bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–11–07
58 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Phosphatases of regenerating liver are key regulators of metabolism in cancer cells - role of Serine/Glycine metabolism.
  2. The Potential Role of Changes in the Glucose and Lipid Metabolic Pathways in Gastrointestinal Cancer Progression: Strategy in Cancer Therapy.
  3. Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer.
  4. Microeconomics of Metabolism: The Warburg Effect as Giffen Behaviour.
  5. Resveratrol mediates its anti-cancer effects by Nrf2 signaling pathway activation.
  6. Biological protein mediated ferroptotic tumor nanotherapeutics.
  7. Targeting regulated cell death (RCD) with small-molecule compounds in cancer therapy: A revisited review of apoptosis, autophagy-dependent cell death and necroptosis.
  8. Role of Pentacyclic Triterpenoid Acids in the Treatment of Bladder Cancer.
  9. Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells During Metastasis.
  10. Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape.
  11. Itaconic acid induces ferroptosis by activating ferritinophagy.
  12. The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma.
  13. Modulation of Long Non-Coding RNAs by Different Classes of Secondary Metabolites from Plants: A Mini-Review on Antitumor Effects.
  14. STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications.
  15. Phenylboronic acid modified lipid nanocarriers mediated co-delivery of immunocytokine TRAIL and gamma-secretase inhibitor to triple negative breast cancer cells and cancer stem cells.
  16. Antiproliferative activity of Tamoxifen, Vitamin D3 and their concomitant treatment.
  17. Enhanced Antiproliferation Potency of Electrical Pulse-Mediated Metformin and Cisplatin Combination Therapy on MDA-MB-231 Cells.
  18. A review on the emerging roles of pyruvate kinase M2 in anti-leukemia therapy.
  19. Library Screening to Identify Highly-Effective Autophagy Inhibitors for Improving Photothermal Cancer Therapy.
  20. Cisplatin chemotherapy and cochlear damage: otoprotective and chemosensitization properties of polyphenols.
  21. High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer.
  22. Metabolic profiling of attached and detached metformin and 2-deoxy-D-glucose treated breast cancer cells reveals adaptive changes in metabolome of detached cells.
  23. Research progress of nanocarriers for gene therapy targeting abnormal glucose and lipid metabolism in tumors.
  24. Identification of the first highly selective inhibitor of human lactate dehydrogenase B.
  25. Epicatechin gallate prevents the de novo synthesis of fatty acid and the migration of prostate cancer cells.
  26. Bidirectional Interaction Between Cancer Cells and Platelets Provides Potential Strategies for Cancer Therapies.
  27. Regulation of Nuclear Factor-kappaB Function by O-GlcNAcylation in Inflammation and Cancer.
  28. Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function.
  29. NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma.
  30. Copper in tumors and the use of copper-based compounds in cancer treatment.
  31. Polychlorinated biphenyl quinone exposure promotes breast cancer aerobic glycolysis: An in vitro and in vivo examination.
  32. Eupafolin induces apoptosis and autophagy of breast cancer cells through PI3K/AKT, MAPKs and NF-κB signaling pathways.
  33. The mechanism of action of Fangji Huangqi Decoction on epithelial-mesenchymal transition in breast cancer using high-throughput next-generation sequencing and network pharmacology.
  34. Gigantol inhibits proliferation and enhanced oxidative stress-mediated apoptosis through modulating of Wnt/β-catenin signaling pathway in HeLa cells.
  35. Yolk-Shell-Type Gold Nanoaggregates for Chemo- and Photothermal Combination Therapy for Drug-Resistant Cancers.
  36. NIR -I and NIR-II irradiation tumor ablation using NbS2 nanosheets as the photothermal agent.
  37. Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer.
  38. Anti-Tumor Effects of Chinese Medicine Compounds by Regulating Immune Cells in Microenvironment.
  39. Diosmin in combination with naringenin enhances apoptosis in colon cancer cells.
  40. Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells.
  41. Chemodynamic Therapy via Fenton and Fenton-Like Nanomaterials: Strategies and Recent Advances.
  42. Targeted Inhibition of HK-II Reversed the Warburg Effect to Improve the Radiosensitivity of Laryngeal Carcinoma.
  43. Dual cancer stem cell manipulation to enhance phototherapy against tumor progression and metastasis.
  44. Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events.
  45. Near Infrared Light Activated Upconversion Nanoparticles (UCNP) based Photodynamic Therapy of Prostate Cancers: an in vitro Study.
  46. Nanobodies: a tool to open new horizons in diagnosis and treatment of prostate cancer.
  47. Inhibitory effects of sulforaphane on NLRP3 inflammasome activation.
  48. [Research progress on therapeutic potential of quercetin].
  49. Miniatured Fluidics-Mediated Modular Self-Assembly of Anticancer Drug-Amino Acid Composite Microbowls for Combined Chemo-Photodynamic Therapy in Glioma.
  50. Molecular characterization of metabolic subtypes of gastric cancer based on metabolism-related lncRNA.
  51. Stimulation and homogenization of the protoporphyrin IX endogenous production by photobiomodulation to increase the potency of photodynamic therapy.
  52. Identification of Dihydroorotate Dehydrogenase Inhibitors─Indoluidins─That Inhibit Cancer Cell Growth.
  53. A Tumor Microenvironment-Responsive Theranostic Agent for Synergetic Therapy of Disulfiram-Based Chemotherapy and Chemodynamic Therapy.
  54. Recent Approaches towards the Development of Ru(II) Polypyridyl Complexes for Anticancer Photodynamic Therapy.
  55. Hybrid theranostic microbubbles for ultrasound/photoacoustic imaging guided starvation/low-temperature photothermal/hypoxia-activated synergistic cancer therapy.
  56. Evaluation of Biological Activity of Different Wavelengths of Low-Level Laser Therapy on the Cancer Prostate Cell Line Compared With Cisplatin.
  57. Recent Advances in Gelatin-Based Nanomedicine for Targeted Delivery of Anti-Cancer Drugs.
  58. A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2.
  1. Curr Opin Clin Nutr Metab Care. 2021 Nov 01.
    Phosphatases of regenerating liver are key regulators of metabolism in cancer cells - role of Serine/Glycine metabolism.
    Pegah Abdollahi, Esten N Vandsemb, Magne Børset.
       PURPOSE OF REVIEW: Phosphatases of regenerating liver (PRL) are dual-specificity phosphatases and comprise three members, PRL-1, -2 and -3. Despite the importance of PRLs as oncoproteins, there is no consensus function for this family of phosphatases. In the current review paper, we summarize recent findings on the role of PRLs in metabolic regulation.
    RECENT FINDINGS: Reprogramming of cellular metabolism is a cancer hallmark. Glucose is the major source of energy in cells. Glucose metabolism occurs through the glycolysis and can continue through the pathways such as serine synthesis pathway or the tricarboxylic acid cycle (TCA). Magnesium (Mg2+), the second most abundant cation in cells, plays an essential role in energy production by acting as a cofactor for most enzymes involved in glycolysis and in TCA. Recent findings have shown that the PRL family has a role in metabolic reprogramming mediated by (1) Mg2+ homeostasis, (2) shifting the energy source preference to glucose consumption and fueling serine/glycine pathway and (3) regulating PI3 kinase/Mammalian target of rapamycin complex. Both the phosphatase and nonphosphatase activity of PRLs appear to be important for its oncogenic role.
    SUMMARY: The PRL family contributes to the metabolic plasticity of cancer cells and, thereby, allows cancer cells to meet the high metabolic demands required for cell proliferation.
    DOI:  https://doi.org/10.1097/MCO.0000000000000797
  2. Gastrointest Tumors. 2021 Oct;8(4): 169-176
    The Potential Role of Changes in the Glucose and Lipid Metabolic Pathways in Gastrointestinal Cancer Progression: Strategy in Cancer Therapy.
    Gordon A Ferns, Milad Shahini Shams Abadi, Ahmad Raeisi, Mohammad-Hassan Arjmand.
       Background: Changes in cell metabolism are a well-known feature of some cancers, and this may be involved in the etiology of tumor formation and progression, as well as tumor heterogeneity. These changes may affect fatty acid metabolism and glycolysis and are required to provide the increase in energy necessary for the high rate of proliferation of cancer cells. Gastrointestinal cancers remain a difficult-to-treat cancer, particularly as they are usually diagnosed at a late stage of disease and are associated with poor outcomes.
    Summary: Recently, the changes in the metabolic pathways, including the expression of the rate-limiting enzymes involved, have been considered to be a potential target for therapy for gastrointestinal tumors.
    Key Message: A combination of routine chemotherapy drugs with metabolic inhibitors may improve the effectiveness of treatment.
    Keywords:  Cancer metabolism; Gastrointestinal tumors; Glucose metabolism; Lipid metabolism
    DOI:  https://doi.org/10.1159/000517771
  3. Biofactors. 2021 Nov 01.
    Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer.
    Leila Kooshki, Parisa Mahdavi, Sajad Fakhri, Esra Küpeli Akkol, Haroon Khan.
      Anticancer drugs are not purely effective because of their toxicity, side effects, high cost, inaccessibility, and associated resistance. On the other hand, cancer is a complex public health problem that could intelligently adopt different signaling pathways and alter the body's metabolism to escape from the immune system. One of the cancer strategies to metastasize is modifying pH in the tumor microenvironment, ranging between 6.5 and 6.9. As a powerful determiner, lactate is responsible for this acidosis. It is involved in immune stimulation, including innate and adaptive immunity, apoptotic-related factors (Bax/Bcl-2, caspase), and glycolysis pathways (e.g., GLUT-1, PKM2, PFK, HK2, MCT-1, and LDH). Lactate metabolism, in turn, is interconnected with several dysregulated signaling mediators, including PI3K/Akt/mTOR, AMPK, NF-κB, Nrf2, JAK/STAT, and HIF-1α. Because of lactate's emerging and critical role, targeting lactate production and its transporters is important for preventing and managing tumorigenesis. Hence, exploring and developing novel promising anticancer agents to minimize human cancers is urgent. Based on numerous studies, natural secondary metabolites as multi-target alternative compounds with health-promoting properties possess more high effectiveness and low side effects than conventional agents. Besides, the mechanism of multi-targeted natural sources is related to lactate production and cancer-associated cross-talked factors. This review focuses on targeting the lactate metabolism/transporters, and lactate-associated mediators, including glycolytic pathways. Besides, interconnected mediators to lactate metabolism are also targeted by natural products. Accordingly, plant-derived secondary metabolites are introduced as alternative therapies in combating cancer through modulating lactate metabolism and glycolytic pathways.
    Keywords:  cancer; glycolysis; lactate; natural products; therapeutic target; tumor microenvironment
    DOI:  https://doi.org/10.1002/biof.1799
  4. Bull Math Biol. 2021 Oct 31. 83(12): 120
    Microeconomics of Metabolism: The Warburg Effect as Giffen Behaviour.
    Jumpei F Yamagishi, Tetsuhiro S Hatakeyama.
      Metabolic behaviours of proliferating cells are often explained as a consequence of rational optimization of cellular growth rate, whereas microeconomics formulates consumption behaviours as optimization problems. Here, we pushed beyond the analogy to precisely map metabolism onto the theory of consumer choice. We thereby revealed the correspondence between long-standing mysteries in both fields: the Warburg effect, a seemingly wasteful but ubiquitous strategy where cells favour aerobic glycolysis over more energetically efficient oxidative phosphorylation, and Giffen behaviour, the unexpected consumer behaviour where a good is demanded more as its price rises. We identified the minimal, universal requirements for the Warburg effect: a trade-off between oxidative phosphorylation and aerobic glycolysis and complementarity, i.e. impossibility of substitution for different metabolites. Thus, various hypotheses for the Warburg effect are integrated into an identical optimization problem with the same universal structure. Besides, the correspondence between the Warburg effect and Giffen behaviour implies that oxidative phosphorylation is counter-intuitively stimulated when its efficiency is decreased by metabolic perturbations such as drug administration or mitochondrial dysfunction; the concept of Giffen behaviour bridges the Warburg effect and the reverse Warburg effect. This highlights that the application of microeconomics to metabolism can offer new predictions and paradigms for both biology and economics.
    Keywords:  Metabolic systems; Overflow metabolism; Reverse Warburg effect; Theory of consumer choice
    DOI:  https://doi.org/10.1007/s11538-021-00952-x
  5. Cancer Cell Int. 2021 Oct 30. 21(1): 579
    Resveratrol mediates its anti-cancer effects by Nrf2 signaling pathway activation.
    Matin Alavi, Tahereh Farkhondeh, Michael Aschner, Saeed Samarghandian.
       AIM AND BACKGROUND: Cancer represents a major health problem with an exceedingly high toll on the patients, their families, and the economy. Cancers are also associated with high mortality rates. Existing therapies for cancer are generally ineffective with many side effects.
    METHOD: A search was conducted on Pubmed, Google Scholar, Scopus, and web of science databases, and articles related to anticancer effects of resveratrol were collected.
    RESULTS: Resveratrol is a natural compound that can activate the Nrf2 transcription factor. Nfr2 translocates to the nucleus and induces antioxidant gene expression. In different cell lines, resveratrol can increase apoptosis and inhibit the proliferation of cancer cells.
    CONCLUSION: We found that resveratrol shows efficacy for the treatment of cancer, but due to high controversy on the Nrf2 signaling pathway and mechanisms of resveratrol action, additional studies should be conducted to better characterize its mode-of-action in cancer.
    Keywords:  Cancer; Nrf2; Resveratrol
    DOI:  https://doi.org/10.1186/s12935-021-02280-5
  6. J Mater Chem B. 2021 Nov 03.
    Biological protein mediated ferroptotic tumor nanotherapeutics.
    Jiaoyang Tao, Chaoqun Li, Yongquan Zheng, Fengmei Wang, Meng Zhang, Xiaodong Wu, Yue Chen, Qingquan Zeng, Fengying Chen, Weidong Fei.
      Ferroptosis, a cell death pathway involving iron-related generation of lipid hydroperoxides for achieving incredible tumor suppression, has reignited the hope of chemotherapy in tumor treatment in the past decade. With extensive research studies, various bioactive proteins and cellular pathways have been demonstrated to regulate the occurrence and development of ferroptosis. The gradually established ferroptotic regulatory network is conducive to find effective proteins from a holistic perspective and guides better designs for future ferroptotic tumor therapies. The first section of this review summarizes the recent advances in ferroptotic regulatory mechanisms of proteins and attempts to clarify their latent function in the ferroptotic regulatory network. Second, the existing protein-mediated ferroptotic tumor nanotherapeutic strategies were reviewed, including the protein-mediated iron supplement, cell membrane transporter inhibition, glutathione peroxidase 4 interference, glutathione depletion, bioenzyme-mediated reactive oxygen species generation, heat shock protein inhibition, and tumor-overexpressed protein-triggered drug release for ferroptotic therapy. Finally, the future expectations and challenges of ferroptotic tumor nanotherapeutics for clinical cancer therapy are highlighted.
    DOI:  https://doi.org/10.1039/d1tb01289d
  7. Drug Discov Today. 2021 Oct 27. pii: S1359-6446(21)00450-5. [Epub ahead of print]
    Targeting regulated cell death (RCD) with small-molecule compounds in cancer therapy: A revisited review of apoptosis, autophagy-dependent cell death and necroptosis.
    Wei Liu, Wenke Jin, Shiou Zhu, Yi Chen, Bo Liu.
      Evasion of regulated cell death (RCD), mainly referring to apoptosis, autophagy-dependent cell death, necroptosis, and other subroutines, is one of the well-established hallmarks of cancer cells. Accumulating evidence has revealed several small-molecule compounds that target different subroutines of RCD in cancer therapy. In this review, we summarize key pathways of apoptosis, autophagy-dependent cell death and necroptosis in cancer, and describe small-molecule compounds that target these pathways and have potential as therapeutics. These inspiring findings light the way towards the discovery of more 'magic bullets' that could work individually or cooperatively to target precisely the three RCD subroutines and so improve cancer treatment.
    Keywords:  Apoptosis; Autophagy-dependent cell death; Cancer therapy; Necroptosis; Regulated cell death (RCD); Small-molecule compound
    DOI:  https://doi.org/10.1016/j.drudis.2021.10.011
  8. Mini Rev Med Chem. 2021 Oct 22.
    Role of Pentacyclic Triterpenoid Acids in the Treatment of Bladder Cancer.
    Anindita Ghosh, Chinmay Kumar Panda.
      Bladder cancer carries a poor prognosis and has proven resistance to chemotherapy. Pentacyclic Triterpenoid Acids (PTAs) are natural bioactive compounds that have a well-known impact on cancer research because of their cytotoxic and chemopreventive activities. This review focuses on bladder cancer which can no longer be successfully treated by DNA damaging drugs. Unlike most of the existing drugs against bladder cancer, PTAs are non-toxic to normal cells. Collecting findings from both in vitro and in vivo studies, it has been concluded that PTAs may serve as promising agents in future bladder cancer therapy. In this review, the roles of various PTAs in bladder cancer have been explored, and their mechanisms of action in the treatment of bladder cancer have been described. Specific PTAs have been shortlisted from each of the chief skeletons of pentacyclic triterpenoids, which could be effective against bladder cancer because of their mode of action. This review thereby throws light on the multi targets and mechanisms of PTAs, which are responsible for their selective anticancer effects and provides guidelines for further research and development of new natural antitumor compounds.
    Keywords:  Pentacyclic triterpenoid acids; apoptosis; bladder cancer; chemotherapy; immunotherapy; natural bioactive compounds; specific proteins
    DOI:  https://doi.org/10.2174/1389557521666211022145052
  9. Front Cell Dev Biol. 2021 ;9 751301
    Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells During Metastasis.
    Félix A Urra, Sebastián Fuentes-Retamal, Charlotte Palominos, Yarcely A Rodríguez-Lucart, Camila López-Torres, Ramiro Araya-Maturana.
      The role of metabolism in tumor growth and chemoresistance has received considerable attention, however, the contribution of mitochondrial bioenergetics in migration, invasion, and metastasis is recently being understood. Migrating cancer cells adapt their energy needs to fluctuating changes in the microenvironment, exhibiting high metabolic plasticity. This occurs due to dynamic changes in the contributions of metabolic pathways to promote localized ATP production in lamellipodia and control signaling mediated by mitochondrial reactive oxygen species. Recent evidence has shown that metabolic shifts toward a mitochondrial metabolism based on the reductive carboxylation, glutaminolysis, and phosphocreatine-creatine kinase pathways promote resistance to anoikis, migration, and invasion in cancer cells. The PGC1a-driven metabolic adaptations with increased electron transport chain activity and superoxide levels are essential for metastasis in several cancer models. Notably, these metabolic changes can be determined by the composition and density of the extracellular matrix (ECM). ECM stiffness, integrins, and small Rho GTPases promote mitochondrial fragmentation, mitochondrial localization in focal adhesion complexes, and metabolic plasticity, supporting enhanced migration and metastasis. Here, we discuss the role of ECM in regulating mitochondrial metabolism during migration and metastasis, highlighting the therapeutic potential of compounds affecting mitochondrial function and selectively block cancer cell migration.
    Keywords:  ECM stiffness; OXPHOS (oxidative phosphorylation); TCA cycle; integrin; metabolic shift; migrastatics; migrating cancer cells
    DOI:  https://doi.org/10.3389/fcell.2021.751301
  10. Cell Metab. 2021 Nov 02. pii: S1550-4131(21)00486-1. [Epub ahead of print]33(11): 2247-2259.e6
    Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape.
    Giulia Salvadori, Federica Zanardi, Fabio Iannelli, Riccardo Lobefaro, Claudio Vernieri, Valter D Longo.
      Metastatic tumors remain lethal due to primary/acquired resistance to therapy or cancer stem cell (CSC)-mediated repopulation. We show that a fasting-mimicking diet (FMD) activates starvation escape pathways in triple-negative breast cancer (TNBC) cells, which can be identified and targeted by drugs. In CSCs, FMD lowers glucose-dependent protein kinase A signaling and stemness markers to reduce cell number and increase mouse survival. Accordingly, metastatic TNBC patients with lower glycemia survive longer than those with higher baseline glycemia. By contrast, in differentiated cancer cells, FMD activates PI3K-AKT, mTOR, and CDK4/6 as survival/growth pathways, which can be targeted by drugs to promote tumor regression. FMD cycles also prevent hyperglycemia and other toxicities caused by these drugs. These data indicate that FMD has wide and differential effects on normal, cancer, and CSCs, allowing the rapid identification and targeting of starvation escape pathways and providing a method potentially applicable to many malignancies.
    Keywords:  CDK4/6; PI3K/AKT; PKA; cancer stem cells; fasting; fasting-mimicking diet; glucose; mTOR; starvation escape pathways; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.cmet.2021.10.008
  11. Biochem Biophys Res Commun. 2021 Oct 25. pii: S0006-291X(21)01463-7. [Epub ahead of print]583 56-62
    Itaconic acid induces ferroptosis by activating ferritinophagy.
    Chunjing Qu, Enyong Dai, Tianru Lai, Guohua Cao, Jiao Liu, Rui Kang, Leng Han, Daolin Tang, Di Zhou.
      Itaconic acid is an unsaturated dicarbonic acid. It has a wide range of applications in the industrial production of resins and is also a mediator of immunometabolism in macrophages. Here, we show a previously unrecognized role of itaconic acid in triggering ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation. We found that supraphysiological itaconic acid dose-dependently induces ferroptosis, rather than apoptosis, in human cancer cell lines. Mechanistically, we determined that itaconic acid activates NOCA4-mediated ferritinophagy, which leads to ferroptosis through ferritin degradation and subsequent iron overload and oxidative damage. In contrast, itaconic acid-induced expression and activation of NFE2L2 serves as a defense mechanism to limit ferroptosis by producing antioxidant genes. Consequently, impaired NCOA4 expression prevented, whereas a disrupted NFE2L2 pathway enhanced, sensitivity to itaconic acid-induced ferroptosis in vitro and in xenograft models. These findings establish a dynamic model of metabolite-induced ferroptotic cancer cell death, which may contribute to the development of new targeted therapies.
    Keywords:  Autophagy; Ferroptosis; Itaconic acid; Metabolism; Transcription factor
    DOI:  https://doi.org/10.1016/j.bbrc.2021.10.054
  12. PLoS One. 2021 ;16(11): e0259241
    The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma.
    Ethan Emberley, Alison Pan, Jason Chen, Rosalyn Dang, Matt Gross, Tony Huang, Weiqun Li, Andrew MacKinnon, Devansh Singh, Natalija Sotirovska, Susanne M Steggerda, Tracy Wang, Francesco Parlati.
      Dysregulated metabolism is a hallmark of cancer that manifests through alterations in bioenergetic and biosynthetic pathways to enable tumor cell proliferation and survival. Tumor cells exhibit high rates of glycolysis, a phenomenon known as the Warburg effect, and an increase in glutamine consumption to support the tricarboxylic acid (TCA) cycle. Renal cell carcinoma (RCC) tumors express high levels of glutaminase (GLS), the enzyme required for the first step in metabolic conversion of glutamine to glutamate and the entry of glutamine into the TCA cycle. We found that RCC cells are highly dependent on glutamine for proliferation, and this dependence strongly correlated with sensitivity to telaglenstat (CB-839), an investigational, first-in-class, selective, orally bioavailable GLS inhibitor. Metabolic profiling of RCC cell lines treated with telaglenastat revealed a decrease in glutamine consumption, which was concomitant with a decrease in the production of glutamate and other glutamine-derived metabolites, consistent with GLS inhibition. Treatment of RCC cells with signal transduction inhibitors everolimus (mTOR inhibitor) or cabozantinib (VEGFR/MET/AXL inhibitor) in combination with telaglenastat resulted in decreased consumption of both glucose and glutamine and synergistic anti-proliferative effects. Treatment of mice bearing Caki-1 RCC xenograft tumors with cabozantinib plus telaglenastat resulted in reduced tumor growth compared to either agent alone. Enhanced anti-tumor activity was also observed with the combination of everolimus plus telaglenastat. Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption.
    DOI:  https://doi.org/10.1371/journal.pone.0259241
  13. Mini Rev Med Chem. 2021 Nov 01.
    Modulation of Long Non-Coding RNAs by Different Classes of Secondary Metabolites from Plants: A Mini-Review on Antitumor Effects.
    Tamires Cunha Almeida, Janaína Brandão Seibert, Tatiane Roquete Amparo, Gustavo Henrique Bianco de Souza, Glenda Nicioli da Silva, David Henrique Dos Santos.
      The broad pharmacological spectrum of plants is related to their secondary metabolism, which is responsible for the synthesis of different compounds that have multiple effects on cellular physiology. Among the biological effects presented by phytochemicals, their use for the prevention and treatment of cancer can be highlighted. This occurs due to several mechanisms of antitumor action demonstrated by these compounds, including regulation of the cell signaling pathways and inhibition of tumor growth. In this way, long non-coding RNAs (lncRNAs) appear to be promising targets for the treatment of cancer. Their deregulation has already been related to a variety of clinical-pathological parameters. However, the effects of secondary metabolites on lncRNAs are still restricted. For this reason, the present review aimed to gather data on phytochemicals with action on lncRNAs in order to confirm their possible antitumor potential. According to the literature, terpenoid and flavonoid are the main examples of secondary metabolites involved with lncRNAs activity. In addition, the lncRNAs H19, CASC2, HOTAIR, NKILA, CCAT1, MALAT1, AFAP1-AS1, MEG3, and CDKN2B-AS1 can be highlighted as important targets in the search for new anti-tumor agents since they act as modulating pathways related to cell proliferation, cell cycle, apoptosis, cell migration and invasion. Finally, challenges for the use of natural products as a commercial drug were also discussed. The low yield, selectivity index and undesirable pharmacokinetic parameters were emphasized as a difficulty for obtaining these compounds on a large scale and for improving the potency of its biological effect. However, the synthesis and/or development of formulations were suggested as a possible approach to solve these problems. All of these data together confirm the potential of secondary metabolites as a source of new anti-tumor agents acting on lncRNAs.
    Keywords:  antitumor activity; cancer; lncRNAs; phytocompounds; plants; secondary metabolites
    DOI:  https://doi.org/10.2174/1389557521666211101161548
  14. Neoplasia. 2021 Oct 29. pii: S1476-5586(21)00088-9. [Epub ahead of print]23(12): 1167-1178
    STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications.
    Isidora Tošić, David A Frank.
      The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is activated constitutively in a wide array of human cancers. It is an appealing molecular target for novel therapy as it directly regulates expression of genes involved in cell proliferation, survival, angiogenesis, chemoresistance and immune responsiveness. In addition to these well-established oncogenic roles, STAT3 has also been found to mediate a wide array of functions in modulating cellular behavior. The transcriptional function of STAT3 is canonically regulated through tyrosine phosphorylation. However, STAT3 phosphorylated at a single serine residue can allow incorporation of this protein into the inner mitochondrial membrane to support oxidative phosphorylation (OXPHOS) and maximize the utility of glucose sources. Conflictingly, its canonical transcriptional activity suppresses OXPHOS and favors aerobic glycolysis to promote oncogenic behavior. Apart from mediating the energy metabolism and controversial effects on ATP production, STAT3 signaling modulates lipid metabolism of cancer cells. By mediating fatty acid synthesis and beta oxidation, STAT3 promotes employment of available resources and supports survival in the conditions of metabolic stress. Thus, the functions of STAT3 extend beyond regulation of oncogenic genes expression to pleiotropic effects on a spectrum of essential cellular processes. In this review, we dissect the current knowledge on activity and mechanisms of STAT3 involvement in transcriptional regulation, mitochondrial function, energy production and lipid metabolism of malignant cells, and its implications to cancer pathogenesis and therapy.
    Keywords:  Adenosine triphosphate; Lipid metabolism; Metabolism; Neoplasms; Protein processing, Post-translational; STAT3 transcription factor
    DOI:  https://doi.org/10.1016/j.neo.2021.10.003
  15. Med Hypotheses. 2021 Oct 20. pii: S0306-9877(21)00235-8. [Epub ahead of print]157 110716
    Phenylboronic acid modified lipid nanocarriers mediated co-delivery of immunocytokine TRAIL and gamma-secretase inhibitor to triple negative breast cancer cells and cancer stem cells.
    Sai Kiran S S Pindiprolu, Harani Avasarala, Sathis Kumar Dinakaran.
      Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with high rates of tumor relapse and metastasis. The existing drugs for treatment of TNBC are unable to target the cells of origin (breast cancer stem cells) of TNBC. TNF-α related apoptosis inducing ligand (TRAIL) has propensity to target TNBC cells including cancer stem cells. However, resistance to TRAIL due to activation of anti-apoptotic mechanisms is a limitation for TRAIL based anticancer therapy for TNBC. In the present study we propose an hypothesis for effective targeting of triple negative breast cancer by overcoming TRAIL resistance.
    Keywords:  Apoptosis; Cancer stem cells; Death receptors; Gamma-secretase; Metastasis; Notch; Phenyl boronate; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.mehy.2021.110716
  16. EXCLI J. 2021 ;20 1394-1406
    Antiproliferative activity of Tamoxifen, Vitamin D3 and their concomitant treatment.
    Derya Yetkin, Ebru Balli, Furkan Ayaz.
      Breast cancer stands out as the most common cancer type among women throughout the world. Especially for the estrogen receptor alpha (ER α +) positive breast cancer cells Tamoxifen has been widely used as an anti-cancer agent. Tamoxifen's mechanism of action is through ER. It binds to the receptor and leads to a conformational change which eventually prevents cancer cells proliferation and survival. In our current study, we aimed to investigate the combination of Tamoxifen with Vitamin D3 to test whether this combination will enhance the anti-cancer effect of Tamoxifen on breast cancer cells in vitro. Vitamin D3 has sterol structure and this property enables it to act similar to hormones. Vitamin D Receptor (VDR) has been commonly found in different types of cancer cells including but not limited to breast and prostate cancer cells. Through this receptor Vitamin D3 acts as an anti-proliferative agent. We examined the proliferation rate, apoptosis and necrosis levels as well as cell cycle progression in MCF-7 breast cancer cell line in the presence of Vitamin D3 and Tamoxifen to compare the changes with the Tamoxifen treated group. Our results suggest that Tamoxifen was a more potent anti-cancer agent than Vitamin D3 or its combination with Vitamin D3 based on cell cycle arrest, apoptosis and cell proliferation levels. This effect in the apoptosis rate and cell cycle stage of the MCF-7 cells were in line with the changes in gene expression profile of P53, BAX and BCL-2. Our results suggest that Tamoxifen by itself is adequate enough and more potent than Vitamin D3 or its combination with Vitamin D3 as anti-cancer agent for the breast cancer cells in vitro.
    Keywords:  Tamoxifen; Vitamin D3; apoptosis; breast cancer; cell cycle; cell proliferation
    DOI:  https://doi.org/10.17179/excli2021-3989
  17. Appl Biochem Biotechnol. 2021 Nov 06.
    Enhanced Antiproliferation Potency of Electrical Pulse-Mediated Metformin and Cisplatin Combination Therapy on MDA-MB-231 Cells.
    Praveen Sahu, Ignacio G Camarillo, Raji Sundararajan.
      We investigated the combined potency of metformin and cisplatin on the MDA-MB-231, triple-negative breast cancer (TNBC) cells with the application of electrical pulses. There are no targeted therapies for this subset of breast cancer because of the absence of specific biomarkers. Cytotoxic chemotherapy is the mainstream mode of treatment for TNBC, and cisplatin is the most commonly used chemotherapeutic drug. While there is a good response initially, TNBC cells develop drug resistance eventually. Thus, there is a need for alternate therapies. Toward this, we studied the antiproliferation characteristics of electrical pulse-mediated combination therapy using metformin, the commonly used Type-2 diabetes drug, along with cisplatin. We used metformin, as it has various anticancer properties caused by repressing energy pathways in a cancer cell. Application of 8 pulses of 1000 V/cm, 100 µs, at 1 Hz frequency, enhanced the drug uptake leading to cell viability as low as 25.86% at 30 µM cisplatin and 5 mM metformin in a 24 h study. Also, the same studies were conducted on MCF10A, a non-cancerous human epithelial cell. It aided in comparing the result for both MDA-MB-231 and MCF10A cell lines while establishing a better understanding of the experimental outcomes. Overall, the various experimental results from colony-forming assay, reactive oxidative analysis, and the intracellular glucose metabolic assay indicate the possibility of the electrical pulses-based cisplatin and metformin drug combination as a potential alternative to TNBC treatment.
    Keywords:  Cisplatin; Electrical pulses; MDA-MB-231 cells; Metformin; Triple-negative breast cancer
    DOI:  https://doi.org/10.1007/s12010-021-03723-5
  18. Int J Biol Macromol. 2021 Nov 02. pii: S0141-8130(21)02378-3. [Epub ahead of print]
    A review on the emerging roles of pyruvate kinase M2 in anti-leukemia therapy.
    Guan-Jun Yang, Jia Wu, Chung-Hang Leung, Dik-Lung Ma, Jiong Chen.
      Glycolysis is an important step in respiration and provides energy for cellular processes. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme of glycolysis, plays an important role in tumor cell metabolism and proliferation. It is also specifically overexpressed in leukemia cells and contributes to leukemic proliferation, differentiation, and drug resistance through both aerobic glycolysis and non-metabolic pathways. In this review, the functions and regulatory roles of PKM2 are firstly introduced. Then, the molecular mechanisms of PKM2 in leukemogenesis are summarized. Next, reported PKM2 modulators and their anti-leukemia mechanisms are described. Finally, the current challenges and the potential opportunities of PKM2 inhibitors or agonists in leukemia therapy are discussed.
    Keywords:  Leukemia; Modulators; Pyruvate kinase M2
    DOI:  https://doi.org/10.1016/j.ijbiomac.2021.10.213
  19. Nano Lett. 2021 Nov 03.
    Library Screening to Identify Highly-Effective Autophagy Inhibitors for Improving Photothermal Cancer Therapy.
    Li Wang, Yitong Wang, Wei Zhao, Kaili Lin, Wei Li, Guodong Wang, Qiang Zhang.
      The small molecular inhibitor-associated downregulation of autophagy can remarkably enhance the efficiency of photothermal cancer therapy. To identify a more effective autophagy inhibitor, we screened a library of 20 compounds and found chloroquine, hydroxychloroquine, dauricine, and daurisoline were more efficient than the others to improve the photothermal killing of cancer cells. Interestingly, the four agents all disturb the autophagosome formation and fusion process, indicating it is a promising target to enhance cancer therapeutic efficiency. Among the four agents, daurisoline was identified to be the most efficient one. It reduced the viability of cancer cells treated by low-energy photothermal therapy from 86.27% to 32.92%. Finally, the combination treatment mediated by nanodrugs loaded with daurisoline and indocyanine green was more efficient than the individual modalities, resulting in complete inhibition of tumor growth. The study gives new inspiration to autophagy modulation-associated photothermal therapy and other therapeutic modalities for cancer treatment.
    Keywords:  autophagy inhibition; cancer; library screen; nanodrugs; photothermal therapy
    DOI:  https://doi.org/10.1021/acs.nanolett.1c02825
  20. Antioxid Redox Signal. 2021 Nov 03.
    Cisplatin chemotherapy and cochlear damage: otoprotective and chemosensitization properties of polyphenols.
    Anna Rita Fetoni, Fabiola Paciello, Diana Troiani.
       SIGNIFICANCE: Cisplatin is an important component of treatment regimens for different cancers. Notwithstanding that therapeutic success often results from partial efficacy or stabilizing the disease, chemotherapy failure is driven by resistance to drug treatment and occurrence of side effects, such as progressive irreversible ototoxicity. Cisplatin's side effects, including ototoxicity, are often dose-limiting. Recent Advances: Cisplatin ototoxicity results from several mechanisms, including: redox imbalance caused by reactive oxygen species (ROS) production and lipid peroxidation, activation of inflammation, p53 and its downstream pathways that culminate in apoptosis. Considerable efforts in research have targeted development of molecular interventions that can be concurrently administered with cisplatin or other chemotherapies in order to reduce side effect toxicities while preserving or enhancing the anti-neoplastic effects. Evidence from studies has indicated some polyphenols, such as curcumin, can help to regulate redox signaling and inflammatory effects. Furthermore, polyphenols can exert opposing effects in different types of tissues, i.e. normal cells undergoing stressful conditions versus cancer cells.
    CRITICAL ISSUES: This review article summarizes evidence of curcumin antioxidant effect against cisplatin-induced ototoxicity that is converted to a pro-oxidant activity in cisplatin-treated cancer cells, thus providing an ideal chemosensitivity combined with otoprotection. Polyphenols can modulate the adaptive responses to stress in the cisplatin-exposed cochlea. These adaptive effects can result from the interaction/crosstalk between the cell's defenses, inflammatory molecules, and the key signaling molecules of STAT-3, NF-κB, p53, and Nrf-2.
    FUTURE DIRECTIONS: We provide molecular evidence for alternative strategies for chemotherapy with cisplatin addressing the otoprotection and chemosensitization properties of polyphenols.
    DOI:  https://doi.org/10.1089/ars.2021.0183
  21. J Exp Clin Cancer Res. 2021 Oct 30. 40(1): 343
    High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer.
    Franziska Böttger, Andrea Vallés-Martí, Loraine Cahn, Connie R Jimenez.
      Mounting evidence indicates that vitamin C has the potential to be a potent anti-cancer agent when administered intravenously and in high doses (high-dose IVC). Early phase clinical trials have confirmed safety and indicated efficacy of IVC in eradicating tumour cells of various cancer types. In recent years, the multi-targeting effects of vitamin C were unravelled, demonstrating a role as cancer-specific, pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator, reversing epithelial-to-mesenchymal transition, inhibiting hypoxia and oncogenic kinase signalling and boosting immune response. Moreover, high-dose IVC is powerful as an adjuvant treatment for cancer, acting synergistically with many standard (chemo-) therapies, as well as a method for mitigating the toxic side-effects of chemotherapy. Despite the rationale and ample evidence, strong clinical data and phase III studies are lacking. Therefore, there is a need for more extensive awareness of the use of this highly promising, non-toxic cancer treatment in the clinical setting. In this review, we provide an elaborate overview of pre-clinical and clinical studies using high-dose IVC as anti-cancer agent, as well as a detailed evaluation of the main known molecular mechanisms involved. A special focus is put on global molecular profiling studies in this respect. In addition, an outlook on future implications of high-dose vitamin C in cancer treatment is presented and recommendations for further research are discussed.
    Keywords:  Ascorbic acid; Cancer; Clinical trials; IVC; Metabolomics; Proteomics; Transcriptomics; Vitamin C
    DOI:  https://doi.org/10.1186/s13046-021-02134-y
  22. Sci Rep. 2021 Nov 01. 11(1): 21354
    Metabolic profiling of attached and detached metformin and 2-deoxy-D-glucose treated breast cancer cells reveals adaptive changes in metabolome of detached cells.
    Jernej Repas, Elmar Zügner, Boris Gole, Maruša Bizjak, Uroš Potočnik, Christoph Magnes, Mojca Pavlin.
      Anchorage-independent growth of cancer cells in vitro is correlated to metastasis formation in vivo. Metformin use is associated with decreased breast cancer incidence and currently evaluated in cancer clinical trials. The combined treatment with metformin and 2-deoxy-D-glucose (2DG) in vitro induces detachment of viable MDA-MB-231 breast cancer cells that retain their proliferation capacity. This might be important for cell detachment from primary tumors, but the metabolic changes involved are unknown. We performed LC/MS metabolic profiling on separated attached and detached MDA-MB-231 cells treated with metformin and/or 2DG. High 2DG and metformin plus 2DG altered the metabolic profile similarly to metformin, inferring that metabolic changes are necessary but not sufficient while the specific effects of 2DG are crucial for detachment. Detached cells had higher NADPH levels and lower fatty acids and glutamine levels compared to attached cells, supporting the role of AMPK activation and reductive carboxylation in supporting anchorage-independent survival. Surprisingly, the metabolic profile of detached cells was closer to untreated control cells than attached treated cells, suggesting detachment might help cells adapt to energy stress. Metformin treated cells had higher fatty and amino acid levels with lower purine nucleotide levels, which is relevant for understanding the anticancer mechanisms of metformin.
    DOI:  https://doi.org/10.1038/s41598-021-98642-0
  23. Drug Deliv. 2021 Dec;28(1): 2329-2347
    Research progress of nanocarriers for gene therapy targeting abnormal glucose and lipid metabolism in tumors.
    Xianhu Zeng, Zhipeng Li, Chunrong Zhu, Lisa Xu, Yong Sun, Shangcong Han.
      In recent years, the incidence of various types of tumors has gradually increased, and it has also been found that there is a certain correlation between abnormal glucose and lipid metabolism and tumors. Glycolipid metabolism can promote tumor progression through multiple pathways, and the expression of related genes also directly or indirectly affects tumor metabolism, metastasis, invasion, and apoptosis. There has been much research on targeted drug delivery systems designed for abnormal glucose and lipid metabolism due to their accuracy and efficiency when used for tumor therapy. In addition, gene mutations have become an important factor in tumorigenesis. For this reason, gene therapy consisting of drugs designed for certain specifically expressed genes have been transfected into target cells to express or silence the corresponding proteins. Targeted gene drug vectors that achieve their corresponding therapeutic purposes are also rapidly developing. The genes related to glucose and lipid metabolism are considered as the target, and a corresponding gene drug carrier is constructed to influence and interfere with the expression of related genes, so as to block the tumorigenesis process and inhibit tumor growth. Designing drugs that target genes related to glucose and lipid metabolism within tumors is considered to be a promising strategy for the treatment of tumor diseases. This article summarizes the chemical drugs/gene drug delivery systems and the corresponding methods used in recent years for the treatment of abnormal glucose and lipid metabolism of tumors, and provides a theoretical basis for the development of glucolipid metabolism related therapeutic methods.
    Keywords:  Targeted nano-drug carrier; abnormal glucose and lipid metabolism; gene carrier drugs; tumors
    DOI:  https://doi.org/10.1080/10717544.2021.1995081
  24. Sci Rep. 2021 Nov 01. 11(1): 21353
    Identification of the first highly selective inhibitor of human lactate dehydrogenase B.
    Sachio Shibata, Satoshi Sogabe, Masanori Miwa, Takuya Fujimoto, Nobuyuki Takakura, Akihiko Naotsuka, Shuji Kitamura, Tomohiro Kawamoto, Tomoyoshi Soga.
      Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD+; it has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To the best of our knowledge, selective inhibitors for LDHB have not yet been reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD+. As a result, we identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. This compound exhibited uncompetitive LDHB inhibition (EC50 = 42 nM). X-ray crystallography revealed that AXKO-0046 bound to the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerisation interface of the two dimers is critical for the enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism.
    DOI:  https://doi.org/10.1038/s41598-021-00820-7
  25. Acta Biochim Biophys Sin (Shanghai). 2021 Oct 30. pii: gmab144. [Epub ahead of print]
    Epicatechin gallate prevents the de novo synthesis of fatty acid and the migration of prostate cancer cells.
    Luyao Chen, Yaping Guo, Zixuan Wu, Shuwu Zhao, Zhaiyi Zhang, Fang Zheng, Likang Sun, Zheng Hao, Chen Xu, Tao Wang, Yanfei Peng.
      Lipid metabolism disorder caused by the upregulation of lipogenic genes is a typical feature of prostate cancer. The synthesis of fatty acids is enhanced to accelerate the development of prostate cancer and is considered as a potential therapeutic target. Epicatechin gallate, an active compound of green tea, has been reported to modulate lipid metabolism. In this research, the potential role of epicatechin gallate in prostate cancer cells was evaluated. The results indicated that epicatechin gallate downregulates the expression of acetyl-CoA carboxylase, ATP citrate lyase, and fatty acid synthase in prostate cancer cells and prostate xenograft tissues, suggesting that epicatechin gallate can inhibit de novo fatty acid synthesis. Moreover, epicatechin gallate significantly restrains the migration rather than the viability of prostate cancer cells. PI3K/AKT/mTOR signaling pathway, which exhibits regulatory effect on lipogenesis, is also inhibited under epicatechin gallate treatment, while pretreatment with AKT activator SC79 or mTOR activator MHY1485 blocks the inhibitory effect of epicatechin gallate on the expression of lipogenic genes and the migration of prostate cancer cells. In conclusion, this study revealed that epicatechin gallate impairs the synthesis of fatty acids via inhibition PI3K/AKT/mTOR signaling pathway and then attenuates the migration of prostate cancer cells.
    Keywords:  epicatechin gallate; fatty acid synthesis; migration; prostate cancer
    DOI:  https://doi.org/10.1093/abbs/gmab144
  26. Front Oncol. 2021 ;11 764119
    Bidirectional Interaction Between Cancer Cells and Platelets Provides Potential Strategies for Cancer Therapies.
    Liuting Yu, Yao Guo, Zhiguang Chang, Dengyang Zhang, Shiqiang Zhang, Hanzhong Pei, Jun Pang, Zhizhuang Joe Zhao, Yun Chen.
      Platelets are essential components in the tumor microenvironment. For decades, clinical data have demonstrated that cancer patients have a high risk of thrombosis that is associated with adverse prognosis and decreased survival, indicating the involvement of platelets in cancer progression. Increasing evidence confirms that cancer cells are able to induce production and activation of platelets. Once activated, platelets serve as allies of cancer cells in tumor growth and metastasis. They can protect circulating tumor cells (CTCs) against the immune system and detachment-induced apoptosis while facilitating angiogenesis and tumor cell adhesion and invasion. Therefore, antiplatelet agents and platelet-based therapies should be developed for cancer treatment. Here, we discuss the mechanisms underlying the bidirectional cancer-platelet crosstalk and platelet-based therapeutic approaches.
    Keywords:  cancer cells; cancer treatment; cancer-platelet crosstalk; platelets; thrombosis
    DOI:  https://doi.org/10.3389/fonc.2021.764119
  27. Front Cell Dev Biol. 2021 ;9 751761
    Regulation of Nuclear Factor-kappaB Function by O-GlcNAcylation in Inflammation and Cancer.
    Angela Rose Liu, Parameswaran Ramakrishnan.
      Nuclear factor-kappaB (NF-κB) is a pleiotropic, evolutionarily conserved transcription factor family that plays a central role in regulating immune responses, inflammation, cell survival, and apoptosis. Great strides have been made in the past three decades to understand the role of NF-κB in physiological and pathological conditions. Carcinogenesis is associated with constitutive activation of NF-κB that promotes tumor cell proliferation, angiogenesis, and apoptosis evasion. NF-κB is ubiquitously expressed, however, its activity is under tight regulation by inhibitors of the pathway and through multiple posttranslational modifications. O-GlcNAcylation is a dynamic posttranslational modification that controls NF-κB-dependent transactivation. O-GlcNAcylation acts as a nutrient-dependent rheostat of cellular signaling. Increased uptake of glucose and glutamine by cancer cells enhances NF-κB O-GlcNAcylation. Growing evidence indicates that O-GlcNAcylation of NF-κB is a key molecular mechanism that regulates cancer cell proliferation, survival and metastasis and acts as link between inflammation and cancer. In this review, we are attempting to summarize the current understanding of the cohesive role of NF-κB O-GlcNAcylation in inflammation and cancer.
    Keywords:  NF-kappaB (NF-κB); O-GlcNAcylation; cancer; hexosamine biosynthetic pathway; inflammation; leukemia; posttranslational modifications (PTMs)
    DOI:  https://doi.org/10.3389/fcell.2021.751761
  28. Front Physiol. 2021 ;12 688485
    Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function.
    Heather L Caslin, Daniel Abebayehu, Julia A Pinette, John J Ryan.
      Lactate and the associated H+ ions are still introduced in many biochemistry and general biology textbooks and courses as a metabolic by-product within fast or oxygen-independent glycolysis. However, the role of lactate as a fuel source has been well-appreciated in the field of physiology, and the role of lactate as a metabolic feedback regulator and distinct signaling molecule is beginning to gain traction in the field of immunology. We now know that while lactate and the associated H+ ions are generally immunosuppressive negative regulators, there are cell, receptor, mediator, and microenvironment-specific effects that augment T helper (Th)17, macrophage (M)2, tumor-associated macrophage, and neutrophil functions. Moreover, we are beginning to uncover how lactate and H+ utilize different transporters and signaling cascades in various immune cell types. These immunomodulatory effects may have a substantial impact in cancer, sepsis, autoimmunity, wound healing, and other immunomodulatory conditions with elevated lactate levels. In this article, we summarize the known effects of lactate and H+ on immune cells to hypothesize potential explanations for the divergent inflammatory vs. anti-inflammatory effects.
    Keywords:  M2; Th17; immune; immunometabolism; immunosuppression; inflammation; lactate; lactic acid
    DOI:  https://doi.org/10.3389/fphys.2021.688485
  29. BMC Cancer. 2021 Nov 05. 21(1): 1181
    NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma.
    Xiangsheng Su, Yihang Yang, Qing Yang, Bo Pang, Shicheng Sun, Yanjun Wang, Qiujiang Qiao, Changfa Guo, Huanting Liu, Qi Pang.
       BACKGROUND: Increased expression of the transcription factor Forkhead box M1 (FOXM1) has been reported to play an important role in the progression and development of multiple tumors, but the molecular mechanisms that regulate FOXM1 expression remain unknown, and the role of FOXM1 in aerobic glycolysis is still not clear.
    METHODS: The expression of FOXM1 and NADPH oxidase 4 (NOX4) in normal brain tissues and glioma was detected in data from the TCGA database and in our specimens. The effect of NOX4 on the expression of FOXM1 was determined by Western blot, qPCR, reactive oxygen species (ROS) production assays, and luciferase assays. The functions of NOX4 and FOXM1 in aerobic glycolysis in glioblastoma cells were determined by a series of experiments, such as Western blot, extracellular acidification rate (ECAR), lactate production, and intracellular ATP level assays. A xenograft mouse model was established to test our findings in vivo.
    RESULTS: The expression of FOXM1 and NOX4 was increased in glioma specimens compared with normal brain tissues and correlated with poor clinical outcomes. Aberrant mitochondrial reactive oxygen species (ROS) generation of NOX4 induced FOXM1 expression. Mechanistic studies demonstrated that NOX4-derived MitoROS exert their regulatory role on FOXM1 by mediating hypoxia-inducible factor 1α (HIF-1α) stabilization. Further research showed that NOX4-derived MitoROS-induced HIF-1α directly activates the transcription of FOXM1 and results in increased FOXM1 expression. Overexpression of NOX4 or FOXM1 promoted aerobic glycolysis, whereas knockdown of NOX4 or FOXM1 significantly suppressed aerobic glycolysis, in glioblastoma cells. NOX4-induced aerobic glycolysis was dependent on elevated FOXM1 expression, as FOXM1 knockdown abolished NOX4-induced aerobic glycolysis in glioblastoma cells both in vitro and in vivo.
    CONCLUSION: Increased expression of FOXM1 induced by NOX4-derived MitoROS plays a pivotal role in aerobic glycolysis, and our findings suggest that inhibition of NOX4-FOXM1 signaling may present a potential therapeutic target for glioblastoma treatment.
    Keywords:  Aerobic glycolysis; FOXM1; Glioblastoma; NOX4; ROS
    DOI:  https://doi.org/10.1186/s12885-021-08933-y
  30. J Inorg Biochem. 2021 Oct 19. pii: S0162-0134(21)00281-6. [Epub ahead of print]226 111634
    Copper in tumors and the use of copper-based compounds in cancer treatment.
    Daniela Almeida da Silva, Anastasia De Luca, Rosanna Squitti, Mauro Rongioletti, Luisa Rossi, Camila M L Machado, Giselle Cerchiaro.
      Copper homeostasis is strictly regulated by protein transporters and chaperones, to allow its correct distribution and avoid uncontrolled redox reactions. Several studies address copper as involved in cancer development and spreading (epithelial to mesenchymal transition, angiogenesis). However, being endogenous and displaying a tremendous potential to generate free radicals, copper is a perfect candidate, once opportunely complexed, to be used as a drug in cancer therapy with low adverse effects. Copper ions can be modulated by the organic counterpart, after complexed to their metalcore, either in redox potential or geometry and consequently reactivity. During the last four decades, many copper complexes were studied regarding their reactivity toward cancer cells, and many of them could be a drug choice for phase II and III in cancer therapy. Also, there is promising evidence of using 64Cu in nanoparticles as radiopharmaceuticals for both positron emission tomography (PET) imaging and treatment of hypoxic tumors. However, few compounds have gone beyond testing in animal models, and none of them got the status of a drug for cancer chemotherapy. The main challenge is their solubility in physiological buffers and their different and non-predictable mechanism of action. Moreover, it is difficult to rationalize a structure-based activity for drug design and delivery. In this review, we describe the role of copper in cancer, the effects of copper-complexes on tumor cell death mechanisms, and point to the new copper complexes applicable as drugs, suggesting that they may represent at least one component of a multi-action combination in cancer therapy.
    Keywords:  Cancer; Cancer therapy; Copper complexes copper in medicine; Copper in cancer; Copper in tumor; Radiotherapy
    DOI:  https://doi.org/10.1016/j.jinorgbio.2021.111634
  31. J Hazard Mater. 2021 Oct 16. pii: S0304-3894(21)02480-8. [Epub ahead of print]424(Pt C): 127512
    Polychlorinated biphenyl quinone exposure promotes breast cancer aerobic glycolysis: An in vitro and in vivo examination.
    Qi Qin, Bingwei Yang, Jing Liu, Erqun Song, Yang Song.
      Polychlorinated biphenyls (PCBs) were classified as group I carcinogenic to humans, as their toxicological mechanisms have been associated with cancer initiation and promotion. However, whether PCBs have effects on cancer progression are still largely veiled. Here, we for the first time discovered that a PCB quinone-type metabolite, namely PCB29-pQ, exposure significantly promoted aerobic glycolysis, a hallmark property of metabolic reprogramming in cancer progression. PCB29-pQ exposure activated corresponding glucose transporter type 1 (GLUT1)/integrin β1/Src/focal adhesion kinase (FAK) signaling pathway in breast cancer MDA-MB-231 cells. Conversely, the inhibition of GLUT1 reversed this effect, as well as the ability of migration and invasion of MDA-MB-231 cells. In addition, PCB29-pQ-induced breast cancer metastasis in 4T1-luc cell inoculated nude mice is repressed by GLUT1 inhibition. Overall, our results demonstrated a novel mechanism that PCB29-pQ exposure promotes aerobic glycolysis in both in vitro and in vivo breast cancer models in a GLUT1-dependent fashion, which may provide a strategy to prevent breast cancer cell spread.
    Keywords:  Aerobic glycolysis; Breast cancer; GLUT1; Metastasis; PCBs
    DOI:  https://doi.org/10.1016/j.jhazmat.2021.127512
  32. Sci Rep. 2021 Nov 02. 11(1): 21478
    Eupafolin induces apoptosis and autophagy of breast cancer cells through PI3K/AKT, MAPKs and NF-κB signaling pathways.
    Jiahui Wei, Yu Ding, Xinmiao Liu, Qing Liu, Yiran Lu, Song He, Bao Yuan, Jiabao Zhang.
      Eupafolin is a flavonoid that can be extracted from common sage. Previous studies have reported that Eupafolin has antioxidant, anti-inflammatory and anti-tumor properties. However, no studies have investigated the role of Eupafolin in breast cancer. Herein, we investigated the effect of Eupafolin on two human breast cancer cell lines, as well as its potential mechanism of action. Next, the data showed that proliferation, migration and invasion ability of breast cancer cells that were treated with Eupafolin was significantly reduced, while the apoptosis rate was significantly increased. In addition, Eupafolin treatment caused breast cancer cell proliferation to be blocked in the S phase. Moreover, Eupafolin significantly induced autophagy in breast cancer cells, with an increase in the expression of LC3B-II. PI3K/AKT, MAPKs and NF-κB pathways were significantly inhibited by Eupafolin treatment. Additionally, 3-MA (a blocker of autophagosome formation) significantly reduced Eupafolin-induced activation of LC3B-II in breast cancer cells. Furthermore, Eupafolin displayed good in vitro anti-angiogenic activity. Additionally, anti-breast cancer activity of Eupafolin was found to be partially mediated by Cav-1. Moreover, Eupafolin treatment significantly weakened carcinogenesis of MCF-7 cells in nude mice. Therefore, this data provides novel directions on the use of Eupafolin for treatment of breast cancer.
    DOI:  https://doi.org/10.1038/s41598-021-00945-9
  33. J Ethnopharmacol. 2021 Oct 30. pii: S0378-8741(21)01023-0. [Epub ahead of print] 114793
    The mechanism of action of Fangji Huangqi Decoction on epithelial-mesenchymal transition in breast cancer using high-throughput next-generation sequencing and network pharmacology.
    Qi Guo, Xiao-Hua Pei, Ai-Jing Chu, Yu-Bo Guo, Ying-Yi Fan, Chun-Hui Wang, Shu-Jing Zhang, Shi-Qing Sun, Yu-Fei Liu, Xuan Wang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Fangji Huangqi Decoction (FHD) is widely used in traditional Chinese medicine (TCM). FHD has been hypothesized to inhibit the epithelial-mesenchymal transition (EMT) process, which may positively impact breast cancer prevention and treatment. However, its exact mechanism of action is still unknown.
    AIM OF THE STUDY: This study aimed to screen potential targets of FHD for the treatment of EMT in breast cancer through network pharmacology, and to verify their therapeutic effects in vitro experiments and high-throughput second-generation sequencing.
    MATERIALS AND METHODS: The data sets of effective components and targets of FHD were established through the Traditional Chinese Medicine Systems Pharmacology database. The GeneCards and OMIM databases were used to establish breast cancer-related target datasets, which were then matched with the TCM target data. The interaction between key target proteins was analyzed using the STRING database; the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to identify the associated biological processes and enriched signal pathways, respectively. The active ingredient disease target network was analyzed using Cytoscape. Finally, next generation sequencing was used to verify the related pathways of FHD intervention in EMT in breast cancer. High-content screening was used to identify the genes/pathways affected by FHD. MDA-MB-231 and HCC-1937 breast cancer cell lines were used to evaluate the impact of FHD on migration, invasion, and EMT.
    RESULTS: Eighty possible significant targets were identified for the treatment of breast cancer EMT with FHD; GO and KEGG were used to identify 173 cell biological processes associated with breast cancer (P < 0.05), including the NF-κB and PI3K-Akt signaling pathways. The high-throughput sequencing and network pharmacology results were highly consistent. The migration and invasion ability of MDA-MB-231 cells was reduced and their EMT status could be reversed by DSHR2 knockdown. The results of morphology and scratch assays showed that FHD could improve the EMT status of HCC-1973.
    CONCLUSIONS: This study provides more evidence to support the clinical application of FHD, which has reliable interventional effects on breast cancer EMT. Its therapeutic effects may involve a multi-target, multi-pathway, and multi-mechanism effect.
    Keywords:  Breast cancer; Epithelial-mesenchymal transition; Fangji Huangqi decoction; Network pharmacology; Next generation sequencing
    DOI:  https://doi.org/10.1016/j.jep.2021.114793
  34. J Biochem Mol Toxicol. 2021 Nov 03. e22944
    Gigantol inhibits proliferation and enhanced oxidative stress-mediated apoptosis through modulating of Wnt/β-catenin signaling pathway in HeLa cells.
    Huanan Kang, Yiming Sun, Xijiao Hu, Li Liu.
      Cervical cancer is one of the leading malignant cancers that is the fourth prominent cause of malignancy-related mortality in women globally. There is a predominant validation to a beneficial target in Wnt/β-catenin signaling in cervical carcinogenesis as they are very much deregulated in cancer. Previous studies reported Gigantol (GG) showed suppressive properties on the Wnt/β-catenin pathway in other tumor cells, but no evidence is available regarding GG suppressing Wnt/β-catenin signaling cervical tumor cells. Hence, the current research was planned to examine the suppressive effects of GG on HeLa cells and investigate the mechanism of action. HeLa cells were treated by GG in various doses and then appraising cell viability, oxidant/antioxidant levels, ∆ѰM status, reactive oxygen species (ROS) generation, apoptosis, and cell proliferation via Wnt/β-catenin signaling. We observed that GG noticeably inhibits cell proliferation, increased ROS generation, lipid peroxidation, mitochondrial membrane depolarization (∆ѰM), and increased apoptotic morphological changes of nuclear fragmentation and condensation. Moreover, GG effectively enhances proapoptotic, decreased ∆ѰM and antioxidant amounts, and mitigated Wnt/β-catenin signaling. Concisely, these findings proved that activating apoptosis and suppression of cell proliferation in GG treated HeLa cells was documented by the alleviation of Wnt/β-catenin signaling. Therefore, this study suggested that GG might develop a therapeutic effect against cervical carcinogenesis.
    Keywords:  Gigantol; HeLa cells; Wnt/β-catenin signaling; apoptosis; cervical cancer
    DOI:  https://doi.org/10.1002/jbt.22944
  35. ACS Appl Mater Interfaces. 2021 Nov 03.
    Yolk-Shell-Type Gold Nanoaggregates for Chemo- and Photothermal Combination Therapy for Drug-Resistant Cancers.
    Hyun-Seok Choe, Min Joo Shin, Seong Gyu Kwon, Haklae Lee, Dae Kyoung Kim, Kyung Un Choi, Jae-Hyuk Kim, Jae Ho Kim.
      Epithelial ovarian cancer is a gynecological cancer with the highest mortality rate, and it exhibits resistance to conventional drugs. Gold nanospheres have gained increasing attention over the years as photothermal therapeutic nanoparticles, owing to their excellent biocompatibility, chemical stability, and ease of synthesis; however, their practical application has been hampered by their low colloidal stability and photothermal effects. In the present study, we developed a yolk-shell-structured silica nanocapsule encapsulating aggregated gold nanospheres (aAuYSs) and examined the photothermal effects of aAuYSs on cell death in drug-resistant ovarian cancers both in vitro and in vivo. The aAuYSs were synthesized using stepwise silica seed synthesis, surface amino functionalization, gold nanosphere decoration, mesoporous organosilica coating, and selective etching of the silica template. Gold nanospheres were agglomerated in the confined silica interior of aAuYSs, resulting in the red-shifting of absorbance and enhancement of the photothermal effect under 808 nm laser irradiation. The efficiency of photothermal therapy was first evaluated by inducing aAuYS-mediated cell death in A2780 ovarian cancer cells, which were cultured in a two-dimensional culture and a three-dimensional spheroid culture. We observed that photothermal therapy using aAuYSs together with doxorubicin treatment synergistically induced the cell death of doxorubicin-resistant A2780 cancer cells in vitro. Furthermore, this type of combinatorial treatment with photothermal therapy and doxorubicin synergistically inhibited the in vivo tumor growth of doxorubicin-resistant A2780 cancer cells in a xenograft transplantation model. These results suggest that photothermal therapy using aAuYSs is highly effective in the treatment of drug-resistant cancers.
    Keywords:  chemo-photothermal therapy; drug resistance; gold nanoaggregates; ovarian cancer; yolk−shell structure
    DOI:  https://doi.org/10.1021/acsami.1c10036
  36. Nanoscale. 2021 Nov 01.
    NIR -I and NIR-II irradiation tumor ablation using NbS2 nanosheets as the photothermal agent.
    Songqiang Sun, Yapai Song, Jiabo Chen, Minfeng Huo, Yu Chen, Lining Sun.
      Photothermal therapy has been considered a powerful means of cancer therapy due to its minimal invasiveness, effectiveness, and convenience. Although promising, the therapeutic effects are greatly limited as they rely on the photothermal agent (PTA). It is urgent to develop new PTAs with high photothermal conversion performance, especially under irradiation in the long-wavelength biowindows. Herein, a dual-biowindow-responsive PTA made of NbS2-PVP nanosheets was fabricated to be used both in the first near-infrared (NIR-I) and the second near-infrared (NIR-II) biowindows. With excellent hydrophilicity and biocompatibility, the nanosheets could effectively convert the near-infrared (NIR) light into heat, showing prominent photothermal stability. The calculated photothermal conversion efficiencies reached 59.2% (under NIR-I excitation) and 69.1% (under NIR-II excitation), respectively, which are comparable to those of metallic PTAs. The NbS2-PVP nanosheets had low cytotoxicity and could trigger strong photothermal treatment and cause cancer cell death upon irradiation by NIR-I or NIR-II light in vitro. Moreover, we have also demonstrated the highly efficient tissue ablation and tumor inhibition capability of NbS2-PVP nanosheets in vivo. This work explores an effective PTA of two-dimensional nanomaterials in NIR-I and NIR-II biowindows and offers a reference for the design of new kinds of PTAs.
    DOI:  https://doi.org/10.1039/d1nr05449j
  37. Mol Carcinog. 2021 Nov 02.
    Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer.
    Shanyi Li, Renyi Wu, Lujing Wang, Hsiao-Chen Dina Kuo, Davit Sargsyan, Xi Zheng, Yujue Wang, Xiaoyang Su, Ah-Ng Kong.
      Ursolic acid (UA) is a triterpenoid phytochemical with a strong anticancer effect. The metabolic rewiring, epigenetic reprogramming, and chemopreventive effect of UA in prostate cancer (PCa) remain unknown. Herein, we investigated the efficacy of UA in PCa xenograft, and its biological effects on cellular metabolism, DNA methylation, and transcriptomic using multi-omics approaches. The metabolomics was quantified by liquid-chromatography-mass spectrometry (LC-MS) while epigenomic CpG methylation in parallel with transcriptomic gene expression was studied by next-generation sequencing technologies. UA administration attenuated the growth of transplanted human VCaP-Luc cells in immunodeficient mice. UA regulated several cellular metabolites and metabolism-related signaling pathways including S-adenosylmethionine (SAM), methionine, glucose 6-phosphate, CDP-choline, phosphatidylcholine biosynthesis, glycolysis, and nucleotide sugars metabolism. RNA-seq analyses revealed UA regulated several signaling pathways, including CXCR4 signaling, cancer metastasis signaling, and NRF2-mediated oxidative stress response. Epigenetic reprogramming study with DNA Methyl-seq uncovered a list of differentially methylated regions (DMRs) associated with UA treatment. Transcriptome-DNA methylome correlative analysis uncovered a list of genes, of which changes in gene expression correlated with the promoter CpG methylation status. Altogether, our results suggest that UA regulates metabolic rewiring of metabolism including SAM potentially driving epigenetic CpG methylation reprogramming, and transcriptomic signaling resulting in the overall anticancer chemopreventive effect.
    Keywords:  cancer; epigenome; metabolome; transcriptome; ursolic acid
    DOI:  https://doi.org/10.1002/mc.23365
  38. Front Oncol. 2021 ;11 746917
    Anti-Tumor Effects of Chinese Medicine Compounds by Regulating Immune Cells in Microenvironment.
    Fengqian Chen, Jingquan Li, Hui Wang, Qian Ba.
      As the main cause of death in the world, cancer is one of the major health threats for humans. In recent years, traditional Chinese medicine has gained great attention in oncology due to the features of multi-targets, multi-pathways, and slight side effects. Moreover, lots of traditional Chinese medicine can exert immunomodulatory effects in vivo. In the tumor microenvironment, tumor cells, immune cells as well as other stromal cells often coexist. With the development of cancer, tumor cells proliferate uncontrollably, metastasize aggressively, and modulate the proportion and status of immune cells to debilitate the antitumor immunity. Reversal of immunosuppressive tumor microenvironment plays an essential role in cancer prevention and therapy. Immunotherapy has become the most promising strategy for cancer therapy. Chinese medicine compounds can stimulate the activation and function of immune cells, such as promoting the maturation of dendritic cells and inducing the differentiation of myeloid-derived suppressor cells to dendritic cells and macrophages. In the present review, we summarize and discuss the effects of Chinese medicine compounds on immune cells in the tumor microenvironment, including innate immune cells (dendritic cells, natural killer cells, macrophages, and myeloid-derived suppressor cells) and adaptive immune cells (CD4+/CD8+ T lymphocytes and regulatory T cells), and the various immunomodulatory roles of Chinese medicine compounds in cancer therapy such as improving tumor-derived inflammation, enhancing the immunity after surgery or chemotherapy, blocking the immune checkpoints, et al., aiming to provide more thoughts for the anti-tumor mechanisms and applications of Chinese medicine compounds in terms of tumor immunity.
    Keywords:  Chinese medicine compounds; antitumor immunity; cancer; immune cell; microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.746917
  39. Oncol Rep. 2022 Jan;pii: 4. [Epub ahead of print]47(1):
    Diosmin in combination with naringenin enhances apoptosis in colon cancer cells.
    Bushra Zeya, Sana Nafees, Khalid Imtiyaz, Laraib Uroog, Khalid Umar Fakhri, M Moshahid A Rizvi.
      Colon cancer is one of the most commonly diagnosed malignancies, which begins as a polyp and grows to become cancer. Diosmin (DS) and naringenin (NR) are naturally occurring flavonoids that exhibit various pharmacological activities. Although several studies have illustrated the effectiveness of these flavonoids as anti‑cancerous agents individually, the combinatorial impact of these compounds has not been explored. In the present study, the combined effect of DS and NR (DiNar) in colon cancer cell lines HCT116 and SW480 were assessed by targeting apoptosis and inflammatory pathways. The MTT assay was used to evaluate the effect of DiNar on cell proliferation, while Chou‑Talalay analysis was employed to determine the combination index of DS and NR. Moreover, flow cytometry was used to monitor cell cycle arrest and population study. The onset of apoptosis was assessed by DAPI staining, DNA fragmentation, and Annexin V‑fluorescein isothiocyanate/propidium iodide (Annexin V‑FITC/PI). The expression levels of apoptotic pathway markers, Bcl‑2, Bax, caspase3, caspase8, caspase9 and p53, and inflammatory markers, NF‑κβ, IKK‑α and IKK‑β, were assessed using western blotting and reverse transcription‑quantitative PCR. These results suggested that DiNar treatment acts synergistically and induces cytotoxicity with a concomitant increase in chromatin condensation, DNA fragmentation and cell cycle arrest in the G0/G1 phase. Annexin V‑FITC/PI apoptosis assay also showed increased number of cells undergoing apoptosis in the DiNar treatment group. Furthermore, the expression of apoptosis and inflammatory markers was also more effectively regulated under the DiNar treatment. Thereby, these findings demonstrated that DiNar treatment could be a potential novel chemotherapeutic alternative in colon cancer.
    Keywords:  apoptosis; colon cancer; diosmin; flavonoids; inflammatory pathway; naringenin
    DOI:  https://doi.org/10.3892/or.2021.8215
  40. Cancer Biol Ther. 2021 Oct 31. 1-8
    Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells.
    Ellen Tully, Santosh Bharti, Juhyung Woo, Zaver Bhujwalla, Edward Gabrielson.
      Biguanide drugs (metformin and phenformin) have drawn interest for potential cancer treatments, and laboratory studies show that some cancer cells are selectively sensitive to growth-inhibitory effects of biguanides. Examining metabolic pathways affected by biguanide treatments in cancer cells that are highly sensitive to biguanides, we found that biguanide treatment depletes cellular levels of both aspartate and NAD+. Experiments to replenish these metabolites or block steps of the aspartate-malate shuttle suggest that depletion of both metabolites, rather than either aspartate of NAD+ individually, is critical for growth-inhibitory effects of biguanide exposure. Even in sensitive cancer cells, though, biguanide treatment alone over a broad range of doses only inhibits cell replication without significantly affecting cell viability. Noting that clinical observations of biguanide efficacy have used combinations of agents that typically include cisplatin, we found that biguanide treatment at a cytostatic level substantially decreases survival of lung cancer and breast cancer cells when co-treated with cisplatin at doses that alone are also non-cytotoxic. This striking enhancement of cisplatin toxicity by biguanides depends on reductions of levels of NAD+ and aspartate, since addition of either of these metabolites prevented this potentiation of cisplatin cytotoxicity. Thus, biguanide drugs can have cytotoxic effects when used in combination with other cancer drugs, such as cisplatin, and depleting cellular levels of NAD+ and aspartate is critical for enhancing the cytotoxicity of cisplatin by biguanide drugs in sensitive cancer cells.
    Keywords:  Biguanides; aspartate; cisplatin; metformin; nad; phenformin
    DOI:  https://doi.org/10.1080/15384047.2021.1982599
  41. Small. 2021 Nov 02. e2103868
    Chemodynamic Therapy via Fenton and Fenton-Like Nanomaterials: Strategies and Recent Advances.
    Chenyang Jia, Yuxin Guo, Fu-Gen Wu.
      Chemodynamic therapy (CDT), a novel cancer therapeutic strategy defined as the treatment using Fenton or Fenton-like reaction to produce •OH in the tumor region, was first proposed by Bu, Shi, and co-workers in 2016. Recently, with the rapid development of Fenton and Fenton-like nanomaterials, CDT has attracted tremendous attention because of its unique advantages: 1) It is tumor-selective with low side effects; 2) the CDT process does not depend on external field stimulation; 3) it can modulate the hypoxic and immunosuppressive tumor microenvironment; 4) the treatment cost of CDT is low. In addition to the Fe-involved CDT strategies, the Fenton-like reaction-mediated CDT strategies have also been proposed, which are based on many other metal elements including copper, manganese, cobalt, titanium, vanadium, palladium, silver, molybdenum, ruthenium, tungsten, cerium, and zinc. Moreover, CDT has been combined with other therapies like chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy for achieving enhanced anticancer effects. Besides, there have also been studies that extend the application of CDT to the antibacterial field. This review introduces the latest advancements in the nanomaterials-involved CDT from 2018 to the present and proposes the current limitations as well as future research directions in the related field.
    Keywords:  Fenton/Fenton-like reactions; antibacterial; anticancer; chemodynamic therapy; reactive oxygen species
    DOI:  https://doi.org/10.1002/smll.202103868
  42. Cancer Manag Res. 2021 ;13 8063-8076
    Targeted Inhibition of HK-II Reversed the Warburg Effect to Improve the Radiosensitivity of Laryngeal Carcinoma.
    Xiao-Hong Chen, Ding-Li Yu, Jiang-Tao Zhong, Shui-Hong Zhou, Jun Fan, Zhong-Jie Lu.
       Purpose: Hexokinase-II (HK-II) is the key enzyme in the first rate-limiting step of glycolysis that catalyzes the conversion of glucose to glucose-6-phosphate. Here, we examined the association between HK-II expression and radioresistance in laryngeal carcinoma and whether the inhibition of HK-II expression can enhance the radiosensitivity of these tumors.
    Methods: The effects of HK-II small interfering RNA (siRNA) on the radiosensitivity of Tu212 cells were examined in vitro and in vivo in a mouse model. Cells were irradiated using a 6-MV linear accelerator. The cell viability, cell survival, proliferation, apoptosis, and cell cycle of Tu212 cells were evaluated using trypan blue staining, colony formation assays, CCK-8 assays, and flow cytometry, respectively. Oxygen consumption, lactic acid production, glucose consumption, and the ATP level of Tu212 cells were also examined. The expression of glycolytic and regulatory enzymes involved in the tricarboxylic acid cycle was assessed using Western blotting.
    Results: The HK-II siRNA and X-ray combination treatment led to a significantly greater reduction of cell viability, inhibition of cell survival and proliferation, increased apoptosis, and increased G2 phase arrest compared to either treatment alone (all, P<0.01). HK-II siRNA increased the oxygen consumption rate of cells, significantly inhibited lactic acid production and glucose consumption, and significantly suppressed the upregulation of HK-II, pyruvate kinase M2 (PKM2), pyruvate dehydrogenase (PDH), phosphofructokinase platelet (PFKP), lactate dehydrogenase (LD), and citrate synthase (CS) (all, P<0.01).
    Conclusion: The inhibition of HK-II by siRNA enhances the radiosensitivity of laryngeal carcinoma Tu212 cells by inhibiting glycolysis and partially inhibiting oxidative phosphorylation.
    Keywords:  Warburg effect; hexokinase-II; laryngeal carcinoma; radiosensitivity; siRNA
    DOI:  https://doi.org/10.2147/CMAR.S324754
  43. J Control Release. 2021 Nov 02. pii: S0168-3659(21)00580-0. [Epub ahead of print]
    Dual cancer stem cell manipulation to enhance phototherapy against tumor progression and metastasis.
    Qi Shang, Shiyao Zhou, Zijia Zhou, Yue Jiang, Yuxia Luan.
      Targeting breast cancer stem cells (BCSCs) therapy is a prospective strategy to eliminate tumors owing to the BCSCs-governed drug resistance, tumor progression and metastasis. BCSCs are intrinsically in a disequilibrium state with favorable ability of self-renewal rather than differentiation, resulting in inability of complete tumor eradication. Besides the original BCSCs, epithelial-mesenchymal transition (EMT) process can further facilitate BCSCs regeneration, accompanied by tumor progression and metastasis. Herein, we, for the first time, engineered a photodynamic nanoplatform to manipulate BCSCs against tumor progression and metastasis by not only remolding the disequilibrium state but also blocking the EMT process. The HP@PP was constructed by haloperidol (HP)-incorporated polyethyleneimine-polyhistidine (PP) micelles, which was further integrated with low molecular weight heparin (LMWH)-chlorin e6 (Ce6) conjugate (LC) to form HP@PP/LC nanoparticles (NPs). For HP@PP/LC NPs, the protonation of PP in tumor tissues precisely targeted HP to BCSCs for remolding the disequilibrium state via promoting BCSCs differentiation into tumor cells. Simultaneously, LC conjugate targeted to tumors for exerting EMT blocking ability with LMWH, as well as exerting photodynamic clearance of tumor cells with Ce6 component. Therefore, our nanoplatform provides an emerging strategy for manipulating BCSCs against tumor progression and metastasis, demonstrating a promising photodynamic platform against tumors.
    Keywords:  Nanoplatform; Photodynamic therapy; Tumor metastasis; Tumor progression
    DOI:  https://doi.org/10.1016/j.jconrel.2021.10.029
  44. Arch Toxicol. 2021 Nov 02.
    Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events.
    Ana Dias-Carvalho, Mariana Ferreira, Rita Ferreira, Maria de Lourdes Bastos, Susana Isabel Sá, João Paulo Capela, Félix Carvalho, Vera Marisa Costa.
      Cognitive dysfunction has been one of the most reported and studied adverse effects of cancer treatment, but, for many years, it was overlooked by the medical community. Nevertheless, the medical and scientific communities have now recognized that the cognitive deficits caused by chemotherapy have a strong impact on the morbidity of cancer treated patients. In fact, chemotherapy-induced cognitive dysfunction or 'chemobrain'  (also named also chemofog) is at present a well-recognized effect of chemotherapy that could affect up to 78% of treated patients. Nonetheless, its underlying neurotoxic mechanism is still not fully elucidated. Therefore, this work aimed to provide a comprehensive review using PubMed as a database to assess the studies published on the field and, therefore, highlight the clinical manifestations of chemobrain and the putative neurotoxicity mechanisms.In the last two decades, a great number of papers was published on the topic, mainly with clinical observations. Chemotherapy-treated patients showed that the cognitive domains most often impaired were verbal memory, psychomotor function, visual memory, visuospatial and verbal learning, memory function and attention. Chemotherapy alters the brain's metabolism, white and grey matter and functional connectivity of brain areas. Several mechanisms have been proposed to cause chemobrain but increase of proinflammatory cytokines with oxidative stress seem more relevant, not excluding the action on neurotransmission and cellular death or impaired hippocampal neurogenesis. The interplay between these mechanisms and susceptible factors makes the clinical management of chemobrain even more difficult. New studies, mainly referring to the underlying mechanisms of chemobrain and protective measures, are important in the future, as it is expected that chemobrain will have more clinical impact in the coming years, since the number of cancer survivors is steadily increasing.
    Keywords:  Chemobrain; Chemofog; Chemotherapy; Cognitive impairment; Neurotoxicity
    DOI:  https://doi.org/10.1007/s00204-021-03171-4
  45. Photodiagnosis Photodyn Ther. 2021 Nov 02. pii: S1572-1000(21)00434-8. [Epub ahead of print] 102616
    Near Infrared Light Activated Upconversion Nanoparticles (UCNP) based Photodynamic Therapy of Prostate Cancers: an in vitro Study.
    Burcu Güleryüz, Uğur Ünal, Murat Gülsoy.
      Photo-activated treatment modality, photodynamic therapy (PDT), has a potential to cure cancerous prostate tissue with minimal side effects. For traditional PDT, however, mostly utilized visible (VIS) light range with direct application of hydrophobic photosensitizers cannot be adequate in clinical practices for especially deep-seated cancer cells because of poor penetration of VIS wavelengths. Here, we report near infrared light (NIR) induced and dual photosensitizers (PS) encapsulated PDT strategy to reduce prostate cancer cells - PC3. The designed nanoplatform (MC540/ZnPc-UCNP@Au), in this study, include upconversion nanoparticles (UCNP) synthesis to convert NIR light into multiple VIS wavelengths, porous silica coating to upload dual photosensitizers (MC540/ZnPc), and gold (Au) functionalization to enhance PDT treatment. High chemical stabilization provided MC540/ZnPc-UCNP@Au show excellent biocompatibility, and efficient PDT treatment for prostate cancer cells. In fact, the fluorescence of the synthesized nanoplatforms, upon NIR light excitation, can produce considerable amount of ROS in 5 minutes, as it is well matched with the absorption of MC540, ZnPc and Au nanoparticles (np). In addition, the easy visualization of cellular internalized/adsorbed nanoplatforms reveal the in situ cell imaging possibility for diagnosis. Based on the evidence of the results, NIR light activated MC540/ZnPc-UCNP@Au may offer a remarkable PDT technique for the treatment of prostate cancer.
    Keywords:  Gold Nanoparticles; MC540/ZnPc; Near Infrared Light; Photodynamic Therapy; Prostate Cancer Treatment; Upconversion Nanoparticles
    DOI:  https://doi.org/10.1016/j.pdpdt.2021.102616
  46. Cancer Cell Int. 2021 Oct 30. 21(1): 580
    Nanobodies: a tool to open new horizons in diagnosis and treatment of prostate cancer.
    Maryam Hosseindokht, Hamid Bakherad, Hamed Zare.
       BACKGROUND: Prostate cancer is one of the most common cancers in men and its incidence has increased dramatically in the last decade. This increase in the detection of this type of cancer is based more on the detection of PSA or PSMA antigens as the most important specific antigens of this cancer, and this early detection has greatly helped in the more optimal treatment of patients.
    MAIN BODY: Many methods have been proposed by researchers for early detection of prostate cancer, but most of the methods used today to detect this type of cancer have been using classical antibodies. Although classical antibodies are able to detect tumor cell markers, but instability, large size, costly and laborious production, and random immobility characteristics, causes many problems. Nanobodies or VHHs, which are derived from camel heavy chain antibodies, have special advantages and have eliminated the disadvantages of classical antibodies which makes them attractive to use in biosensors and cancer diagnostic kits. The research that has been done so far shows that the introduced nanobodies are created for the purpose of targeting, detecting and sensing prostate cancer cells with two main purposes. The first is the efficient identification of prostate cancer and the second is the elimination of cancer cells.
    CONCLUSION: Research shows the use of specific nanobodies against prostate cancer antigens in the design of biosensors and target therapy will be very interesting. In this review article, these nanobodies are introduced and categorized based on their performance.
    Keywords:  Nanobody; PSA; PSMA; Prostate cancer; VHH
    DOI:  https://doi.org/10.1186/s12935-021-02285-0
  47. Mol Immunol. 2021 Oct 28. pii: S0161-5890(21)00304-7. [Epub ahead of print]140 175-185
    Inhibitory effects of sulforaphane on NLRP3 inflammasome activation.
    Cagla Kiser, Ceren Perihan Gonul, Melis Olcum, Sermin Genc.
      SFN, a dietary phytochemical, is a significant member of isothiocyanates present in cruciferous vegetables at high levels in broccoli. It is a well-known activator of the Nrf2/ARE antioxidant pathway. Long since, the therapeutic effects of SFN have been widely studied in several different diseases. Other than the antioxidant effect, SFN also exhibits an anti-inflammatory effect through suppression of various mechanisms, including inflammasome activation. Considerably, SFN has been demonstrated to inhibit multiple inflammasomes, including NLRP3 inflammasome. NLRP3 inflammasome induces secretion of pro-inflammatory cytokines and promotes inflammatory cell death. The release of pro-inflammatory cytokines enhances the inflammatory response, in turn leading to tissue damage. These self-propelling inflammatory responses would need modulation with exogenous therapeutic agents to suppress them. SFN is a promising candidate molecule for the mitigation of NLRP3 inflammasome activation, which has been related to the pathogenesis of numerous disorders. In this review, we have provided fundamental knowledge about Sulforaphane, elaborated its characteristics, and evidentially focused on its mechanisms of action with regard to its anti-inflammatory, anti-oxidative, and neuroprotective features. Thereafter, we have summarized both in vitro and in vivo studies regarding SFN effect on NLRP3 inflammasome activation.
    Keywords:  NLRP3 inflammasome; Phytochemical; Sulforaphane
    DOI:  https://doi.org/10.1016/j.molimm.2021.10.014
  48. Zhongguo Zhong Yao Za Zhi. 2021 Oct;46(20): 5185-5193
    [Research progress on therapeutic potential of quercetin].
    Ya-Li Feng, Hao Li, Juan Liu, Zheng Ruan, Guang-Yu Zhai.
      Quercetin is a naturally occurring phytochemical with good bioactivity, which mainly exists in the form of glycoside in vegetables, fruits, tea, and wine and exhibits beneficial health effects. Quercetin is a dietary polyphenol that exerts the protective effects through diet or use as a food supplement. Compared with chemical agents, quercetin is widely available and safe. Quercetin has been extensively studied for its anti-diabetic, anti-hypertensive, anti-Alzheimer's disease, anti-arthritic, anti-influenza virus, anti-microbial infection, anti-aging, autophagy-regulating, and cardiovascular protective effects. Studies on its activities against different can-cer cell lines have also been reported recently. However, the poor water solubility, rapid in vivo metabolism, and short half-life of quercetin have led to its low bioavailability, thus limiting its application in the field of medicine. Quercetin nanoparticles and nanoparticle drug delivery system have been effectively utilized for enhancing its bioavailability. This paper reviewed the therapeutic potential of quercetin from both preclinical and clinical aspects and proposed solutions to improve its bioavailability, so as to provide a reference for the therapeutic application of natural compounds in the field of medicine.
    Keywords:  bioactivity; clinical; preclinical; quercetin; therapeutic potential
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20210524.602
  49. ACS Biomater Sci Eng. 2021 Nov 01.
    Miniatured Fluidics-Mediated Modular Self-Assembly of Anticancer Drug-Amino Acid Composite Microbowls for Combined Chemo-Photodynamic Therapy in Glioma.
    Sonika Chibh, Vibhav Katoch, Manish Singh, Bhanu Prakash, Jiban Jyoti Panda.
      A particulate carrier with the ability to load a combination of therapeutic molecules acting via diverse modes to initiate cancer cell ablation would help heighten anticancer therapeutic outcomes and mitigate harmful side effects due to high doses of mono drug therapy. Moving a step closer, herein, we have developed doxorubicin-curcumin-amino acid-based composite microbowls (CMBs) following miniaturized fluid flow-based self-assembly. The CMBs were further exploited as dual chemo-photodynamic therapeutic agents in C6 glioma cells cultured in both two-dimensional (2D) monolayer and as three-dimensional (3D) spheroids. These CMBs showed synergistic and visible (blue)-light-sensitive cell-killing effects in both C6 cells and 3D spheroids. Furthermore, these bowl-shaped structures also demonstrated good stability and excellent in vitro cytocompatibility in C6 glioma cells. Our results indicated that CMBs with asymmetric cavities could potentially be used as a combinatorial drug carrier enabling simultaneous chemo- and phototherapy for effective cancer treatment. The use of blue light, from the visible part of the electromagnetic system, to generate the phototherapeutic effect further advocates for the ease and widespread applicability of the systems.
    Keywords:  amino acid; composite microbowls; microfluidics; photodynamic therapy; self-assembly; tumor spheroids
    DOI:  https://doi.org/10.1021/acsbiomaterials.1c01023
  50. Sci Rep. 2021 Nov 02. 11(1): 21491
    Molecular characterization of metabolic subtypes of gastric cancer based on metabolism-related lncRNA.
    Lingdi Li, Jianfei Ma.
      Increasing evidence has demonstrated that lncRNAs are critical regulators in diverse biological processes, but the function of lncRNA in metabolic regulation remains largely unexplored. In this study, we evaluated the association between lncRNA and metabolic pathways and identified metabolism-related lncRNAs. Gastric cancer can be mainly subdivided into 2 clusters based on these metabolism-related lncRNA regulators. Comparative analysis shows that these subtypes are found to be highly consistent with previously identified subtypes based on other omics data. Functional enrichment analysis shows that they are enriched in distinct biological processes. Mutation analysis shows that ABCA13 is a protective factor in subtype C1 but a risk factor in C2. Analysis of chemotherapeutic and immunotherapeutic sensitivity shows that these subtypes tend to display distinct sensitivity to the same chemical drugs. In conclusion, these findings demonstrated the significance of lncRNA in metabolic regulation. These metabolism-related lncRNA regulators can improve our understanding of the underlying mechanism of lncRNAs and advance the research of immunotherapies in the clinical management of gastric cancer.
    DOI:  https://doi.org/10.1038/s41598-021-00410-7
  51. J Photochem Photobiol B. 2021 Oct 28. pii: S1011-1344(21)00226-8. [Epub ahead of print]225 112347
    Stimulation and homogenization of the protoporphyrin IX endogenous production by photobiomodulation to increase the potency of photodynamic therapy.
    Jaroslava Joniová, Cyrus Kazemiraad, Emmanuel Gerelli, Georges Wagnières.
      Protoporphyrin IX (PpIX) is produced in the mitochondria and used as fluorescent contrast agent or photosensitizer after exogenous 5-aminolevulinic acid (ALA) delivery in cancer photodynamic detection and therapy (PDT). Although routinely used in the clinics, the stimulated production of PpIX is often insufficient and/or heterogeneous within the lesions, thereby limiting the PDT performances. Since photobiomodulation, which is based on the illumination of the tissues with sub-thermal radiometric conditions in the red or near-infrared, is known to stimulate the cell metabolism, we have optimized these conditions in vitro. Some of them lead to the homogenization and strong stimulation of the PpIX endogenous production. Interestingly, combined sequentially, PBM enhanced significantly the potency of PpIX-based PDT in vitro and in vivo in tumors grown on the chicken embryo chorioallantoic membrane. These results are in excellent agreement with other assays based on measurements of the cell survival/death, the production of reactive oxygen species, including singlet oxygen, and the mitochondrial membrane potential.
    Keywords:  Homogenization; Photobiomodulation; Photodynamic therapy; Protoporphyrin IX
    DOI:  https://doi.org/10.1016/j.jphotobiol.2021.112347
  52. ACS Chem Biol. 2021 Nov 03.
    Identification of Dihydroorotate Dehydrogenase Inhibitors─Indoluidins─That Inhibit Cancer Cell Growth.
    Makoto Kawatani, Harumi Aono, Takeshi Shimizu, Shouta Ohkura, Sayoko Hiranuma, Makoto Muroi, Naoko Ogawa, Tomokazu Ohishi, Shun-Ichi Ohba, Manabu Kawada, Kanami Yamazaki, Shingo Dan, Hiroyuki Osada.
      Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis and is a promising cancer treatment target. This study reports the identification of indoluidin D and its derivatives as inhibitors of DHODH. Cell-based phenotypic screening revealed that indoluidin D promoted myeloid differentiation and inhibited the proliferation of acute promyelocytic leukemia HL-60 cells. Indoluidin D also suppressed cell growth in various other types of cancer cells. Cancer cell sensitivity profiling with JFCR39 and proteomic profiling with ChemProteoBase revealed that indoluidin D is a DHODH inhibitor. Indoluidin D inhibited human DHODH activity in vitro; the DHODH reaction product orotic acid rescued indoluidin D-induced cell differentiation. We synthesized several indoluidin D diastereomer derivatives and demonstrated that stereochemistry was vital to their molecular activity. The indoluidin D derivative indoluidin E showed similar activity to its parent compound and suppressed tumor growth in a murine lung cancer xenograft model. Hence, indoluidin D and its derivatives selectively inhibit DHODH and suppress cancer cell growth.
    DOI:  https://doi.org/10.1021/acschembio.1c00625
  53. J Phys Chem Lett. 2021 Nov 03. 10880-10885
    A Tumor Microenvironment-Responsive Theranostic Agent for Synergetic Therapy of Disulfiram-Based Chemotherapy and Chemodynamic Therapy.
    Hao Zhang, Zhijia Lv, Dongzhi Xue, Tianqi Zhang, Longhai Jin, Yue Cao, Shuai Zhang, Yinghui Wang, Hongjie Zhang.
      Despite the fact that chemotherapy has been widely used in the clinical treatment of breast cancer, the toxicity of chemotherapeutics to normal tissues cannot be ignored due to the low specificity. Therefore, due to the non-negligible toxicity of chemotherapeutic agents to normal tissues, tumor microenvironment (TME)-responsive cancer therapy has attracted a great deal of attention. Here, we report a TME-responsive theranostic nanoagent MnOx@PAA@HKUST-1-DSF@BSA fabricated via a layer-by-layer synthesis method. Once endocytosed by tumor cells, the nanoagent can be degraded into Mn2+ for magnetic resonance imaging and Cu2+ for Fenton-like reaction and chelating with released disulfiram in situ, achieving enhanced chemotherapy. Both in vitro and in vivo experiments demonstrate that the TME-targeted nanoagent can efficiently kill tumor cells. This work provides an alternative option for effective imaging and treatment of breast cancer without collateral damage to normal tissues.
    DOI:  https://doi.org/10.1021/acs.jpclett.1c03184
  54. Chimia (Aarau). 2021 Oct 27. 75(10): 845-855
    Recent Approaches towards the Development of Ru(II) Polypyridyl Complexes for Anticancer Photodynamic Therapy.
    Albert Gandioso, Kallol Purkait, Gilles Gasser.
      Photodynamic therapy (PDT) is a remarkable alternative or complementary technique to chemotherapy, radiotherapy or immunotherapy to treat certain forms of cancer. The synergistic effect of light, photosensitizer (PS) and oxygen allows for the treatment of tumours with an extremely high spatio-tumoral control, therefore minimizing the severe side effects usually observed in chemotherapy. The currently employed PDT PSs based on porphyrins have, in some cases, some limitations, which include a low absorbance in the therapeutic window, a low body clearance, photobleaching, among others. In this context, Ru(ii) polypyridyl complexes are interesting alternatives. They have low lying excited energy states and the presence of a heavy metal increases the possibility of spin-orbit coupling. Moreover, their photophysical properties are relatively easy to tune and they have very low photobleaching rates. All of these make them attractive candidates for further development as therapeutically suitable PDT PSs. In this review, after having presented this field of research, we discuss the developments made by our group in this field of research since 2017. We notably describe how we tuned the photophysical properties of our complexes from the visible region to the therapeutically suitable red region. This was accompanied by the preparation of PSs with enhanced phototoxicity and high phototoxicity index. We also discuss the use of two-photon excitation to eradicate tumours in nude mice. Furthermore, we describe our approach for the selective delivery of our complexes using targeting agents. Lastly, we report on our very recent synergistic approach to treat cancer using bimetallic Ru(ii)-Pt(iv) prodrug candidates.
    DOI:  https://doi.org/10.2533/chimia.2021.845
  55. J Mater Chem B. 2021 Nov 02.
    Hybrid theranostic microbubbles for ultrasound/photoacoustic imaging guided starvation/low-temperature photothermal/hypoxia-activated synergistic cancer therapy.
    Feng Tian, Xingjian Zhong, JunKai Zhao, Yutian Gu, Yadi Fan, Fan Shi, Yu Zhang, Youhua Tan, Wen Chen, Changqing Yi, Mo Yang.
      Constructing a theranostic agent for high-contrast multimodality imaging-guided synergistic therapy with long-term tumor retention and minimum systemic side effects still remains a major challenge. Herein, a hybrid microbubble-based theranostic platform was developed for dual-modality ultrasound (US) and enhanced photoacoustic (PA) imaging-guided synergistic tumor therapy by combining starvation therapy, low-temperature photothermal therapy (PTT), and hypoxia-activated therapy, based on polydopamine (PDA) doped poly(vinyl alcohol) microbubbles loaded with glucose oxidase (GOx) (PDA-PVAMBs@GOx) and hypoxia-activated prodrug (HAP) tirapazamine (TPZ). For dual-modality US/enhanced PA imaging, PDA-PVAMBs provided 6.5-fold amplified PA signals relative to freely dispersed PDA nanoparticles (PDA NPs). For synergistic cancer therapy, oxygen (O2) carried by PDA-PVAMBs@GOx was first released to promote starvation therapy by loaded GOx. Then, moderate near-infrared (NIR) laser irradiation triggered PTT and improved enzymatic activity of GOx with its optimal activity around 47 °C. Subsequently, GOx-mediated tumor starvation depleted O2 and exacerbated the hypoxia environment, thereby activating the toxicity of TPZ in the tumor site. Through dual-modality US/PA imaging monitoring, PDA-PVAMBs@GOx with long-term retention (∼7 days) combined with PTT and TPZ significantly inhibited the growth of solid tumors with minimum systemic side effects, which might be a powerful tool for effective tumor treatment.
    DOI:  https://doi.org/10.1039/d1tb01735g
  56. J Lasers Med Sci. 2021 ;12 e17
    Evaluation of Biological Activity of Different Wavelengths of Low-Level Laser Therapy on the Cancer Prostate Cell Line Compared With Cisplatin.
    Jaber Zafari, Hossein Abbasinia, Hediyeh Gharehyazi, Fatemeh Javani Jouni, Saeed Jamali, Mohammadreza Razzaghi.
      Introduction: Cancer is one of the most important problems in the world. Low-level laser therapy (LLLT) has been emerged as a new approach, having both stimulation and inhibition effects on cellular function. The goal of this study was to analyze and compare the different concentrations of cisplatin and wavelengths of laser therapy on the LnCap cell lines. Methods: LnCap cells were cultured and treated with different concentrations of cisplatin (0.1, 0.4, 0.8, 1.2 and 2 µg/mL for 24 hours) and wavelengths of laser therapy (610, 630 and 810 nm) (0.45 J/cm2) separately. The viability of cells was examined by MTT assay and IC50 was also calculated. Furthermore, a combination of cisplatin IC50 (24 hours) and different wavelengths of the laser was examined. Results: The results of this study showed that 2 µg/mL of cisplatin has the most significant reduction effect on the cell viability of the LnCap cell line. Cisplatin decreased the viability of cells in a dose-dependent manner. Moreover, IC50 of cisplatin was 1.24 µg/mL. On the other hand, LLLT with wavelengths of 610, 630 and 810 nm did not show notable biological effects on cell viability. Conclusion: As known, cisplatin has the capability to reduce the viability of LnCap cell lines. However, LLLT cannot be a remarkable option for the treatment of prostate cancer. Therefore, although laser therapy showed praiseful therapeutic activity against some cancer cell lines, in this study the results indicated that defined laser wavelengths had no inhibitory effects against the prostate cancer cell line.
    Keywords:  Chemotherapy; Cisplatin; Low-Level Laser Therapy; Prostate Cancer
    DOI:  https://doi.org/10.34172/jlms.2021.17
  57. Curr Pharm Des. 2021 Nov 01.
    Recent Advances in Gelatin-Based Nanomedicine for Targeted Delivery of Anti-Cancer Drugs.
    Faisal Raza, Liu Siyu, Hajra Zafar, Zul Kamal, Bo Zheng, Jing Su, Mingfeng Qiu.
      Nanoparticles based on natural polymers are utilized for the development of a wide range of drug delivery systems (DDS) in the current era. Gelatin-based nanoparticles, for example, are a remarkable cancer therapy with high efficacy and specificity. This paper reviews the recent advancements in gelatin-based nanomedicine for use in cancer therapeutics. Due to the characteristics features of gelatin, such as biocompatibility, biodegradability, stability, and good surface properties, these nanoparticles provide high therapeutic potency in cancer nanomedicine. The surface of gelatin can be modified in a number of ways using various ligands to explore the platform for the development of a more novel DDS. Various methods are available for the preparation of gelatin nanomedicine discussed in this review. In addition, various cross-linkers to stabilized nanocarriers and stimuli base gelatin nanoparticles are reviewed. Furthermore, recent advances and research in gelatin-based nanomedicine are discussed. Also, some drawbacks and challenges are evaluated. In general, this paper paves the pathway to identify the details about the gelatin-based DDS for cancer therapy.
    Keywords:  Gelatin; cancer; nanomedicine; nanoparticles; stimuli-responsive; targeted drug delivery; tumor microenvironment
    DOI:  https://doi.org/10.2174/1381612827666211102100118
  58. J Med Chem. 2021 Nov 02.
    A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2.
    Sahil Arora, Gaurav Joshi, Anuhar Chaturvedi, Michael Heuser, Santoshkumar Patil, Raj Kumar.
      The allosteric regulation of pyruvate kinase M2 (PKM2) affects the switching of the PKM2 protein between the high-activity and low-activity states that allow ATP and lactate production, respectively. PKM2, in its low catalytic state (dimeric form), is chiefly active in metabolically energetic cells, including cancer cells. More recently, PKM2 has emerged as an attractive target due to its role in metabolic dysfunction and other interrelated conditions. PKM2 (dimer) activity can be inhibited by modulating PKM2 dimer-tetramer dynamics using either PKM2 inhibitors that bind at the ATP binding active site of PKM2 (dimer) or PKM2 activators that bind at the allosteric site of PKM2, thus activating PKM2 from the dimer formation to the tetrameric formation. The present perspective focuses on medicinal chemistry approaches to design and discover PKM2 inhibitors and activators and further provides a scope for the future design of compounds targeting PKM2 with better efficacy and selectivity.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c00981
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