam El-Fouani, Ralph Abi-Habib, Mirvat El-Sibai.
      Genetic alterations drive tumor onset and progression. However, the cross‑talk between tumor cells and the benign components of the surrounding stroma can also promote the initiation, progression and metastasis of solid tumors. These cellular and non‑cellular stromal components form the tumor microenvironment (TME), which co‑evolves with tumor cells. Their dynamic and mutualistic interactions are currently considered to be among the distinctive hallmarks of cancer. Biochemical and physical cues from the TME serve an essential role in regulating tumor onset and progression. They are also associated with resistance to treatment and poor prognosis in patients with cancer. Therefore, a deep understanding of the TME is vital for developing potent anticancer therapeutics and improving patient outcomes. The present review aims to review the biology of both cellular and non‑cellular constituents of the TME and novel findings regarding their contribution to core as well as emerging cancer hallmarks. The present review also describes key TME markers that are either targeted in interventional clinical trials or serve as promising potential anticancer therapies. Understanding TME components and their intercellular interactions is key toward identifying the mechanisms of progression and treatment resistance. Such understanding is of utmost significance for personalized and effective cancer therapy strategies.
    Keywords:  CAFs; ECM; TME; solid tumors; therapy
    DOI:  https://doi.org/10.3892/ijo.2022.5471
  12. Bioact Mater. 2023 Jun;24 26-36
    Nanoengineered sonosensitive platelets for synergistically augmented sonodynamic tumor therapy by glutamine deprivation and cascading thrombosis.
    Liqiang Zhou, Wei Feng, Yuhang Mao, Yu Chen, Xuanjun Zhang.
      Ultrasound (US)-activated sonodynamic therapy (SDT) stands for a distinct antitumor modality because of its attractive characteristics including intriguing noninvasiveness, desirable safety, and high tissue penetration depth, which, unfortunately, suffers from compromised therapeutic efficacy due to cancer cell-inherent adaptive mechanisms, such as glutathione (GSH) neutralization response to reactive oxygen species (ROS), and glutamine addictive properties of tumors. In this work, we developed a biological sonosensitive platelet (PLT) pharmacytes for favoring US/GSH-responsive combinational therapeutic of glutamine deprivation and augmented SDT. The amino acid transporter SLC6A14 blockade agent α-methyl-DL-tryptophan (α-MT)-loaded and MnO2-coated porphyrinic metal-organic framework (MOF) nanoparticles were encapsulated in the PLTs through the physical adsorption of electrostatic attraction and the intrinsic endocytosis of PLTs. When the sonosensitive PLT pharmacytes reached tumor sites through their natural tendencies to TME, US stimulated the PLTs-loaded porphyrinic MOF to generate ROS, resulting in morphological changes of the PLTs and the release of nanoparticles. Subsequently, intracellular high concentration of GSH and extracellular spatio-temporal controlled US irradiation programmatically triggered the release of α-MT, which enabled the synergistically amplified SDT by inducing amino acid starvation, inhibiting mTOR, and mediating ferroptosis. In addition, US stimulation achieved the targeted activation of PLTs at tumor vascular site, which evolved from circulating PLTs to dendritic PLTs, effectively blocking the blood supply of tumors through thrombus formation, and revealing the encouraging potential to facilitate tumor therapeutics.
    Keywords:  Amino acid starvation; Drug delivery; Glutamine deprivation; Sonodynamic tumor therapy; Sonosensitive platelets
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.11.020
  13. Front Oncol. 2022 ;12 1104877
    Editorial: Induced cell senescence as a therapeutic strategy for cancer treatment.
    Kaiyue He, Liyuan Lu, Yong-Ping Jian, Zhi-Xiang Xu.
      
    Keywords:  cancer treatment; cell senescence; cell-cycle arrest; tumor nanotherapeutics; tumor suppressor genes
    DOI:  https://doi.org/10.3389/fonc.2022.1104877
  14. Int J Pharm. 2022 Dec 23. pii: S0378-5173(22)01091-2. [Epub ahead of print]631 122536
    Apocynin-loaded PLGA nanomedicine tailored with galactosylated chitosan intrigue asialoglycoprotein receptor in hepatic carcinoma: Prospective targeted therapy.
    Hend Mohamed Anter, Reham Mokhtar Aman, Dina Ibrahim Ali Othman, Khaled M Elamin, Irhan Ibrahim Abu Hashim, Mahasen Mohamed Meshali.
      Nature serves as a priceless source for phytomedicines to treat different types of cancer, including hepatocellular carcinoma (HCC). Apocynin (APO), an anti-cancer phytomedicine, is a particular nicotinamide adenine dinucleotide phosphate-oxidase (NADPH-oxidase) inhibitor, which has recently dawned for its multilateral pharmacological activities. As far as we are aware, no investigation has been carried out yet to develop a targeted-nanostructured delivery system of APO to HCC. Consequently, chitosan derivative with galactose groups namely; galactosylated chitosan (GC), particularly recognized by the asialoglycoprotein receptor (ASGR), was synthesized and its chemical structure was thoroughly characterized by substantial techniques. Afterwards, GC-coated nanoplatform for hepatocyte attachment "APO-loaded galactosylated chitosan-coated poly(d,l-lactide-co-glycolide) nanoparticles (APO-loaded GC-coated PLGA NPs)" was developed. The prosperous APO-loaded GC-coated PLGA NPs would be comprehensively appraised through extensive investigations. Their solid state characterization using Fourier transform-infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry proved APO's encapsulation in the polymeric matrix. Transmission electron microscopy imaging of the investigated NPs highlighted their spherical architecture with a nanosized range and a characteristic halo-like appearance traceable to the GC coating of the NPs' surface. Saliently, the results of in vitro cytotoxicity screening revealed the spectacular anti-cancer efficacy of APO-loaded GC-coated PLGA NPs formula against the HepG2 cell line. Moreover, the fluorescence microscope disclosed the distinguished cellular uptake of such formula via ASGPR mediated endocytosis. Inclusively, a multifunctional nano-phytomedicine delivery system with a promising active hepatocyte-targeting, effective uptake into HepG2 cells, and sustained drug release pattern was successfully developed.
    Keywords:  Anti-cancer; Apocynin; Asialoglycoprotein receptor mediated endocytosis; Galactosylated chitosan; Hepatocellular carcinoma; Nano-phytomedicine
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122536
  15. Assay Drug Dev Technol. 2022 Dec 22.
    Preparation and Optimization of Liposome Containing Thermosensitive In Situ Nasal Hydrogel System for Brain Delivery of Sumatriptan Succinate.
    Dyandevi Mathure, Ashish Dilip Sutar, Hemantkumar Ranpise, Atmaram Pawar, Rajendra Awasthi.
      Drug absorption is improved by the intranasal route's wide surface area and avoidance of first-pass metabolism. For the treatment of central nervous system diseases such as migraine, intranasal administration delivers the medication to the brain. The study's purpose was to develop an in situ nasal hydrogel that contained liposomes that were loaded with sumatriptan succinate (SS). A thin-film hydration approach was used to create liposomes, and a 32 factorial design was used to optimize them. The optimized liposomes had a spherical shape, a 171.31 nm particle size, a high drug encapsulation efficiency of 83.54%, and an 8-h drug release of 86.11%. To achieve in situ gel formation, SS-loaded liposomes were added to the liquid gelling system of poloxamer-407, poloxamer-188, and sodium alginate. The final product was tested for mucoadhesive strength, viscosity, drug content, gelation temperature, and gelation time. Following intranasal delivery, in vivo pharmacokinetic investigations showed a significant therapeutic concentration of the medication in the brain with a Cmax value of 167 ± 78 ng/mL and an area under the curve value of 502 ± 63 ng/min·mL. For SS-loaded liposomal thermosensitive nasal hydrogel, significantly higher values of the nose-to-brain targeting parameters, that is, drug targeting index (2.61) and nose-to-brain drug direct transport (57.01%), confirmed drug targeting to the brain through the nasal route. Liposomes containing thermosensitive in situ hydrogel demonstrated potential for intranasal administration of SS.
    Keywords:  brain delivery; drug delivery; in situ nasal gel; liposome; thermosensitive hydrogel
    DOI:  https://doi.org/10.1089/adt.2022.088
  16. Front Mol Biosci. 2022 ;9 1045885
    Indocyanine green as a near-infrared theranostic agent for ferroptosis and apoptosis-based, photothermal, and photodynamic cancer therapy.
    Hsiang-Ching Tseng, Chan-Yen Kuo, Wei-Ting Liao, Te-Sen Chou, Jong-Kai Hsiao.
      Ferroptosis is a recently discovered programmed cell death pathway initiated by reactive oxygen species (ROS). Cancer cells can escape ferroptosis, and strategies to promote cancer treatment are crucial. Indocyanine green (ICG) is a near-infrared (NIR) fluorescent molecule used in the imaging of residual tumor removal during surgery. Growing attention has been paid to the anticancer potential of ICG-NIR irradiation by inducing ROS production and theranostic effects. Organic anion transmembrane polypeptide (OATP) 1B3 is responsible for ICG metabolism. Additionally, the overexpression of OATP1B3 has been reported in several cancers. However, whether ICG combined with NIR exposure can cause ferroptosis remains unknown and the concept of treating OATP1B3-expressing cells with ICG-NIR irradiation has not been validated. We then used ICG as a theranostic molecule and an OATP1B3-transfected fibrosarcoma cell line, HT-1080 (HT-1080-OATP1B3), as a cell model. The HT-1080-OATP1B3 cell could promote the uptake of ICG into the cytoplasm. We observed that the HT-1080-OATP1B3 cells treated with ICG and exposed to 808-nm laser irradiation underwent apoptosis, as indicated by a reduction in mitochondrial membrane potential, and upregulation of cleaved Caspase-3 and Bax but downregulation of Bcl-2 expression. Moreover, lipid ROS production and consequent ferroptosis and hyperthermic effect were noted after ICG and laser administration. Finally, in vivo study findings also revealed that ICG with 808-nm laser irradiation has a significant effect on cancer suppression. ICG is a theranostic molecule that exerts synchronous apoptosis, ferroptosis, and hyperthermia effects and thus can be used in cancer treatment. Our findings may facilitate the development of treatment modalities for chemo-resistant cancers.
    Keywords:  apoptosis; ferroptosis; indocyanine green; near-infrared; organic anion transmembrane polypeptide; theranostic effect
    DOI:  https://doi.org/10.3389/fmolb.2022.1045885
  17. Front Pharmacol. 2022 ;13 1093244
    Induction mechanism of ferroptosis: A novel therapeutic target in lung disease.
    Lingyu Pan, Chunxia Gong, Yehong Sun, Yeke Jiang, Xianchun Duan, Yanquan Han, Yongzhong Wang.
      Ferroptosis is a newly discovered form of non-apoptotic regulatory cell death driven by iron-dependent lipid peroxidation. Ferroptosis significantly differs from other forms of cell death in terms of biochemistry, genetics, and morphology. Ferroptosis affects many metabolic processes in the body, resulting in disruption of homeostasis, and is related to many types of lung disease. Although current research on ferroptosis remains in the early stage, existing studies have confirmed that ferroptosis is regulated by a variety of genes, mainly involving changes in genes involved in iron homeostasis and lipid peroxidation metabolism. Furthermore, the mechanism of ferroptosis is complex. This review summarizes the confirmed mechanisms that can cause ferroptosis, including activation of glutathione peroxidase 4, synthesis of glutathione, accumulation of reactive oxygen species, and the influence of ferrous ions and p53 proteins. In recent years, the mechanism of ferroptosis in the occurrence and development of many diseases has been studied; the occurrence of ferroptosis will produce an inflammatory storm, and most of the inducing factors and pathological manifestations of lung diseases are also inflammatory reactions. Therefore, we believe that the association between ferroptosis and lung disease deserves further study. This article aims to help readers to better understand the mechanism of ferroptosis, provide new ideas and targets for the treatment of lung diseases, and point out the direction for the development of new targeted drugs for the clinical treatment of lung diseases.
    Keywords:  ferroptosis; glutathione; glutathione peroxidase 4; lung disease; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphar.2022.1093244
  18. J Control Release. 2022 Dec 26. pii: S0168-3659(22)00865-3. [Epub ahead of print]
    Polysaccharide-based nanocarriers for efficient transvascular drug delivery.
    Min Zhang, He Ma, Xijie Wang, Bing Yu, Hailin Cong, Youqing Shen.
      Polysaccharide-based nanocarriers (PBNs) are the focus of extensive investigation because of their biocompatibility, low cost, wide availability, and chemical versatility, which allow a wide range of anticancer agents to be loaded within the nanocarriers. Similar to other nanocarriers, most PBNs are designed to extravasate out of tumor vessels, depending on the enhanced permeability and retention (EPR) effect. However, the EPR effect is compromised in some tumors due to the heterogeneity of tumor structures. Transvascular transport efficacy is decreased by complex blood vessels and condensed tumor stroma. The limited extravasation impedes efficient drug delivery into tumor parenchyma, and thus affects the subsequent tumor accumulation, which hinders the therapeutic effect of PBNs. Therefore, overcoming the biological barriers that restrict extravasation from tumor vessels is of great importance in PBN design. Many strategies have been developed to enhance the EPR effect that involve nanocarrier property regulation and tumor structure remodeling. Moreover, some researchers have proposed active transcytosis pathways that are complementary to the paracellular EPR effect to increase the transvascular extravasation efficiency of PBNs. In this review, we summarize the recent advances in the design of PBNs with enhanced transvascular transport to enable optimization of PBNs in the extravasation of the drug delivery process. We also discuss the obstacles and challenges that need to be addressed to clarify the transendothemial mechanism of PBNs and the potential interactions between extravasation and other drug delivery steps.
    Keywords:  Increased delivery efficacy; Intratumoral drug transportation; Polysaccharide-based nanocarriers; Transvascular extravasation
    DOI:  https://doi.org/10.1016/j.jconrel.2022.12.051
  19. Integr Cancer Ther. 2022 Jan-Dec;21:21 15347354221144312
    Traditional Herbal Medicine: A Potential Therapeutic Approach for Adjuvant Treatment of Non-small Cell Lung Cancer in the Future.
    Jie Huang, Jia-Xin Li, Lin-Rui Ma, Dong-Han Xu, Peng Wang, Li-Qi Li, Li-Li Yu, Yu Li, Run-Ze Li, Hao Zhang, Yu-Hong Zheng, Ling Tang, Pei-Yu Yan.
      Lung carcinoma is the primary reason for cancer-associated mortality, and it exhibits the highest mortality and incidence in developed and developing countries. Non-small cell lung cancer (NSCLC) and SCLC are the 2 main types of lung cancer, with NSCLC contributing to 85% of all lung carcinoma cases. Conventional treatment mainly involves surgery, chemoradiotherapy, and immunotherapy, but has a dismal prognosis for many patients. Therefore, identifying an effective adjuvant therapy is urgent. Historically, traditional herbal medicine has been an essential part of complementary and alternative medicine, due to its numerous targets, few side effects and substantial therapeutic benefits. In China and other East Asian countries, traditional herbal medicine is increasingly popular, and is highly accepted by patients as a clinical adjuvant therapy. Numerous studies have reported that herbal extracts and prescription medications are effective at combating tumors. It emphasizes that, by mainly regulating the P13K/AKT signaling pathway, the Wnt signaling pathway, and the NF-κB signaling pathway, herbal medicine induces apoptosis and inhibits the proliferation and migration of tumor cells. The present review discusses the anti-NSCLC mechanisms of herbal medicines and provides options for future adjuvant therapy in patients with NSCLC.
    Keywords:  adjuvant treatment; herbal medicine; non-small cell lung cancer; traditional Chinese medicine
    DOI:  https://doi.org/10.1177/15347354221144312
  20. Autophagy. 2022 Dec 29. 1-2
    Autophagy induction sensitizes cancer cells to anti-cancer drugs.
    Mei Luo, Leng Han.
      Resistance to anti-cancer therapy is a major challenge for cancer treatment. Many studies revealed that macroautophagy/autophagy inhibition can overcome autophagy-mediated therapy resistance, but these efforts have not yet led to the success of clinical applications. In a recent paper, we established a 37-gene autophagy signature to estimate the autophagy status of approximately 10,000 tumor samples across 33 cancer types from The Cancer Genome Atlas, and muti-omics characterization reveals that autophagy induction may also sensitize cancer cells to anti-cancer drugs. These findings provide a comprehensive resource of molecular alterations associated with autophagy and highlight the potential to utilize drug sensitivity induced by autophagy to overcome the resistance of cancer therapy.
    Keywords:  Autophagy; drug sensitivity; gene signature; multi-omics; therapy
    DOI:  https://doi.org/10.1080/15548627.2022.2162703
  21. J Biol Chem. 2022 Dec 26. pii: S0021-9258(22)01281-9. [Epub ahead of print] 102838
    Regulation and function of the mammalian tricarboxylic acid cycle.
    Paige K Arnold, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle, otherwise known as the Krebs cycle, is a central metabolic pathway that performs the essential function of oxidizing nutrients to support cellular bioenergetics. More recently, it has become evident that TCA cycle behavior is dynamic and products of the TCA cycle can be co-opted in cancer and other pathologic states. In this review, we revisit the TCA cycle, including its potential origins and the history of its discovery. We provide a detailed accounting of the requirements for sustained TCA cycle function and the critical regulatory nodes that can stimulate or constrain TCA cycle activity. We also discuss recent advances in our understanding of the flexibility of TCA cycle wiring and the increasingly appreciated heterogeneity in TCA cycle activity exhibited by mammalian cells. Deeper insight into how the TCA cycle can be differentially regulated and, consequently, configured in different contexts will shed light on how this pathway is primed to meet the requirements of distinct mammalian cell states.
    DOI:  https://doi.org/10.1016/j.jbc.2022.102838
  22. ACS Appl Mater Interfaces. 2022 Dec 28.
    Nanoenabled Tumor Energy Metabolism Disorder via Sonodynamic Therapy for Multidrug Resistance Reversal and Metastasis Inhibition.
    Xun Guo, Peng Tu, Leilei Zhu, Chen Cheng, Weixi Jiang, Chier Du, Xiaoting Wang, Xiaoling Qiu, Yuanli Luo, Li Wan, Rui Tang, Haitao Ran, Zhigang Wang, Jianli Ren.
      Cancer multidrug resistance (MDR) is an important reason that results in chemotherapy failure. As a main mechanism of MDR, overexpressed P-glycoprotein (P-gp) utilizes adenosine triphosphate (ATP) to actively pump chemotherapy drugs out of cells. In addition, metabolic reprogramming of drug-resistant tumor cells (DRTCs) exacerbates the specific hypoxic microenvironment and promotes tumor metastasis and recurrence. Therefore, we propose a novel sonodynamic therapy (SDT) paradigm to induce energy metabolism disorder and drug resistance change of DRTCs. A US-controlled "Nanoenabled Energy Metabolism Jammer" (TL@HPN) is designed using perfluoropentane (PFP) adsorbing oxygen in the core, and a targeting peptide (CGNKRTR) is attached to the liposome as the delivery carrier shell to incorporate hematoporphyrin monomethyl ether (HMME) and paclitaxel (PTX). The TL@HPN with ultrasonic/photoacoustic imaging (PAI/USI) precisely controlled the release of drugs and oxygen after being triggered by ultrasound (US), which attenuated the hypoxic microenvironment. SDT boosted the reactive oxygen species (ROS) content in tumor tissues, preferentially inducing mitochondrial apoptosis and maximizing immunogenic cell death (ICD). Persistently elevated oxidative stress levels inhibited ATP production and downregulated P-gp expression by disrupting the redox balance and electron transfer of the respiratory chain. We varied the effect of TL@HPN combined with PD-1/PD-L1 to activate autoimmunity and inhibit tumor metastasis, providing a practical strategy for expanding the use of SDT-mediated tumor energy metabolism.
    Keywords:  immunogenic cell death; mitochondrial apoptosis; multidrug resistance; sonodynamic therapy; tumor energy metabolism
    DOI:  https://doi.org/10.1021/acsami.2c16278
  23. Front Chem. 2022 ;10 1063152
    Application of nanomaterials in diagnosis and treatment of glioblastoma.
    Shuangqi Yu, Lijie Chen, Hongyu Xu, Shengrong Long, Jiazhi Jiang, Wei Wei, Xing Niu, Xiang Li.
      Diagnosing and treating glioblastoma patients is currently hindered by several obstacles, such as tumor heterogeneity, the blood-brain barrier, tumor complexity, drug efflux pumps, and tumor immune escape mechanisms. Combining multiple methods can increase benefits against these challenges. For example, nanomaterials can improve the curative effect of glioblastoma treatments, and the synergistic combination of different drugs can markedly reduce their side effects. In this review, we discuss the progression and main issues regarding glioblastoma diagnosis and treatment, the classification of nanomaterials, and the delivery mechanisms of nanomedicines. We also examine tumor targeting and promising nano-diagnosis or treatment principles based on nanomedicine. We also summarize the progress made on the advanced application of combined nanomaterial-based diagnosis and treatment tools and discuss their clinical prospects. This review aims to provide a better understanding of nano-drug combinations, nano-diagnosis, and treatment options for glioblastoma, as well as insights for developing new tools.
    Keywords:  blood-brain barrier; glioblastoma; glioma; nanomaterial; tumor targeting
    DOI:  https://doi.org/10.3389/fchem.2022.1063152
  24. J Transl Med. 2022 Dec 31. 20(1): 630
    Cucurbitacins as potential anticancer agents: new insights on molecular mechanisms.
    Carla Varela, Catarina Melim, Beatriz G Neves, Javad Sharifi-Rad, Daniela Calina, Assem Mamurova, Célia Cabral.
      Since ancient times, plants have been an extensive reservoir of bioactive compounds with therapeutic interest for new drug development and clinical application. Cucurbitacins are a compelling example of these drug leads, primarily present in the plant kingdom, especially in the Cucurbitaceae family. However, these natural compounds are also known in several genera within other plant families. Beyond the Cucurbitaceae family, they are also present in other plant families, as well as in some fungi and one shell-less marine mollusc. Despite the natural abundance of cucurbitacins in different natural species, their obtaining and isolation is limited, as a result, an increase in their chemical synthesis has been developed by researchers. Data on cucurbitacins and their anticancer activities were collected from databases such as PubMed/MedLine, TRIP database, Web of Science, Google Scholar, and ScienceDirect and the information was arranged sequentially for a better understanding of the antitumor potential. The results of the studies showed that cucurbitacins have significant biological activities, such as anti-inflammatory, antioxidant, antimalarial, antimicrobial, hepatoprotective and antitumor potential. In conclusion, there are several studies, both in vitro and in vivo reporting this important anticancer/chemopreventive potential; hence a comprehensive review on this topic is recommended for future clinical research.
    Keywords:  Anticancer mechanisms; Apoptosis; Chemical synthesis; Chemoprevention; Cucurbitacins; Malignant tumor; Molecular targets
    DOI:  https://doi.org/10.1186/s12967-022-03828-3
  25. Front Oncol. 2022 ;12 1031000
    Advanced diagnostic and therapeutic strategies in nanotechnology for lung cancer.
    Yujuan Duan, Chen Shen, Yinan Zhang, Yao Luo.
      As a highly invasive thoracic malignancy with increasing prevalence, lung cancer is also the most lethal cancer worldwide due to the failure of effective early detection and the limitations of conventional therapeutic strategies for advanced-stage patients. Over the past few decades, nanotechnology has emerged as an important technique to obtain desired features by modifying and manipulating different objects on a molecular level and gained a lot of attention in many fields of medical applications. Studies have shown that in lung cancer, nanotechnology may be more effective and specific than traditional methods for detecting extracellular cancer biomarkers and cancer cells in vitro, as well as imaging cancer in vivo; Nanoscale drug delivery systems have developed rapidly to overcome various forms of multi-drug resistance and reduce detrimental side effects to normal tissues by targeting cancerous tissue precisely. There is no doubt that nanotechnology has the potential to enhance healthcare systems by simplifying and improving cancer diagnostics and treatment. Throughout this review, we summarize and highlight recent developments in nanotechnology applications for lung cancer in diagnosis and therapy. Moreover, the prospects and challenges in the translation of nanotechnology-based diagnostic and therapeutic methods into clinical applications are also discussed.
    Keywords:  early diagnosis; lung cancer; nanotechnology; potential strategy; therapy
    DOI:  https://doi.org/10.3389/fonc.2022.1031000
  26. Biomed Pharmacother. 2022 Dec 22. pii: S0753-3322(22)01540-2. [Epub ahead of print]158 114151
    Endothelial GLUTs and vascular biology.
    Wan-Zhou Wu, Yong-Ping Bai.
      Endothelial metabolism is a promising target for vascular functional regulation and disease therapy. Glucose is the primary fuel for endothelial metabolism, supporting ATP generation and endothelial cell survival. Multiple studies have discussed the role of endothelial glucose catabolism, such as glycolysis and oxidative phosphorylation, in vascular functional remodeling. However, the role of the first gatekeepers of endothelial glucose utilization, glucose transporters, in the vasculature has long been neglected. Here, this review summarizes glucose transporter studies in vascular research. We mainly focus on GLUT1 and GLUT3 because they are the most critical glucose transporters responsible for most endothelial glucose uptake. Some interesting topics are also discussed, intending to provide directions for endothelial glucose transporter research in the future.
    Keywords:  Endothelial cell; Glucose transporter; Metabolism; Vascular biology
    DOI:  https://doi.org/10.1016/j.biopha.2022.114151
  27. J Agric Food Chem. 2022 Dec 26.
    Methionine-Restricted Diet: A Feasible Strategy Against Chronic or Aging-Related Diseases.
    Guoqing Wu, Jingxuan Xu, Qiyao Wang, Ziyang Fang, Yucheng Fang, Yujie Jiang, Xiaohong Zhang, Xiangrong Cheng, Jin Sun, Guowei Le.
      Dietary methionine restriction (MR) has been associated with multifaceted health-promoting effects. MR is conducive to prevention of several chronic diseases and cancer, and extension of lifespan. A growing number of studies on new phenotypes and mechanisms of MR have become available in the past five years, especially in angiogenesis, neurodegenerative diseases, intestinal microbiota, and intestinal barrier function. In this review, we summarize the characteristics and advantages of MR, and current knowledge on the physiological responses and effects of MR on chronic diseases and aging-associated pathologies. Potential mechanisms, in which hydrogen sulfide, fibroblast growth factor 21, gut microbiota, short-chain fatty acids, and so on are involved, are discussed. Moreover, directions for epigenetics and gut microbiota in an MR diet are presented in future perspectives. This review comprehensively summarizes the novel roles and interpretations of the mechanisms underlying MR in the prevention of chronic diseases and aging.
    Keywords:  aging; chronic diseases; gut microbiota; hydrogen sulfide; methionine restriction
    DOI:  https://doi.org/10.1021/acs.jafc.2c05829
  28. J Pharm Investig. 2022 Dec 19. 1-15
    Nanomedicine-based commercial formulations: current developments and future prospects.
    Raj Kumar Thapa, Jong Oh Kim.
       Background: In recent decades, there has been a considerable increase in the number of nanomedicine-based formulations, and their advantages, including controlled/targeted drug delivery with increased efficacy and reduced toxicity, make them ideal candidates for therapeutic delivery in the treatment of complex and difficult-to-treat diseases, such as cancer.
    Areas covered: This review focuses on nanomedicine-based formulation development, approved and marketed nanomedicines, and the challenges faced in nanomedicine development as well as their future prospects.
    Expert opinion: To date, the Food and Drug Administration and the European Medicines Agency have approved several nanomedicines, which are now commercially available. However, several critical challenges, including reproducibility, proper characterization, and biological evaluation, e.g., via assays, are still associated with their use. Therefore, rigorous studies alongside stringent guidelines for effective and safe nanomedicine development and use are still warranted. In this study, we provide an overview of currently available nanomedicine-based formulations. Thus, the findings here reported may serve as a basis for further studies regarding the use of these formulations for therapeutic purposes in near future.
    Keywords:  Clinical trials; Commercial formulations; Nanomedicines; Pharmacokinetics
    DOI:  https://doi.org/10.1007/s40005-022-00607-6
  29. Drug Deliv Transl Res. 2022 Dec 28.
    Harnessing immunotherapy to enhance the systemic anti-tumor effects of thermosensitive liposomes.
    Maximilian Regenold, Xuehan Wang, Kan Kaneko, Pauric Bannigan, Christine Allen.
      Chemotherapy plays an important role in debulking tumors in advance of surgery and/or radiotherapy, tackling residual disease, and treating metastatic disease. In recent years many promising advanced drug delivery strategies have emerged that offer more targeted delivery approaches to chemotherapy treatment. For example, thermosensitive liposome-mediated drug delivery in combination with localized mild hyperthermia can increase local drug concentrations resulting in a reduction in systemic toxicity and an improvement in local disease control. However, the majority of solid tumor-associated deaths are due to metastatic spread. A therapeutic approach focused on a localized target area harbors the risk of overlooking and undertreating potential metastatic spread. Previous studies reported systemic, albeit limited, anti-tumor effects following treatment with thermosensitive liposomal chemotherapy and localized mild hyperthermia. This work explores the systemic treatment capabilities of a thermosensitive liposome formulation of the vinca alkaloid vinorelbine in combination with mild hyperthermia in an immunocompetent murine model of rhabdomyosarcoma. This treatment approach was found to be highly effective at heated, primary tumor sites. However, it demonstrated limited anti-tumor effects in secondary, distant tumors. As a result, the addition of immune checkpoint inhibition therapy was pursued to further enhance the systemic anti-tumor effect of this treatment approach. Once combined with immune checkpoint inhibition therapy, a significant improvement in systemic treatment capability was achieved. We believe this is one of the first studies to demonstrate that a triple combination of thermosensitive liposomes, localized mild hyperthermia, and immune checkpoint inhibition therapy can enhance the systemic treatment capabilities of thermosensitive liposomes.
    Keywords:  Abscopal effect; Drug delivery; Hyperthermia; Immunotherapy; Nanomedicine; Thermosensitive liposomes; Triggered drug release; Vinorelbine
    DOI:  https://doi.org/10.1007/s13346-022-01272-w
  30. Med Oncol. 2022 Dec 28. 40(1): 63
    Combined time-restricted feeding and cisplatin enhance the anti-tumor effects in cisplatin-resistant and -sensitive lung cancer cells.
    Jianling Li, Qianyao Chen, Dan Shi, Xuemei Lian.
      Combination therapy as an important treatment option for lung cancer has been attracting attention due to the primary and acquired resistance of chemotherapeutic drugs in the clinical application. In the present study, as a new therapy strategy, concomitant treatment with time-restricted feeding (TRF) plus cisplatin (DDP) on lung cancer growth was investigated in DDP-resistant and DDP-sensitive lung cancer cells. We first found that TRF significantly enhanced the drug susceptibility of DDP in DDP-resistant A549 (A549/DDP) cell line, illustrated by reversing the inhibitory concentration 50 (IC50) values of A549/DDP cells to normal level of parental A549 cells. We also found that TRF markedly enhanced DDP inhibition on cell proliferation, migration, as well as promoted apoptosis compared to the DDP alone group in A549, H460 and A549/DDP cells lines. We further revealed that the synergistic anti-tumor effect of combined DDP and TRF was greater than that of combined DDP and simulated fasting condition (STS), a known anti-tumor cellular medium. Moreover, mRNA sequence analysis from A549/DDP cell line demonstrated the synergistic anti-tumor effect involved in upregulated pathways in p53 signaling pathway and apoptosis. Notably, compared with the DDP alone group, combination of TRF and DDP robustly upregulated the P53 protein expression without mRNA level change by regulating its stability via promoting protein synthesis and inhibiting degradation, revealed by cycloheximide and MG132 experiments. Collectively, our results suggested that TRF in combination with cisplatin might be an additional novel therapeutic strategy for patients with lung cancer.
    Keywords:  Cisplatin; Lung cancer; P53; Time-restricted feeding; mRNA sequence
    DOI:  https://doi.org/10.1007/s12032-022-01923-5
  31. Toxicol Lett. 2022 Dec 27. pii: S0378-4274(22)01823-9. [Epub ahead of print]
    Bisphenols S and F drive ovarian granulosa cell tumor invasion via a metabolic switch.
    Justyna Gogola-Mruk, Kinga Krawczyk, Weronika Marynowicz, Magdalena Rokita, Samantha Nimpsz, Anna Ptak.
      Alterations in the metabolism of cancer cells are crucial for tumor growth and progression. However, the mechanism whereby environmental pollutants such as bisphenols F (BPF) and S (BPS) affect glucose metabolism through the glycolytic pathway, and therefore influence tumor progression, are unclear. Both bisphenols are endocrine-disrupting molecules that are used in plastics. As a consequence of their widespread use, these compounds have been detected in various human body fluids. Thus, hormone-sensitive cancers, such as ovarian cancers, are exposed to these compounds. In the present study, we aimed to determine the effects of the concentrations of BPS and BPF found in body fluids on the cell viability, glucose uptake, glycolysis, oxygen consumption, and invasion by the adult ovarian granulosa cell tumor (AGCT) cell line. We found that BPS and BPF increased the glucose uptake, hexokinase activity, proliferation, and invasion of the cells at environmentally relevant concentrations. Furthermore, we identified an inhibition of glycolysis in parallel with an increase in oxygen consumption, suggesting a BPS/BPF-induced switch from aerobic glycolysis to mitochondrial respiration. In summary, these findings demonstrate a new mechanism through which BPS and BPF promote ovarian granulosa cell tumor progression by increasing energy production through mitochondrial respiration. Thus, both bisphenols induced a metabolic switch that appears to be a stimulus for AGCT progression.
    Keywords:  Bisphenol S and F; glucose uptake; glycolysis; granulosa cell tumor; spheroid invasion
    DOI:  https://doi.org/10.1016/j.toxlet.2022.12.011
  32. Semin Cancer Biol. 2022 Dec 27. pii: S1044-579X(22)00259-0. [Epub ahead of print]
    Cancer Plasticity: Investigating the causes for this agility.
    Shubhraneel Saha, Nikita Pradhan, B Neha, Ravikiran Mahadevappa, Shilpi Minocha, Saran Kumar.
      Cancer is not a hard-wired phenomenon but an evolutionary disease. From the onset of carcinogenesis, cancer cells continuously adapt and evolve to satiate their ever-growing proliferation demands. This results in the formation of multiple subtypes of cancer cells with different phenotypes, cellular compositions, and consequently displaying varying degrees of tumorigenic identity and function. This phenomenon is referred to as cancer plasticity, during which the cancer cells exist in a plethora of cellular states having distinct phenotypes. With the advent of modern technologies equipped with enhanced resolution and depth, for example, single-cell RNA-sequencing and advanced computational tools, unbiased cancer profiling at a single-cell resolution are leading the way in understanding cancer cell rewiring both spatially and temporally. In this review, the processes and mechanisms that give rise to cancer plasticity include both intrinsic genetic factors such as epigenetic changes, differential expression due to changes in DNA, RNA, or protein content within the cancer cell, as well as extrinsic environmental factors such as tissue perfusion, extracellular milieu are detailed and their influence on key cancer plasticity hallmarks such as epithelial-mesenchymal transition (EMT) and cancer cell stemness (CSCs) are discussed. Due to therapy evasion and drug resistance, tumor heterogeneity caused by cancer plasticity has major therapeutic ramifications. Hence, it is crucial to comprehend all the cellular and molecular mechanisms that control cellular plasticity. How this process evades therapy, and the therapeutic avenue of targeting cancer plasticity must be diligently investigated.
    Keywords:  Cancer Stem Cells; Cancer heterogeneity; Cancer plasticity; Cancer therapy; Epithelial-Mesenchymal Transition; Therapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.semcancer.2022.12.005
  33. Int J Toxicol. 2022 Dec 26. 10915818221148436
    Nonclinical Testing Evaluation of Liposomes as Drug Delivery Systems.
    Paul Baldrick.
      Various marketed drugs, as well as many in-development, have utilized liposomes, vesicles composed of one or more phospholipid bilayers, as a drug delivery system, often with the statement that they are "non-toxic" materials. This paper examined safety testing considerations and reviewed nonclinical packages used to support the safe clinical use and marketing of drugs using a liposomal drug delivery system, including liposome-only study findings. It was found that most experience has come from use of an established drug (especially in the oncology field) in a liposome formulation with known excipients. From this knowledge, it is proposed that the minimal package of studies (using an oncology indication as an example) needed to support clinical entry should include in vivo pharmacology in selected mouse xenograft models, pharmacokinetic characterization showing enhanced kinetics or disposition and including tumor exposure evaluation along with repeat-dose toxicity testing in one species. It was also found that the liposomes used in drug delivery systems are not truly "non-toxic" materials. However, the majority of findings in toxicity testing relate to macrophage processing of large amounts of lipid material, with no human known safety consequence. Of note, however, are cases of hypersensitivity for some PEGylated liposome forms which translate to the clinic.
    Keywords:  liposome; nonclinical testing; pharmacokinetics; pharmacology; toxicology
    DOI:  https://doi.org/10.1177/10915818221148436
  34. Front Oncol. 2022 ;12 1064127
    Turbulence of glutamine metabolism in pan-cancer prognosis and immune microenvironment.
    Songjiang He, Shi Zhang, Yi Yao, Bin Xu, Zhili Niu, Fuben Liao, Jie Wu, Qibin Song, Minglun Li, Zheming Liu.
       Introduction: Glutamine is characterized as the nutrient required in tumor cells. The study based on glutamine metabolism aimed to develop a new predictive factor for pan-cancer prognostic and therapeutic analyses and to explore the mechanisms underlying the development of cancer.
    Methods: The RNA-sequence data retrieved from TCGA, ICGC, GEO, and CGGA databases were applied to train and further validate our signature. Single-cell RNA transcriptome data from GEO were used to investigate the correlation between glutamine metabolism and cell cycle progression. A series of bioinformatics and machine learning approaches were applied to accomplish the statistical analyses in this study.
    Results: As an individual risk factor, our signature could predict the overall survival (OS) and immunotherapy responses of patients in the pan-cancer analysis. The nomogram model combined several clinicopathological features, provided the GMscore, a readable measurement to clinically predict the probability of OS and improve the predictive capacity of GMscore. While analyzing the correlations between glutamine metabolism and malignant features of the tumor, we observed that the accumulation of TP53 inactivation might underlie glutamine metabolism with cell cycle progression in cancer. Supposedly, CAD and its upstream genes in glutamine metabolism would be potential targets in the therapy of patients with IDH-mutated glioma. Immune infiltration and sensitivity to anti-cancer drugs have been confirmed in the high-risk group.
    Discussion: In summary, glutamine metabolism is significant to the clinical outcomes of patients with pan-cancer and is tightly associated with several hallmarks of a malignant tumor.
    Keywords:  cell cycle; glutamine metabolism; immunotherapy; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.1064127
  35. Front Pharmacol. 2022 ;13 1029123
    Withania somnifera (L.) Dunal (Ashwagandha); current understanding and future prospect as a potential drug candidate.
    Javeed Ahmad Bhat, Tahira Akther, Rauf Ahmad Najar, Faheem Rasool, Abid Hamid.
      Cancer and Neurodegenerative diseases are one of the most dreadful diseases to cure and chemotherapy has found a prime place in cancerous treatments while as different strategies have been tested in neurodegenerative diseases as well. However, due to adverse shortcomings like the resistance of cancerous cells and inefficiency in neurodegenerative disease, plant sources have always found a prime importance in medicinal use for decades, Withania somnifera (L.) Dunal (W. somnifera) is a well-known plant with medicinal use reported for centuries. It is commonly known as winter cherry or ashwagandha and is a prime source of pharmaceutically active compounds withanolides. In recent years research is being carried in understanding the extensive role of W. somnifera in cancer and neurological disorders. W. somnifera has been reported to be beneficial in DNA repair mechanisms; it is known for its cellular repairing properties and helps to prevent the apoptosis of normal cells. This review summarizes the potential properties and medicinal benefits of W. somnifera especially in cancer and neurodegenerative diseases. Available data suggest that W. somnifera is effective in controlling disease progressions and could be a potential therapeutic target benefiting human health status. The current review also discusses the traditional medicinal applications of W. somnifera, the experimental evidence supporting its therapeutical potential as well as obstacles that necessitate being overcome for W. somnifera to be evaluated as a curative agent in humans.
    Keywords:  Alzheimer’s disease; Withania somnifera; cancer; neurodegenerative disorders; stroke
    DOI:  https://doi.org/10.3389/fphar.2022.1029123
  36. Chin Med. 2022 Dec 27. 17(1): 145
    Dicoumarol: from chemistry to antitumor benefits.
    Vera L M Silva, Rita Silva-Reis, Alexandra Moreira-Pais, Tiago Ferreira, Paula A Oliveira, Rita Ferreira, Susana M Cardoso, Javad Sharifi-Rad, Monica Butnariu, Maria Alina Costea, Ioana Grozea.
      Dicoumarol, a coumarin-like compound, is known for its anticoagulant properties associated with the ability to inhibit vitamin K, being prescribed as a drug for several decades. The pharmaceutical value of dicoumarol turned it into a focus of chemists' attention, aiming its synthesis and of dicoumarol derivatives, bringing to light new methodologies. In recent years, several other bioactive effects have been claimed for dicoumarol and its derivatives, including anti-inflammatory, antimicrobial, antifungal, and anticancer, although the mechanisms of action underlying them are mostly not disclosed and additional research is needed to unravel them. This review presents a state of the art on the chemistry of dicoumarols, and their potential anticancer characteristics, highlighting the mechanisms of action elucidated so far. In parallel, we draw attention to the lack of in vivo studies and clinical trials to assess the safety and efficacy as drugs for later application.
    Keywords:  Anticancer; Biological activity; Coumarins; Dicoumarol; Synthesis
    DOI:  https://doi.org/10.1186/s13020-022-00699-0
  37. Curr Res Pharmacol Drug Discov. 2022 ;3 100122
    Plant metabolite diosmin as the therapeutic agent in human diseases.
    Saad Mustafa, Mahmood Akbar, Mohammad Aasif Khan, Kumari Sunita, Shabana Parveen, Jogendra Singh Pawar, Sheersh Massey, Nupur Rani Agarwal, Syed Akhtar Husain.
      Plant-derived flavonoids have been the focus of research for many years mainly in the last decade owing to their therapeutic properties. So far, about 4000 flavonoids have been identified from plants and diosmin (a flavone glycoside) is one of them. Online databases, previous studies, and reviews have been used to gather information on anti-oxidant, immunomodulatory, anti-cancer, anti-parasitic, and anti-microbialproperties of diosmin. Effects of diosmin in combination with other flavonoids have been reviewed thoroughly and its administrative routes are also summarized. Additionally, we studied the effect of diosmin on critical protein networks. It exhibits therapeutic effects in diabetes and its associated complications such as neuropathy and dyslipidemia. Combination of diosmin with hesperidin is found to be very effective in the treatment of chronic venous insufficiency and haemorrhoids. Diosmin is an exquisite therapeutic agent alone as well as in combination with other flavonoids.
    Keywords:  Anti-Diabetic; Anti-oxidant; Diosmin; Herbal drug; Immunomodulation; Target pathways; chemoprevention; haemorrhoids
    DOI:  https://doi.org/10.1016/j.crphar.2022.100122
  38. Curr Drug Metab. 2022 Dec 28.
    The Influences and Mechanisms of High-altitude Hypoxia Exposure on Drug Metabolism.
    Anpeng Zhao, Wenbin Li, Rong Wang.
       BACKGROUND: The special environment of high-altitude hypoxia not only changes the physiological state of the body but also affects the metabolic process of many drugs, which may affect the safety and efficacy of these drugs. The number of drugs is huge, so it is not wise to blindly repeat the pharmacokinetic studies of all of them on the plateau. Mastering the law of drug metabolism on the plateau is conducive to the comprehensive development of rational drug use on the plateau. Therefore, it is very important to determine the impacts and elucidate the mechanism of drug metabolism in hypobaric hypoxia conditions.
    METHODS: In this review, we searched published studies on changes in drug metabolism in hypoxia conditions to summarize and analyze the mechanisms by which hypoxia alters drug metabolism.
    RESULTS: Although the reported effects of high-altitude hypoxia on drug metabolism are sometimes controversial, metabolism kinetics for most of the tested drugs are found to be affected. Mechanism studies showed that the major reasons causing metabolism changes are: regulated drug-metabolizing enzymes expression and activity mediated by HIF-1, nuclear receptors and inflammatory cytokines, and change in direct or indirect effects of intestinal microflora on drug metabolism by itself or the host mediated by microflora-derived drug-metabolizing enzymes, metabolites, and immunoregulation.
    CONCLUSION: Altered enzyme expression and activity in the liver and altered intestinal microflora are the two major reasons to cause altered drug metabolism in hypoxia conditions.
    Keywords:  Drug-metabolizing enzymes; High altitude; Intestinal microflora; Metabolism; Pharmacokinetics
    DOI:  https://doi.org/10.2174/1389200224666221228115526
  39. Phytomedicine. 2022 Dec 24. pii: S0944-7113(22)00711-5. [Epub ahead of print]110 154624
    Suppressive effects of bioactive herbal polysaccharides against different cancers: From mechanisms to translational advancements.
    Ammad Ahmad Farooqi, Venera Rakhmetova, Gulnara Kapanova, Akmaral Mussakhanova, Gulnara Tashenova, Aigul Tulebayeva, Aida Akhenbekova, Baojun Xu.
       BACKGROUND: Fueled by rapidly evolving comprehension of multifaceted nature of cancers, recently emerging preclinical and clinical data have supported researchers in the resolution of knowledge gaps to deepen the understanding of the molecular mechanisms. The extra-ordinary and bewildering chemical diversity encompassed by biologically active natural products continues to be of relevance to drug discovery. Accumulating evidence has spurred a remarkable evolution of concepts related to pharmacological target of oncogenic signaling pathways by polysaccharides in different cancers.
    PURPOSE: The objective of the current review is to provide new insights into study progress on anticancer effects of bioactive herbal polysaccharides.
    METHODS: PubMed, Scopus, Web of Science, Embase, and other databases were searched for articles related to anticancer effects of polysaccharides. Searches were conducted to locate relevant publications published up to October 2022.
    RESULTS: Polysaccharides have been reported to pleiotropically modulate TGF/SMAD, BMP/SMAD, TLR4, mTOR, CXCR4 and VEGF/VEGFR cascades. We have also summarized how different polysaccharides regulated apoptosis and non-coding RNAs. Additionally, this mini-review describes increasingly sophisticated understanding related to polysaccharides mediated tumor suppressive and anti-metastatic effects in tumor-bearing mice. We have also provided an overview of the clinical trials related to chemopreventive role of polysaccharides.
    CONCLUSION: Genomic and proteomic findings from these studies will facilitate 'next-generation' clinical initiatives in the prevention/inhibition of cancer.
    Keywords:  Polysaccharides; Signaling cascades; Tumor suppressive effects
    DOI:  https://doi.org/10.1016/j.phymed.2022.154624
  40. Int J Biol Macromol. 2022 Dec 26. pii: S0141-8130(22)03154-3. [Epub ahead of print]228 273-285
    Chitosan - dextran phosphate carbamate hydrogels for locally controlled co-delivery of doxorubicin and indomethacin: From computation study to in vivo pharmacokinetics.
    Sergey O Solomevich, Uladzislau E Aharodnikau, Egor I Dmitruk, Pavel A Nikishau, Pavel M Bychkovsky, Daria A Salamevich, Guohua Jiang, Kirill I Pavlov, Yanfang Sun, Tatiana L Yurkshtovich.
      The development of synergistic drug combinations is a promising strategy for effective cancer suppression. Here, we report all-polysaccharide biodegradable polyelectrolyte complex hydrogels (DPCS) based on dextran phosphate carbamate (DP) and chitosan (CS) for controlled co-delivery of the anticancer drug doxorubicin (DOX) and the non-steroidal anti-inflammatory drug indomethacin (IND). IND can induce more apoptosis in tumor cells by reducing the level of multidrug resistance-associated protein 1. Based on calculations using density functional theory and zeta potential analysis data, carriers with high drug loading were obtained. The release profile of both drugs from the hydrogels was tuned by changing the molecular weight and functional groups content of the polysaccharides. The optimized DPCS showed a steady release of DOX both in vitro and in vivo, and a gradual release of IND, which constantly induced the action of DOX. Considering all of these benefits, DOX- and IND-loaded DPCS offer a promising long-acting polysaccharide-based antitumor platform.
    Keywords:  Chitosan; Co-delivery; Dextran phosphate carbamate; Drug release; Pharmacokinetics; Polyelectrolyte complexes
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.12.243
  41. J Biomol Struct Dyn. 2022 Dec 28. 1-10
    Exploring the possibility of drug repurposing for cancer therapy targeting human lactate dehydrogenase A: a computational approach.
    Sanjay Kumar Paul, Kaustav Dutta Chowdhury, Santi Ranjan Dey, Ayantika Paul, Rajen Haldar.
      Human lactate dehydrogenase A (LDHA) is an anaerobic glycolytic enzyme involved in the inter-conversion of pyruvate to lactate. The level of LDHA in various types of cancer cells is found to be elevated and the dependence of cancer cells on anaerobic glycolysis is viewed as the reason for this elevation. Moreover, inhibition of LDHA activity has been shown to be effective in impairing the growth of tumors, making the LDHA as a potential target for cancer therapy. In this computational study, we have performed a pharmacophore based screening of approved drugs followed by a molecular docking based screening to find a few potential LDHA inhibitors. Molecular dynamics simulations have also been performed to examine the stability of the LDHA-drug complexes as obtained from the docking study. The result of the study showed that darunavir, moxalactam and eprosartan can bind to the active site of LDHA with high affinity in comparison to two known synthetic inhibitors of LDHA. The results of the molecular dynamics simulation showed that these drugs can bind stably with the enzyme through hydrogen bond and hydrophobic interactions. Hence, it is concluded that darunavir, moxalactam and eprosartan may be considered as potential inhibitors of LDHA and can be used for cancer therapy after proper validation of their effectiveness through in vitro, in vivo and clinical trials.Communicated by Ramaswamy H. Sarma.
    Keywords:  darunavir; drug repurposing; eprosartan; lactate dehydrogenase A; moxalactam
    DOI:  https://doi.org/10.1080/07391102.2022.2158134
  42. Med Gas Res. 2023 Jul-Sep;13(3):13(3): 94-98
    Molecular hydrogen therapy for neurological diseases: a review of current evidence.
    Dinesh Ramanathan, Lei Huang, Taylor Wilson, Warren Boling.
      Reactive oxygen species and other free radicals cause oxidative stress which is the underlying pathogenesis of cellular injury in various neurological diseases. Molecular hydrogen therapy with its unique biological property of selectively scavenging pathological free radicals has demonstrated therapeutic potential in innumerable animal studies and some clinical trials. These studies have implicated several cellular pathways affected by hydrogen therapy in explaining its anti-inflammatory and antioxidative effects. This article reviews relevant animal and clinical studies that demonstrate neuroprotective effects of hydrogen therapy in stroke, neurodegenerative diseases, neurotrauma, and global brain injury.
    Keywords:  animal; antioxidant; brain injury; clinical study; hydrogen therapy; molecular hydrogen; neurodegenation; neuroinflammation; oxidative stress; stroke
    DOI:  https://doi.org/10.4103/2045-9912.359677
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