bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–10–31
fifty-five papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Avenues of research in dietary interventions to target tumor metabolism in osteosarcoma.
  2. Oxygen and metabolic reprogramming in the tumor microenvironment influences metastasis homing.
  3. Aberrant Metabolism as Inductor of Epigenetic Changes in Breast Cancer: Therapeutic Opportunities.
  4. A Balancing Act: p53 Activity from Tumor Suppression to Pathology and Therapeutic Implications.
  5. Pan-Cancer Analysis of Glycolytic and Ketone Bodies Metabolic Genes: Implications for Response to Ketogenic Dietary Therapy.
  6. Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells.
  7. Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow.
  8. An ROS-activatable Nanoassembly Remodulates Tumor Cell Metabolism for Enhanced Ferroptosis Therapy.
  9. Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors.
  10. Riluzole: A neuroprotective drug with potential as a novel anti‑cancer agent (Review).
  11. Defueling the cancer: ATP synthase as an emerging target in cancer therapy.
  12. Metabolic requirements of the metastatic cascade.
  13. An understanding of mitochondria and its role in targeting nanocarriers for diagnosis and treatment of cancer.
  14. Chemoprotective and chemosensitizing effects of apigenin on cancer therapy.
  15. The impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells.
  16. High-fat diet aggravates colitis-associated carcinogenesis by evading ferroptosis in the ER stress-mediated pathway.
  17. Metabolic memory underlying minimal residual disease in breast cancer.
  18. Development of next generation nanomedicine-based approaches for the treatment of cancer: we've barely scratched the surface.
  19. Synthetic Materials that Affect the Extracellular Matrix via Cellular Metabolism and Responses to a Metabolic State.
  20. Genomic and Transcriptomic Differences at the Pyruvate Kinase M (PKM) Locus in Patient-Derived Glioblastoma Multiforme (GBM) Cell Lines.
  21. Heptamethine Cyanine Dye MHI-148-Mediated Drug Delivery System to Enhance the Anticancer Efficiency of Paclitaxel.
  22. Active mitochondrial respiration in cancer: a target for the drug.
  23. Metabolic reprogramming in cancer: the bridge that connects intracellular stresses and cancer behaviors.
  24. Modulating hypoxia inducible factor-1 by nanomaterials for effective cancer therapy.
  25. Insights into oxidative stress in bone tissue and novel challenges for biomaterials.
  26. [6]-Gingerol Suppresses Oral Cancer Cell Growth by Inducing the Activation of AMPK and Suppressing the AKT/mTOR Signaling Pathway.
  27. KRAS Inhibitors- yes but what next? Direct targeting of KRAS- vaccines, adoptive T cell therapy and beyond.
  28. A Novel Fluorescent Dye Invades Mitochondria to Selectively Kill Cancer Stem Cells via Increased ROS Production.
  29. The effects of herbal medicines on cancer therapy-induced oral mucositis: A literature review.
  30. Kirsten rat sarcoma inhibitors in clinical development against nonsmall cell lung cancer.
  31. A Metabolomics Analysis of Circulating Carotenoids and Breast Cancer Risk.
  32. A Low Dose of Hydrous Icaritin Nano-Formulation with Remarkable Efficacy and Tumor Targeting in Cancer Therapy.
  33. Surface engineered nanocarriers for the management of breast cancer.
  34. Designing new nanoliposomal formulations and evaluating their effects on myeloid-derived suppressor cells and regulatory T cells in a colon cancer model aiming to develop an efficient delivery system for cancer treatment; an in vitro and in vivo study.
  35. Synergistic effect of metformin and vemurufenib (PLX4032) as a molecular targeted therapy in anaplastic thyroid cancer: an in vitro study.
  36. Saikosaponin D: review on the antitumour effects, toxicity and pharmacokinetics.
  37. 6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function.
  38. Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis.
  39. Targeted Lipid Nanoparticles Encapsulating Dihydroartemisinin and Chloroquine Phosphate for Suppressing the Proliferation and Liver Metastasis of Colorectal Cancer.
  40. High density lipoproteins and oxidative stress in breast cancer.
  41. Effects of Curcumin on Aging: Molecular Mechanisms and Experimental Evidence.
  42. Harnessing nanomedicine for enhanced immunotherapy for breast cancer brain metastases.
  43. Curcumin and its derivatives in cancer therapy: Potentiating antitumor activity of cisplatin and reducing side effects.
  44. Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.
  45. Intravesical Mucoadhesive Hydrogel Induces Chemoresistant Bladder Cancer Ferroptosis through Delivering Iron Oxide Nanoparticles in a Three-Tier Strategy.
  46. Titaniumdioxide mediated sonophotodynamic therapy against prostate cancer.
  47. Induction of Iron Stress in Hepatocellular Carcinoma Cell Lines by Siderophore of Aspergillus nidulans Towards Promising Anticancer Effect.
  48. ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.
  49. The Relationship Between Mesenchymal Stem Cells and Tumor Dormancy.
  50. Targeting glioblastoma stem cells: the first steps of photodynamic therapy.
  51. Multistage targeted "Photoactive neutrophil" for enhancing synergistic photo-chemotherapy.
  52. Reactive oxygen species / photothermal therapy dual-triggered biomimetic gold nanocages nanoplatform for combination cancer therapy via ferroptosis and tumor-associated macrophage repolarization mechanism.
  53. Evaluation of Apigenin Inhibiting Lactate Dehydrogenase Activity Based on CdTe Quantum Dots Fluorescence.
  54. Polymeric Nanoparticles for Mitochondria Targeting Mediated Robust Cancer Therapy.
  55. Mitochondria targeted composite enzyme nanogels for synergistic starvation and photodynamic therapy.
  1. J Transl Med. 2021 Oct 29. 19(1): 450
    Avenues of research in dietary interventions to target tumor metabolism in osteosarcoma.
    Taiana Campos Leite, Rebecca Jean Watters, Kurt Richard Weiss, Giuseppe Intini.
      Osteosarcoma (OS) is the most frequent primary bone cancer, affecting mostly children and adolescents. Although much progress has been made throughout the years towards treating primary OS, the 5-year survival rate for metastatic OS has remained at only 20% for the last 30 years. Therefore, more efficient treatments are needed. Recent studies have shown that tumor metabolism displays a unique behavior, and plays important roles in tumor growth and metastasis, making it an attractive potential target for novel therapies. While normal cells typically fuel the oxidative phosphorylation (OXPHOS) pathway with the products of glycolysis, cancer cells acquire a plastic metabolism, uncoupling these two pathways. This allows them to obtain building blocks for proliferation from glycolytic intermediates and ATP from OXPHOS. One way to target the metabolism of cancer cells is through dietary interventions. However, while some diets have shown anticancer effects against certain tumor types in preclinical studies, as of yet none have been tested to treat OS. Here we review the features of tumor metabolism, in general and about OS, and propose avenues of research in dietary intervention, discussing strategies that could potentially be effective to target OS metabolism.
    Keywords:  Caloric restriction; Fasting; Ketogenic diet; Osteosarcoma; Quercetin; Tumor metabolism
    DOI:  https://doi.org/10.1186/s12967-021-03122-8
  2. Cancer Biol Ther. 2021 Oct 25. 1-20
    Oxygen and metabolic reprogramming in the tumor microenvironment influences metastasis homing.
    Vinod S Bisht, Kuldeep Giri, Deepak Kumar, Kiran Ambatipudi.
      Tumor metastasis is the leading cause of cancer mortality, often characterized by abnormal cell growth and invasion to distant organs. The cancer invasion due to epithelial to mesenchymal transition is affected by metabolic and oxygen availability in the tumor-associated micro-environment. A precise alteration in oxygen and metabolic signaling between healthy and metastatic cells is a substantial probe for understanding tumor progression and metastasis. Molecular heterogeneity in the tumor microenvironment help to sustain the metastatic cell growth during their survival shift from low to high metabolic-oxygen-rich sites and reinforces the metastatic events. This review highlighted the crucial role of oxygen and metabolites in metastatic progression and exemplified the role of metabolic rewiring and oxygen availability in cancer cell adaptation. Furthermore, we have also addressed potential applications of altered oxygen and metabolic networking with tumor type that could be a signature pattern to assess tumor growth and chemotherapeutics efficacy in managing cancer metastasis.
    Keywords:  Cancer metabolism; angeogenesis; cancer recurrence; dormancy; lymphogenesis; metabolic reprogramming; metastasis
    DOI:  https://doi.org/10.1080/15384047.2021.1992233
  3. Front Oncol. 2021 ;11 676562
    Aberrant Metabolism as Inductor of Epigenetic Changes in Breast Cancer: Therapeutic Opportunities.
    Jossimar Coronel-Hernández, Eloy Andrés Pérez-Yépez, Izamary Delgado-Waldo, Carlos Contreras-Romero, Nadia Jacobo-Herrera, David Cantú-De León, Carlos Pérez-Plasencia.
      Aberrant metabolism is arising interest in the scientific community not only because of the role it plays in the development and establishment of the tumor mass but also the possibility of drug poisoning of key enzymes overexpressed in tumor cells. Moreover, tumor metabolism provides key molecules to maintain the epigenetic changes that are also an undisputed characteristic of each tumor type. This metabolic change includes the Warburg effect and alterations in key pathways involved in glutaminolysis, pentose phosphate, and unsaturated fatty acid biosynthesis. Modifications in all these pathways have consequences that impact genetics and epigenetics processes such as DNA methylation patterns, histone post-translational modifications, triggering oncogenes activation, and loss in tumor suppressor gene expression to lead the tumor establishment. In this review, we describe the metabolic rearrangement and its association with epigenetic regulation in breast cancer, as well as its implication in biological processes involved in cancer progression. A better understanding of these processes could help to find new targets for the diagnosis, prognosis, and treatment of this human health problem.
    Keywords:  breast cancer; epigenetic modifications; glycolysis; metabolism; therapeutic targets
    DOI:  https://doi.org/10.3389/fonc.2021.676562
  4. Annu Rev Pathol. 2021 Oct 26.
    A Balancing Act: p53 Activity from Tumor Suppression to Pathology and Therapeutic Implications.
    Mengxiong Wang, Laura D Attardi.
      TP53, encoding the p53 transcription factor, is the most frequently mutated tumor suppressor gene across all human cancer types. While p53 has long been appreciated to induce antiproliferative cell cycle arrest, apoptosis, and senescence programs in response to diverse stress signals, various studies in recent years have revealed additional important functions for p53 that likely also contribute to tumor suppression, including roles in regulating tumor metabolism, ferroptosis, signaling in the tumor microenvironment, and stem cell self-renewal/differentiation. Not only does p53 loss or mutation cause cancer, but hyperactive p53 also drives various pathologies, including developmental phenotypes, premature aging, neurodegeneration, and side effects of cancer therapies. These findings underscore the importance of balanced p53 activity and influence our thinking of how to best develop cancer therapies based on modulating the p53 pathway. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-pathol-042320-025840
  5. Front Oncol. 2021 ;11 689068
    Pan-Cancer Analysis of Glycolytic and Ketone Bodies Metabolic Genes: Implications for Response to Ketogenic Dietary Therapy.
    Liyuan Qian, Yunzheng Li, Yajuan Cao, Gang Meng, Jin Peng, Huan Li, Ye Wang, Tiancheng Xu, Laizhu Zhang, Beicheng Sun, Binghua Li, Decai Yu.
       Background: The Warburg effect, also termed "aerobic glycolysis", is one of the most remarkable and ubiquitous metabolic characteristics exhibited by cancer cells, representing a potential vulnerability that might be targeted for tumor therapy. Ketogenic diets (KDs), composed of high-fat, moderate-protein and low carbohydrates, are aimed at targeting the Warburg effect for cancer treatment, which have recently gained considerable attention. However, the efficiency of KDs was inconsistent, and the genotypic contribution is still largely unknown.
    Methods: The bulk RNA-seq data from The Cancer Genome Atlas (TCGA), single cell RNA sequencing (scRNA-seq), and microarray data from Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) were collected. A joint analysis of glycolysis and ketone bodies metabolism (KBM) pathway was performed across over 10,000 tumor samples and nearly 1,000 cancer cell lines. A series of bioinformatic approaches were combined to identify a metabolic subtype that may predict the response to ketogenic dietary therapy (KDT). Mouse xenografts were established to validate the predictive utility of our subtypes in response to KDT.
    Results: We first provided a system-level view of the expression pattern and prognosis of the signature genes from glycolysis and KBM pathway across 33 cancer types. Analysis by joint stratification of glycolysis and KBM revealed four metabolic subtypes, which correlated extensively but diversely with clinical outcomes across cancers. The glycolytic subtypes may be driven by TP53 mutations, whereas the KB-metabolic subtypes may be mediated by CTNNB1 (β-catenin) mutations. The glycolytic subtypes may have a better response to KDs compared to the other three subtypes. We preliminarily confirmed the idea by literature review and further performed a proof-of-concept experiment to validate the predictive value of the metabolic subtype in liver cancer xenografts.
    Conclusions: Our findings identified a metabolic subtype based on glycolysis and KBM that may serve as a promising biomarker to predict the clinical outcomes and therapeutic responses to KDT.
    Keywords:  biomarker; ketogenic diets; ketone body metabolism; metabolic subtypes; warburg effect
    DOI:  https://doi.org/10.3389/fonc.2021.689068
  6. Front Oncol. 2021 ;11 738961
    Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells.
    Vivek Kumar Soni, Arundhati Mehta, Yashwant Kumar Ratre, Vikas Chandra, Dhananjay Shukla, Ajay Kumar, Naveen Kumar Vishvakarma.
      Along with direct anticancer activity, curcumin hinders the onset of chemoresistance. Among many, high glucose condition is a key driving factor for chemoresistance. However, the ability of curcumin remains unexplored against high glucose-induced chemoresistance. Moreover, chemoresistance is major hindrance in effective clinical management of liver cancer. Using hepatic carcinoma HepG2 cells, the present investigation demonstrates that high glucose induces chemoresistance, which is averted by the simultaneous presence of curcumin. Curcumin obviated the hyperglycemia-induced modulations like elevated glucose consumption, lactate production, and extracellular acidification, and diminished nitric oxide and reactive oxygen species (ROS) production. Modulated molecular regulators are suggested to play a crucial role as curcumin pretreatment also prevented the onset of chemoresistance by high glucose. High glucose instigated suppression in the intracellular accumulation of anticancer drug doxorubicin and drug-induced chromatin compactness along with declined expression of drug efflux pump MDR-1 and transcription factors and signal transducers governing the survival, aggressiveness, and apoptotic cell death (p53, HIF-1α, mTOR, MYC, STAT3). Curcumin alleviated the suppression of drug retention and nuclear condensation along with hindering the high glucose-induced alterations in transcription factors and signal transducers. High glucose-driven resistance in cancer cells was associated with elevated expression of metabolic enzymes HKII, PFK1, GAPDH, PKM2, LDH-A, IDH3A, and FASN. Metabolite transporters and receptors (GLUT-1, MCT-1, MCT-4, and HCAR-1) were also found upregulated in high glucose exposed HepG2 cells. Curcumin inhibited the elevated expression of these enzymes, transporters, and receptors in cancer cells. Curcumin also uplifted the SDH expression, which was inhibited in high glucose condition. Taken together, the findings of the present investigation first time demonstrate the ability of curcumin against high glucose-induced chemoresistance, along with its molecular mechanism. This will have implication in therapeutic management of malignancies in diabetic conditions.
    Keywords:  chemoresistance; curcumin; glucose; hepatic cancer; metabolism
    DOI:  https://doi.org/10.3389/fonc.2021.738961
  7. J Histochem Cytochem. 2021 Oct 29. 221554211054585
    Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow.
    Cornelis J F van Noorden, Barbara Breznik, Metka Novak, Amber J van Dijck, Saloua Tanan, Miloš Vittori, Urban Bogataj, Noëlle Bakker, Joseph D Khoury, Remco J Molenaar, Vashendriya V V Hira.
      Energy production by means of ATP synthesis in cancer cells has been investigated frequently as a potential therapeutic target in this century. Both (an)aerobic glycolysis and oxidative phosphorylation (OXPHOS) have been studied. Here, we review recent literature on energy production in glioblastoma stem cells (GSCs) and leukemic stem cells (LSCs) versus their normal counterparts, neural stem cells (NSCs) and hematopoietic stem cells (HSCs), respectively. These two cancer stem cell types were compared because their niches in glioblastoma tumors and in bone marrow are similar. In this study, it became apparent that (1) ATP is produced in NSCs and HSCs by anaerobic glycolysis, whereas fatty acid oxidation (FAO) is essential for their stem cell fate and (2) ATP is produced in GSCs and LSCs by OXPHOS despite the hypoxic conditions in their niches with FAO and amino acids providing its substrate. These metabolic processes appeared to be under tight control of cellular regulation mechanisms which are discussed in depth. However, our conclusion is that systemic therapeutic targeting of ATP production via glycolysis or OXPHOS is not an attractive option because of its unwanted side effects in cancer patients.
    Keywords:  angiogenesis; bone marrow; brain tumors; cancer stem cells; hematopoietic stem cells; leukemia; leukemic stem cells; metabolism; neural stem cells; niches; stem cells; stemness; tumor heterogeneity; tumor immune infiltrate; tumor microenvironment
    DOI:  https://doi.org/10.1369/00221554211054585
  8. Adv Healthc Mater. 2021 Oct 28. e2101702
    An ROS-activatable Nanoassembly Remodulates Tumor Cell Metabolism for Enhanced Ferroptosis Therapy.
    Yuchen Zhang, Liqi Li, Yanan Li, Yang Fei, Chencheng Xue, Xuemei Yao, Youbo Zhao, Xuan Wang, Menghuan Li, Zhong Luo.
      Ferroptosis is an emerging antitumor option and has demonstrated unique advantages against many tumor indications. However, its efficacy is potentially hindered by the endogenous lipid peroxide-scavenging mechanisms and the reliance on acidic pH. Herein, we have developed a nanointegrated strategy based on clinically-safe components to synergistically remodel glutathione and lactate metabolism in tumor cells for enhanced ferroptosis therapy. We first conjugated ferrocene on PEGylated polyamidoamine dendrimers via ROS-cleavable thioketal linkage, which would further self-assemble with the glutathione (GSH)-depleting agent diethyl maleate (DEM) and monocarboxylate transporter 4-inhibiting siRNA (siMCT4) to afford biostable nanoassemblies (siMCT4-PAMAM-PEG-TK-Fc@DEM). The nanoassemblies could be activated by the elevated ROS levels in tumor intracellular environment and readily release the incorporated therapeutic contents, afterwards DEM could directly conjugate to GSH to disrupt the glutathione peroxidase 4 (GPX4)-mediated antioxidant defense while siMCT4 could block the MCT4-mediated efflux of lactic acid and acidify the intracellular milieu, both of which could improve the ferrocene-catalyzed lipid peroxidation and induce pronounced ferroptotic damage. The siMCT4-PAMAM-PEG-TK-Fc@DEM nanoplatform demonstrated high ferroptosis-based antitumor potency and good biocompatibility in vitro and in vivo, which may offer new avenues for the development of more advanced antitumor therapeutics with improved translatability. This article is protected by copyright. All rights reserved.
    Keywords:  Ferroptosis sensitization; ROS-activatable nanoassembly; drug delivery; metabolic regulation
    DOI:  https://doi.org/10.1002/adhm.202101702
  9. Cell Chem Biol. 2021 Oct 22. pii: S2451-9456(21)00441-4. [Epub ahead of print]
    Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors.
    Kellen Olszewski, Anthony Barsotti, Xiao-Jiang Feng, Milica Momcilovic, Kevin G Liu, Ji-In Kim, Koi Morris, Christophe Lamarque, Jack Gaffney, Xuemei Yu, Jeegar P Patel, Joshua D Rabinowitz, David B Shackelford, Masha V Poyurovsky.
      Efforts to target glucose metabolism in cancer have been limited by the poor potency and specificity of existing anti-glycolytic agents and a poor understanding of the glucose dependence of cancer subtypes in vivo. Here, we present an extensively characterized series of potent, orally bioavailable inhibitors of the class I glucose transporters (GLUTs). The representative compound KL-11743 specifically blocks glucose metabolism, triggering an acute collapse in NADH pools and a striking accumulation of aspartate, indicating a dramatic shift toward oxidative phosphorylation in the mitochondria. Disrupting mitochondrial metabolism via chemical inhibition of electron transport, deletion of the malate-aspartate shuttle component GOT1, or endogenous mutations in tricarboxylic acid cycle enzymes, causes synthetic lethality with KL-11743. Patient-derived xenograft models of succinate dehydrogenase A (SDHA)-deficient cancers are specifically sensitive to KL-11743, providing direct evidence that TCA cycle-mutant tumors are vulnerable to GLUT inhibitors in vivo.
    Keywords:  GLUT inhibitor; PDX models; electron transport chain inhibitors; glycolysis; imaging; malate-aspartate shuttle; mitochondrial inhibitors; pharmacology; redox biology; toxicology
    DOI:  https://doi.org/10.1016/j.chembiol.2021.10.007
  10. Int J Oncol. 2021 Nov;pii: 95. [Epub ahead of print]59(5):
    Riluzole: A neuroprotective drug with potential as a novel anti‑cancer agent (Review).
    Angelina Blyufer, Sonam Lhamo, Cassey Tam, Iffat Tariq, Thongthai Thavornwatanayong, Shahana S Mahajan.
      Riluzole, a glutamate release inhibitor, has been in use for the treatment of amyotrophic lateral sclerosis for over two decades since its approval by the Food and Drug Administration. Recently, riluzole has been evaluated in cancer cells and indicated to block cell proliferation and/or induce cell death. Riluzole has been proven effective as an anti‑neoplastic drug in cancers of various tissue origins, including the skin, breast, pancreas, colon, liver, bone, brain, lung and nasopharynx. While cancer cells expressing glutamate receptors frequently respond to riluzole treatment, numerous types of cancer cell lacking glutamate receptors unexpectedly responded to riluzole treatment as well. Riluzole was demonstrated to interfere with glutamate secretion, growth signaling pathways, Ca2+ homeostasis, glutathione synthesis, reactive oxygen species generation and integrity of DNA, as well as autophagic and apoptotic pathways. Of note, riluzole is highly effective in inducing cell death in cisplatin‑resistant lung cancer cells. Furthermore, riluzole pretreatment sensitizes glioma and melanoma to radiation therapy. In addition, in triple‑negative breast cancer, colorectal cancer, melanoma and glioblastoma, riluzole has synergistic effects in combination with select drugs. In an effort to highlight the therapeutic potential of riluzole, the current study reviewed the effect and outcome of riluzole treatment on numerous cancer types investigated thus far. The mechanism of action and the various molecular pathways affected by riluzole are discussed.
    Keywords:  DNA damage; apoptosis; cell cycle arrest; combination therapy; glutamate secretion and signaling; reactive oxygen species; riluzole
    DOI:  https://doi.org/10.3892/ijo.2021.5275
  11. Mol Ther Oncolytics. 2021 Dec 17. 23 82-95
    Defueling the cancer: ATP synthase as an emerging target in cancer therapy.
    Ting Wang, Fei Ma, Hai-Li Qian.
      Reprogramming of cellular metabolism is a hallmark of cancer. Mitochondrial ATP synthase (MAS) produces most of the ATP that drives the cell. High expression of the MAS-composing proteins is found during cancer and is linked to a poor prognosis in glioblastoma, ovarian cancer, prostate cancer, breast cancer, and clear cell renal cell carcinoma. Cell surface-expressed ATP synthase, translocated from mitochondrion to cell membrane, involves the angiogenesis, tumorigenesis, and metastasis of cancer. ATP synthase has therefore been considered a therapeutic target. We review recent various ATP synthase inhibitors that suppress tumor growth and are being tested for the clinic.
    Keywords:  ATP synthase inhibitor; cancer metabolism; chemotherapy; mitochondrial ATP synthase; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.omto.2021.08.015
  12. Curr Opin Syst Biol. 2021 Dec;pii: 100381. [Epub ahead of print]28
    Metabolic requirements of the metastatic cascade.
    Stanislav Drapela, Ana P Gomes.
      Metastases represent a major cause of cancer-associated deaths. Despite extensive research, targeting metastasis remains the main obstacle in cancer therapy. Therefore, it is of tremendous importance to elucidate the mechanisms that impinge on the different steps of the metastatic cascade. Metabolic plasticity is a cornerstone of the tumorigenic process that not only enables cancer cells to rapidly proliferate but also thrive and retain vitality. Plasticity of the metabolic networks that wire cancer cells is of utmost importance during the metastatic cascade when cancer cells are at their most vulnerable and have to survive in a panoply of inhospitable environments as they make their journey to form metastatic lesions. Here, we highlight which metabolic processes are known to power metastasis formation and lay the foundation for additional work aimed at discovering regulatory nodes of metabolic plasticity that can be used to target metastatic disease.
    DOI:  https://doi.org/10.1016/j.coisb.2021.100381
  13. Asian J Pharm Sci. 2021 Jul;16(4): 397-418
    An understanding of mitochondria and its role in targeting nanocarriers for diagnosis and treatment of cancer.
    Devendra Choudhary, Hanmant Goykar, Tukaram Karanwad, Suraj Kannaujia, Vedant Gadekar, Manju Misra.
      Nanotechnology has changed the entire paradigm of drug targeting and has shown tremendous potential in the area of cancer therapy due to its specificity. In cancer, several targets have been explored which could be utilized for the better treatment of disease. Mitochondria, the so-called powerhouse of cell, portrays significant role in the survival and death of cells, and has emerged as potential target for cancer therapy. Direct targeting and nanotechnology based approaches can be tailor-made to target mitochondria and thus improve the survival rate of patients suffering from cancer. With this backdrop, in present review, we have reemphasized the role of mitochondria in cancer progression and inhibition, highlighting the different targets that can be explored for targeting of disease. Moreover, we have also summarized different nanoparticulate systems that have been used for treatment of cancer via mitochondrial targeting.
    Keywords:  Cancer; Mitochondrial targeting; Nanocarriers; Photodynamic therapy; Photothermal therapy
    DOI:  https://doi.org/10.1016/j.ajps.2020.10.002
  14. Cancer Cell Int. 2021 Oct 29. 21(1): 574
    Chemoprotective and chemosensitizing effects of apigenin on cancer therapy.
    Zahra Nozhat, Shabnam Heydarzadeh, Zahra Memariani, Amirhossein Ahmadi.
       BACKGROUND: Therapeutic resistance to radiation and chemotherapy is one of the major obstacles in cancer treatment. Although synthetic radiosensitizers are pragmatic solution to enhance tumor sensitivity, they pose concerns of toxicity and non-specificity. In the last decades, scientists scrutinized novel plant-derived radiosensitizers and chemosensitizers, such as flavones, owing to their substantial physiological effects like low toxicity and non-mutagenic properties on the human cells. The combination therapy with apigenin is potential candidate in cancer therapeutics. This review explicates the combinatorial strategies involving apigenin to overcome drug resistance and boost the anti-cancer properties.
    METHODS: We selected full-text English papers on international databases like PubMed, Web of Science, Google Scholar, Scopus, and ScienceDirect from 1972 up to 2020. The keywords included in the search were: Apigenin, Chemoprotective, Chemosensitizing, Side Effects, and Molecular Mechanisms.
    RESULTS: In this review, we focused on combination therapy, particularly with apigenin augmenting the anti-cancer effects of chemo drugs on tumor cells, reduce their side effects, subdue drug resistance, and protect healthy cells. The reviewed research data implies that these co-therapies exhibited a synergistic effect on various cancer cells, where apigenin sensitized the chemo drug through different pathways including a significant reduction in overexpressed genes, AKT phosphorylation, NFκB, inhibition of Nrf2, overexpression of caspases, up-regulation of p53 and MAPK, compared to the monotherapies. Meanwhile, contrary to the chemo drugs alone, combined treatments significantly induced apoptosis in the treated cells.
    CONCLUSION: Briefly, our analysis proposed that the combination therapies with apigenin could suppress the unwanted toxicity of chemotherapeutic agents. It is believed that these expedient results may pave the path for the development of drugs with a high therapeutic index. Nevertheless, human clinical trials are a prerequisite to consider the potential use of apigenin in the prevention and treatment of various cancers. Conclusively, the clinical trials to comprehend the role of apigenin as a chemoprotective agent are still in infancy.
    Keywords:  Apigenin; Chemoprotective; Chemosensitizing; Molecular mechanisms; Side effects
    DOI:  https://doi.org/10.1186/s12935-021-02282-3
  15. Nat Commun. 2021 Oct 26. 12(1): 6176
    The impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells.
    Marc Hennequart, Christiaan F Labuschagne, Mylène Tajan, Steven E Pilley, Eric C Cheung, Nathalie M Legrave, Paul C Driscoll, Karen H Vousden.
      Serine is a non-essential amino acid that is critical for tumour proliferation and depletion of circulating serine results in reduced tumour growth and increased survival in various cancer models. While many cancer cells cultured in a standard tissue culture medium depend on exogenous serine for optimal growth, here we report that these cells are less sensitive to serine/glycine depletion in medium containing physiological levels of metabolites. The lower requirement for exogenous serine under these culture conditions reflects both increased de novo serine synthesis and the use of hypoxanthine (not present in the standard medium) to support purine synthesis. Limiting serine availability leads to increased uptake of extracellular hypoxanthine, sparing available serine for other pathways such as glutathione synthesis. Taken together these results improve our understanding of serine metabolism in physiologically relevant nutrient conditions and allow us to predict interventions that may enhance the therapeutic response to dietary serine/glycine limitation.
    DOI:  https://doi.org/10.1038/s41467-021-26395-5
  16. Free Radic Biol Med. 2021 Oct 21. pii: S0891-5849(21)00773-5. [Epub ahead of print]177 156-166
    High-fat diet aggravates colitis-associated carcinogenesis by evading ferroptosis in the ER stress-mediated pathway.
    Xiaoli Zhang, Weiwei Li, Yiming Ma, Xinhua Zhao, Longmei He, Peng Sun, Hongying Wang.
      Ferroptosis, a type of programmed cell death caused by lipid peroxidation has recently been observed in colitis. Whether a high-fat diet (HFD) affects ferroptosis and whether it contributes to colitis-associated carcinogenesis (CAC) has not been explored. We found iron, lipid peroxidation, and ferroptotic markers to be elevated in AOM/DSS (azoxymethane/dextran sulfate sodium)-induced mouse CAC model. Transmission electron microscopy also confirmed the occurrence of ferroptosis in colonic tissues. Treatment with the ferroptosis inhibitor, ferrostatin-1 increased the incidence of CAC. Compared with iso-caloric control mice, HFD mice exhibited increased tumor number and a higher degree of dysplasia following repression of lipid peroxidation and ferroptosis marker expression in mouse colon tissue. Furthermore, ferroptosis markers were negatively correlated with the tumor number in mice. In vitro, a lipid mixture blocked ferroptosis in various colorectal cancer cell lines and inhibited GSH degradation by negatively regulating CHAC1, a target in ER stress signaling. Finally, the ferroptosis inducer partly abolished the pro-tumor effect of the HFD on CAC in vivo. Collectively, these findings suggest that a HFD aggravates CAC through the evasion of ferroptosis in the ER stress-mediated pathway and provide a new perspective for CAC prevention in the future.
    Keywords:  CHAC1; Colitis-associated carcinogenesis; Endoplasmic reticulum stress; Ferroptosis; High-fat diet
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.10.022
  17. Mol Syst Biol. 2021 Oct;17(10): e10141
    Metabolic memory underlying minimal residual disease in breast cancer.
    Ksenija Radic Shechter, Eleni Kafkia, Katharina Zirngibl, Sylwia Gawrzak, Ashna Alladin, Daniel Machado, Christian Lüchtenborg, Daniel C Sévin, Britta Brügger, Kiran R Patil, Martin Jechlinger.
      Tumor relapse from treatment-resistant cells (minimal residual disease, MRD) underlies most breast cancer-related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here, we integrated multi-omics data from a tractable organoid system with a metabolic modeling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non-proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzyme reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo-adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment-resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small-molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post-treatment care to prevent breast tumor recurrence.
    Keywords:  glycolysis; metabolic modeling; multi-omics integration; oncogenic memory; organoids
    DOI:  https://doi.org/10.15252/msb.202010141
  18. Biochem Soc Trans. 2021 Oct 28. pii: BST20210343. [Epub ahead of print]
    Development of next generation nanomedicine-based approaches for the treatment of cancer: we've barely scratched the surface.
    Shannon R Tracey, Peter Smyth, Caroline J Barelle, Christopher J Scott.
      Interest in nanomedicines has grown rapidly over the past two decades, owing to the promising therapeutic applications they may provide, particularly for the treatment of cancer. Personalised medicine and 'smart' actively targeted nanoparticles represent an opportunity to deliver therapies directly to cancer cells and provide sustained drug release, in turn providing overall lower off-target toxicity and increased therapeutic efficacy. However, the successful translation of nanomedicines from encouraging pre-clinical findings to the clinic has, to date, proven arduous. In this review, we will discuss the use of nanomedicines for the treatment of cancer, with a specific focus on the use of polymeric and lipid nanoparticle delivery systems. In particular, we examine approaches exploring the surface functionalisation of nanomedicines to elicit active targeting and therapeutic effects as well as challenges and future directions for nanoparticles in cancer treatment.
    Keywords:  cancer; conjugation; drug delivery; nanomedicine; surface functionalisation; targeted therapeutics
    DOI:  https://doi.org/10.1042/BST20210343
  19. Front Bioeng Biotechnol. 2021 ;9 742132
    Synthetic Materials that Affect the Extracellular Matrix via Cellular Metabolism and Responses to a Metabolic State.
    Mireille M J P E Sthijns, Clemens A van Blitterswijk, Vanessa L S LaPointe.
      In regenerative medicine and tissue engineering, many materials are developed to mimic the extracellular matrix (ECM). However, these ECM-mimicking materials do not yet completely recapitulate the diversity and complexity of biological tissue-specific ECM. In this review, an alternative strategy is proposed to generate ECM, namely synthesizing a material that functions as a drug delivery system, releasing molecules that target cellular metabolic pathways and thereby stimulate the local cells to create their own ECM. This is based on the fact that ECM synthesis, modification, composition, signaling, stiffness, and degradation are modulated by cellular metabolism. Metabolism can be targeted at different levels, ranging from modulating the availability of substrates or co-factors to regulating the activity of essential transcription factors. Depending on the drug of interest, its characteristics, mechanism of action, cellular target, and application, a different drug delivery system should be designed. Metabolic drugs modulating the ECM require cellular uptake for their function, therefore reversible linkers are recommended. Preferably the metabolic modulators are only released when needed, which will be upon a specific metabolic state, a change in ECM stiffness, or ECM remodeling. Therefore, reversible linkers that respond to an environmental stimulus could be incorporated. All in all, a novel strategy is suggested to develop a tissue-specific ECM by generating a synthetic material that releases metabolic molecules modulating the ECM. Various ways to modulate the ECM properties via the metabolism are reviewed and guidelines for the development of these materials are provided.
    Keywords:  extracellar matrix; materials; metabolism; regenerative medicine; tissue engineering
    DOI:  https://doi.org/10.3389/fbioe.2021.742132
  20. Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)02458-5. [Epub ahead of print]111(3S): e593-e594
    Genomic and Transcriptomic Differences at the Pyruvate Kinase M (PKM) Locus in Patient-Derived Glioblastoma Multiforme (GBM) Cell Lines.
    K J Lee, C Willey.
       PURPOSE/OBJECTIVE(S): Glioblastoma multiforme (GBM), a particularly devastating primary CNS tumor, alters the expression and activity of multiple metabolic genes to enhance its ability to grow and divide, buffer against oxidative stress, and resist apoptosis. The shift from oxidative metabolism in the mitochondria to aerobic glycolysis is known as the Warburg effect, a phenomenon mediated by gene expression changes like the isoform switch at the pyruvate kinase muscle-type (PKM) locus from PKM1 to PKM2. Novel pharmaceuticals targeting this tumor-specific isoform have entered clinical trials, but the effect of genetic or transcriptomic background on the effectiveness of these drugs is unknown. The purpose of this work is to characterize the PKM locus at the level of DNA and mRNA.
    MATERIALS/METHODS: Our lab has previously collected and curated patient-derived GBM cell lines and characterized them with high-throughput transcriptome sequencing (RNA-seq). Herein, RNA-seq reads were mapped to the genome. Limiting analysis to the PKM locus, variant calling including single nucleotide polymorphism (SNP) calling is performed, and absolute expression and relative isoform abundance is measured and compared across lines.
    RESULTS: In this analysis of 16 GBM cell lines, multiple SNPs are identified that are predicted to be deleterious to the function of the protein. Additionally, concordant with previous findings in astrocytomas, the PKM2 isoform is the dominant pyruvate kinase transcript in all cell lines profiled. One cell line, in particular, had substantially higher PKM expression compared to the other cell lines.
    CONCLUSION: Previous studies have queried the mutational burden of PKM in other cancer types, but no mutational analysis has been performed on GBM. This work suggests genetic variation at this important locus. Targeting tumor-specific metabolism can increase the effectiveness of current standard-of-care therapies while leaving normal tissue intact. This characterization of the PKM locus at the level of DNA variants and gene expression will inform planned future work using a novel pharmaceutical targeting PKM2.
    AUTHOR DISCLOSURE: K.J. Lee: None. C. Willey: None.
    DOI:  https://doi.org/10.1016/j.ijrobp.2021.07.1588
  21. Int J Nanomedicine. 2021 ;16 7169-7180
    Heptamethine Cyanine Dye MHI-148-Mediated Drug Delivery System to Enhance the Anticancer Efficiency of Paclitaxel.
    Athira Raveendran, Suchithra Poilil Surendran, Jinhui Ser, Khurshed Alam, Hoonsung Cho, Yong Yeon Jeong.
       Introduction: Paclitaxel (PTX) is a conventional chemotherapeutic drug that effectively treats various cancers. The cellular uptake and therapeutic potential of PTX are limited by its slow penetration and low solubility in water. The development of cancer chemotherapy methods is currently facing considerable challenges with respect to the delivery of the drugs, particularly in targeting the tumor site without exerting detrimental effects on the healthy surrounding cells. One possibility for improving the therapeutic potential is through the development of tumor-targeted delivery methods.
    Methods: We successfully synthesized paclitaxel-MHI-148 conjugates (PTX-MHI) by coupling PTX with the tumor-targeting heptamethine cyanine dye MHI-148. Synthesis and purification were characterized using the absorbance spectrum and the results of time-of-flight mass spectrometry. Cellular uptake and cytotoxicity studies were conducted in vitro and in vivo.
    Results: PTX-MHI accumulates in tumor cells but not in normal cells, as observed by in vitro near-infrared fluorescent (NIRF) imaging along with in vivo NIRF imaging and organ biodistribution studies. We observed that MHI-148-conjugated PTX shows greater efficiency in cancer cells than PTX alone, even in the absence of light treatment. PTX-MHI could also be used for specific drug delivery to intracellular compartments, such as the mitochondria and lysosomes of cancer cells, to improve the outcomes of tumor-targeting therapy.
    Conclusion: The results indicated that PTX-MHI-mediated cancer therapy exerts an excellent inhibitory effect on colon carcinoma (HT-29) cell growth with low toxicity in normal fibroblasts (NIH3T3).
    Keywords:  bioconjugation; cancer therapy; colon cancer; fluorescent dye; paclitaxel
    DOI:  https://doi.org/10.2147/IJN.S325322
  22. Mol Cell Biochem. 2021 Oct 30.
    Active mitochondrial respiration in cancer: a target for the drug.
    Minakshi Bedi, Manju Ray, Alok Ghosh.
      The relative contribution of mitochondrial respiration and subsequent energy production in malignant cells has remained controversial to date. Enhanced aerobic glycolysis and impaired mitochondrial respiration have gained more attention in the metabolic study of cancer. In contrast to the popular concept, mitochondria of cancer cells oxidize a diverse array of metabolic fuels to generate a majority of the cellular energy by respiration. Several mitochondrial respiratory chain (MRC) subunits' expressions are critical for the growth, metastasis, and cancer cell invasion. Also, the assembly factors, which regulate the integration of individual MRC complexes into native super-complexes, are upregulated in cancer. Moreover, a series of anti-cancer drugs function by inhibiting respiration and ATP production. In this review, we have specified the roles of mitochondrial fuels, MRC subunits, and super-complex assembly factors that promote active respiration across different cancer types and discussed the potential roles of MRC inhibitor drugs in controlling cancer.
    Keywords:  Cancer; Drugs; Metabolic fuels; Mitochondria; Respiratory chain subunits; Super-complex
    DOI:  https://doi.org/10.1007/s11010-021-04281-4
  23. Natl Sci Rev. 2020 Aug;7(8): 1270-1273
    Metabolic reprogramming in cancer: the bridge that connects intracellular stresses and cancer behaviors.
    Yi Zhou, Huiyan Sun, Ying Xu.
      Extensive changes in cellular metabolisms have been observed in cancer. They are probably induced by the same intracellular stressor, persistent off-balance in intracellular pH across possibly all adult cancers. It is these altered metabolisms that gives rise to a variety of cancerous behaviors such as continuous cell division, metastasis and drug resistance.
    DOI:  https://doi.org/10.1093/nsr/nwaa082
  24. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2021 Oct 28. e1766
    Modulating hypoxia inducible factor-1 by nanomaterials for effective cancer therapy.
    Yun Sun, Zhiguo Zhou, Shiping Yang, Hong Yang.
      Hypoxia, which is induced by abnormal tumor growth when it outstrips its oxygen supply, is a major character of cancer. The reaction of cells against hypoxia is mainly concentrated on the hypoxia-induced transcription factors (HIFs), especially HIF-1, which remain stabilized during hypoxia. Additionally, the oxygen-independent mechanism of regulating HIF-1 acts a vital part in different stages of tumor progression as well as chemo-/radio-/PDT resistance, resulting in poor curative effects and prognosis. In this review, we will outline the up-to-date information about how HIF-1 interferes with tumor metastasis and therapy resistance, followed by a detailed introduction of motivating techniques based on various nanomaterials to interfere with HIF signaling for effective cancer therapy. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
    Keywords:  HIF-1; cancer therapy; nanomaterials
    DOI:  https://doi.org/10.1002/wnan.1766
  25. Mater Sci Eng C Mater Biol Appl. 2021 Nov;pii: S0928-4931(21)00573-7. [Epub ahead of print]130 112433
    Insights into oxidative stress in bone tissue and novel challenges for biomaterials.
    Giorgia Cerqueni, Annachiara Scalzone, Caterina Licini, Piergiorgio Gentile, Monica Mattioli-Belmonte.
      The presence of Reactive Oxygen Species (ROS) in bone can influence resident cells behaviour as well as the extra-cellular matrix composition and the tissue architecture. Aging, in addition to excessive overloads, unbalanced diet, smoking, predisposing genetic factors, lead to an increase of ROS and, if it is accompanied with an inappropriate production of scavengers, promotes the generation of oxidative stress that encourages bone catabolism. Furthermore, bone injuries can be triggered by numerous events such as road and sports accidents or tumour resection. Although bone tissue possesses a well-known repair and regeneration capacity, these mechanisms are inefficient in repairing large size defects and bone grafts are often necessary. ROS play a fundamental role in response after the implant introduction and can influence its success. This review provides insights on the mechanisms of oxidative stress generated by an implant in vivo and suitable ways for its modulation. The local delivery of active molecules, such as polyphenols, enhanced bone biomaterial integration evidencing that the management of the oxidative stress is a target for the effectiveness of an implant. Polyphenols have been widely used in medicine for cardiovascular, neurodegenerative, bone disorders and cancer, thanks to their antioxidant and anti-inflammatory properties. In addition, the perspective of new smart biomaterials and molecular medicine for the oxidative stress modulation in a programmable way, by the use of ROS responsive materials or by the targeting of selective molecular pathways involved in ROS generation, will be analysed and discussed critically.
    Keywords:  Biomaterial; Bone; Molecular medicine; Polyphenol; ROS; Tissue regeneration
    DOI:  https://doi.org/10.1016/j.msec.2021.112433
  26. In Vivo. 2021 Nov-Dec;35(6):35(6): 3193-3201
    [6]-Gingerol Suppresses Oral Cancer Cell Growth by Inducing the Activation of AMPK and Suppressing the AKT/mTOR Signaling Pathway.
    Haibo Zhang, Eungyung Kim, Junkoo Yi, Huang Hai, Hyeonjin Kim, Sijun Park, Su-Geun Lim, Si-Yong Kim, Soyoung Jang, Kirim Kim, Eun-Kyong Kim, Youngkyun Lee, Zaeyoung Ryoo, Myoungok Kim.
       BACKGROUND/AIM: [6]-Gingerol, a compound extracted from ginger, has been studied for its therapeutic potential in various types of cancers. However, its effects on oral cancer remain largely unknown. Here, we aimed to investigate the potential anticancer activity and underlying mechanisms of [6]-gingerol in oral cancer cells.
    MATERIALS AND METHODS: We analyzed the antigrowth effects of [6]-gingerol in oral cancer cell lines by cell proliferation, colony formation, migration, and invasion assays. We detected cell cycle and apoptosis with flow cytometry and further explored the mechanisms of action by immunoblotting.
    RESULTS: [6]-Gingerol significantly inhibited oral cancer cell growth by inducing apoptosis and cell cycle G2/M phase arrest. [6]-Gingerol also inhibited oral cancer cell migration and invasion by up-regulating E-cadherin and down-regulating N-cadherin and vimentin. Moreover, [6]-gingerol induced the activation of AMPK and suppressed the AKT/mTOR signaling pathway in YD10B and Ca9-22 cells.
    CONCLUSION: [6]-Gingerol exerts anticancer activity by activating AMPK and suppressing the AKT/mTOR signaling pathway in oral cancer cells. Our findings highlight the potential of [6]-gingerol as a therapeutic drug for oral cancer treatment.
    Keywords:  AKT; AMPK; [6]-Gingerol; mTOR; oral cancer
    DOI:  https://doi.org/10.21873/invivo.12614
  27. Cancer Treat Rev. 2021 Oct 21. pii: S0305-7372(21)00157-2. [Epub ahead of print]101 102309
    KRAS Inhibitors- yes but what next? Direct targeting of KRAS- vaccines, adoptive T cell therapy and beyond.
    Misako Nagasaka, Bindu Potugari, Alexis Nguyen, Ammar Sukari, Asfar S Azmi, Sai-Hong Ignatius Ou.
      Kirsten rat sarcoma viral oncogene homolog (KRAS) is a proto-oncogene of the RAS-MAPK pathway. KRAS mutations are present in a variety of malignancies including lung, colorectal, and pancreatic cancer. Until the recent approval of sotorasib, a KRAS G12C inhibitor, lack of targeted therapy for KRAS has resulted in poor prognosis of patients with tumors harboring KRAS mutations. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS G12C mutations, G12C only accounts for a fraction of those with KRAS mutations and eventual resistance to G12C inhibitors are unavoidable. This comprehensive review on KRAS inhibitors covers accumulating evidence on not only the G12C inhibitors but also other therapeutic attempts to tackle KRAS including combination therapy as well as direct inhibition with vaccines, adoptive T cell therapy, proteolysis-targeted chimeras (PROTACs) and CRISPR/Cas9.
    Keywords:  Adagrasib; G12C; G12D; KRAS inhibitors; Kirsten rat sarcoma viral oncogene homolog; PROTAC; Sotorasib; Vaccine
    DOI:  https://doi.org/10.1016/j.ctrv.2021.102309
  28. Bioinorg Chem Appl. 2021 ;2021 4763944
    A Novel Fluorescent Dye Invades Mitochondria to Selectively Kill Cancer Stem Cells via Increased ROS Production.
    Bei-Bei Zhang, Jun-Gang Liu, Xian-Yu Bai, Yuan-Jiao Huang, Ning Xu, Tao Ren.
      Development of multiple agents has a significant impact on the cancer diagnosis and therapy. Several fluorescent dyes including near-infrared (NIR) fluorescent agents have been already well studied in the field of photodynamic therapy (PDT). In the present study, we reported a novel fluorescent dye could obviously inhibit cancer cell proliferation with slight toxic effects on the biological organism. Furthermore, it displayed selective staining on cancer cells, particularly on cancer stem cells (CSCs), rather than normal cells. Mechanically, this dye preferred to invading mitochondria of cancer cells and inducing overwhelming reactive oxygen species (ROS) production. The in vivo experiments further demonstrated that this dye could image cancer cells and even CSCs in a short-time intratumor injection manner using a zebrafish model and subsequently inhibit cancer cell proliferation after a relatively long-time drug exposure. Taken together, the future development of this agent will promise to make an essential contribution to the cancer diagnosis and therapeutics.
    DOI:  https://doi.org/10.1155/2021/4763944
  29. Phytother Res. 2021 Oct 28.
    The effects of herbal medicines on cancer therapy-induced oral mucositis: A literature review.
    Saba Safarzadeh, Farinaz Shirban, Mohammad Bagherniya, Thozhukat Sathyapalan, Amirhossein Sahebkar.
      Cancer therapy-induced oral mucositis (OM) is one of the most troublesome morbidities after radio-chemotherapy. Age, nutritional status, tumor type, oral hygiene, and treatment method are the determinants for OM incidence. In addition, oxygen-free radicals can act as a trigger for an inflammatory milieu that causes OM. Based on the debilitating nature of OM, finding a safe and inexpensive agent with anti-inflammatory, anti-microbial, and antioxidative properties can be valuable for this situation. Considering the harmful effects of some chemical agents, herbal medicine has been suggested as a potential alternative owing to unique properties such as safety, availability and low cost. Many studies have illustrated several pharmacological properties of herbal medicines in recent years, such as anti-inflammatory, anti-microbial, and antioxidative activities, which are essential factors in the palliation of cancer therapy-induced OM. This review aimed to evaluate herbal medicines' effects on cancer therapy-induced OM. According to this comprehensive review, it is concluded that medicinal plants and phytochemicals can be used as practical agents in the palliation of cancer therapy-induced OM without any serious side effects.
    Keywords:  cancer; chemotherapy; herbal medicine; oral mucositis; radiotherapy
    DOI:  https://doi.org/10.1002/ptr.7308
  30. Curr Opin Oncol. 2021 Oct 22.
    Kirsten rat sarcoma inhibitors in clinical development against nonsmall cell lung cancer.
    Yunchang Li, Lanlin Hu, Chuan Xu.
       PURPOSE OF REVIEW: The unique structure made Kirsten rat sarcoma (KRAS) 'undruggable' for quite an extended period. The functional mechanism of this small protein is well illustrated. However, there is no precision medicine for nonsmall cell lung cancer (NSCLC) patients burden with KRAS mutation. The attempts made by scientists to make challenge history against KRAS mutation and their druggable targets are worth elucidating.
    RECENT FINDINGS: The appearance of orphan drug AMG510 in the market specifically targeting KRASG12C is a tremendous breakthrough. Several KRAS inhibitors are under development now. More studies focus on combo treatment of KRAS inhibition and immune checkpoint inhibitors (ICIs). Recent preclinical and clinical investigations have been reported that NSCLC patients with KRAS mutation can benefit from ICIs.
    SUMMARY: The current review elucidates the development of KRAS inhibitors from basic research to clinical precision medicines. We retrospectively analyze the development of KRAS mutation targeting drugs and discuss the investigations for future development of KRAS inhibitors.
    DOI:  https://doi.org/10.1097/CCO.0000000000000808
  31. Cancer Epidemiol Biomarkers Prev. 2021 Oct 25. pii: cebp.0837.2021. [Epub ahead of print]
    A Metabolomics Analysis of Circulating Carotenoids and Breast Cancer Risk.
    Cheng Peng, Oana A Zeleznik, Katherine H Shutta, Bernard A Rosner, Peter Kraft, Clary B Clish, Meir J Stampfer, Walter C Willett, Rulla M Tamimi, A Heather Eliassen.
       BACKGROUND: Higher circulating carotenoids are associated with lower breast cancer risk. The underlying biology remains under-explored.
    METHODS: We profiled 293 pre-diagnostic plasma metabolites in a nested case-control study (n=887 cases) within the Nurses' Health Studies. Associations between circulating carotenoids and metabolites were identified using linear-mixed models (FDR less/equal to 0.05), and we further selected metabolites most predictive of carotenoids with LASSO. Metabolic signatures for carotenoids were calculated as weighted sums of LASSO selected metabolites. We further evaluated the metabolic signatures in relation to breast cancer risk using conditional logistic-regression.
    RESULTS: We identified 48-110 metabolites associated with plasma levels of α-carotene, β-carotene, β-cryptoxanthin, estimated-vitamin-A-potential, lutein/zeaxanthin, and lycopene, which included primarily positively associated metabolites implicated in immune regulation (tryptophan), redox balance (plasmalogens, glutamine), epigenetic regulations (acetylated-/methylated-metabolites), and primarily inversely associated metabolites involved in β-oxidation (carnitines). The metabolomic signatures derived for β-carotene (Q4 vs. Q1 relative risk RR=0.74, p-trend=0.02), and estimated-vitamin-A-potential (Q4 vs. Q1 RR=0.74, p-trend=0.02)-measured greater than 10 years before diagnosis-were associated with lower breast cancer risk. Modest attenuations of RR for measured levels of β-carotene and estimated-vitamin-A-potential were seen when we adjusted for their corresponding metabolic signatures.
    CONCLUSIONS: Metabolites involved in immune regulation, redox balance, membrane signaling and β-oxidation were associated with plasma carotenoids. While some metabolites may reflect shared common food sources or compartmental co-localization with carotenoids, others may signal the underlying pathways of carotenoids-associated lowered breast cancer risk.
    IMPACT: Consumption of carotenoid-rich diet is associated with a wide-range of metabolic changes which may help to reduce breast cancer risk.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-21-0837
  32. J Biomed Nanotechnol. 2021 Oct 01. 17(10): 2003-2013
    A Low Dose of Hydrous Icaritin Nano-Formulation with Remarkable Efficacy and Tumor Targeting in Cancer Therapy.
    Jingxin Fu, Yian Wang, Haowen Li, Likang Lu, Hui Ao, Meihua Han, Yifei Guo, Xiangtao Wang.
      Background: The use of chemotherapeutic drugs is restricted in the tumor-therapy because of the severely toxic and side effects among most important factors. The active herbal extracts are always used as a high dose while in the tumortherapy to achieve good anti-tumor effects. Hydrous icaritin has a high activity while there are few existing dosage forms as a result of low solubility in water and poor bioavailability. Results: The prepared hydrous icaritin nanorods (DP-HICT NRs) using mPEG2000-DSPE as a stabilizer, presented a narrow distribution of particle size with of 217 nm and a properly high drug-loading content of approximately 65.3±1.5%. A low dose of hydrous icaritin nano-formulation shows remarkable efficacy in cancer therapy (tumor inhibition rate: 61.36±10.80%) compared with the same dose of Paclitaxel injection (tumor inhibition rate: 66.80±4.43%), which approved as medicaments. Not only that, DP-HICT NRs can escape the clearance of the immune system and enhance targeting ability to the tumor site with only one excipient and such a low dose. Conclusions: This kind of nanoparticles contain a low dose of HICT used mPEG2000-DSPE as a stabilizer, while can achieve good tumor targeting as some active targeting agents and an anti-tumor effect as the PTX injection. There are broad prospects in drug safety, anti-tumor efficacy and even prognosis.
    DOI:  https://doi.org/10.1166/jbn.2021.3176
  33. Mater Sci Eng C Mater Biol Appl. 2021 Nov;pii: S0928-4931(21)00581-6. [Epub ahead of print]130 112441
    Surface engineered nanocarriers for the management of breast cancer.
    Yanamandala Nitheesh, Rajesh Pradhan, Siddhant Hejmady, Rajeev Taliyan, Gautam Singhvi, Amit Alexander, Prashant Kesharwani, Sunil Kumar Dubey.
      Breast cancer is commonly known life-threatening malignancy in women after lung cancer. The standard of care (SOC) treatment for breast cancer primarily includes surgery, radiotherapy, hormonal therapy, and chemotherapy. However, the effectiveness of conventional chemotherapy is restricted by several limitations such as poor targeting, drug resistance, poor drug delivery, and high toxicity. Nanoparticulate drug delivery systems have gained a lot of interest in the scientific community because of its unique features and promising potential in breast cancer diagnosis and treatment. The unique physicochemical and biological properties of the nanoparticulate drug delivery systems promotes the drug accumulation, Pharmacokinetic profile towards the tumor site and thereby, reduces the cytotoxicity towards healthy cells. In addition, to improve tumor-specific drug delivery, researchers have focused on surface engineered nanocarrier system with targeting molecules/ligands that are specific to overexpressed receptors present on cancer cells. In this review, we have summarized the different biological ligands and surface-engineered nanoparticles, enlightening the physicochemical characteristics, toxic effects, and regulatory considerations of nanoparticles involved in treatment of breast cancer.
    Keywords:  Biological ligands; Breast cancer; Chemotherapy; Nanomedicine; Nanoparticle toxicity; Nanoparticles; Radiotherapy; Targeting ligand
    DOI:  https://doi.org/10.1016/j.msec.2021.112441
  34. Biotechnol Appl Biochem. 2021 Oct 26.
    Designing new nanoliposomal formulations and evaluating their effects on myeloid-derived suppressor cells and regulatory T cells in a colon cancer model aiming to develop an efficient delivery system for cancer treatment; an in vitro and in vivo study.
    Ramezan Ali Taheri, Ali Bahramifar, Mahmoud Reza Jaafari, Mahdi Fasihi-Ramandi, Amin Reza Nikpoor, Reza Zolfaghari Emameh, Saeed Mohammadian Haftcheshmeh, Maryam Nik Ebrahimi.
      Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are common immunosuppressive cells in the tumor microenvironment. These cells, through various mechanisms, inhibit antitumor immune responses and impede effective therapies. Therefore, designing an efficient protocol for inducing immune surveillance in tumors is highly recommended. Recently, nanoliposomes have provided broad-spectrum and state-of-the-art vehicles to deliver antigens or immune system compartments in immunotherapies. It has been shown that different lipids in the structure of liposomes and various liposomal formulations can affect immune responses in the tumor microenvironment. This study was aimed to evaluate the effects of four different liposomal formulations on MDSCs and Tregs in C26 tumor-bearing mice. To this end, after preparing liposomes, they were injected into tumor-inoculated mice and analyzed MDSC and Treg population and functions in spleen and tumor tissues. Results showed that DOTAP-containing liposomes reduced MDSC population and activity in the spleen, but not tumor, compared with other groups significantly (P <0.05 and P <0.01, respectively). Moreover, DOTAP-containing liposomes reduced the expression of S100A8 and arginase-1 genes in splenic MDSCs (P < 0.05). In conclusion, we provided evidence that DOTAP-containing liposomes contributed to stimulating immune responses and provided a situation to inhibit immunosuppression in the tumor microenvironment. This article is protected by copyright. All rights reserved.
    Keywords:  Cancer; Immunosuppression; Liposome; MDSC; regulatory T cell
    DOI:  https://doi.org/10.1002/bab.2275
  35. Mol Biol Rep. 2021 Oct 30.
    Synergistic effect of metformin and vemurufenib (PLX4032) as a molecular targeted therapy in anaplastic thyroid cancer: an in vitro study.
    Latha Durai, Soundharya Ravindran, Krishnamurthy Arvind, Devarajan Karunagaran, Ramshankar Vijayalakshmi.
       BACKGROUND: Survival rate of patients affected with anaplastic thyroid carcinoma (ATC) is less than 5% with current treatment. In ATC, BRAFV600E mutation is the major mutation that results in the transformation of normal cells in to an undifferentiated cancer cells via aberrant molecular signaling mechanisms. Although vemurufenib is a selective oral drug for the BRAFV600E mutant kinase with a response rate of nearly 50% in metastatic melanoma, our study has showed resistance to this drug in ATC. Hence the rationale of the study is to explore combinational therapeutic effect to improve the efficacy of vemurafenib along with metformin. Metformin, a diabetic drug is an AMPK activator and has recently proved to be involved in preventing or treating several types of cancer.
    METHODS AND RESULTS: Using iGEMDock software, a protein-ligand interaction was successful between Metformin and TSHR (receptor present in the thyroid follicular cells). Our study demonstrates that combination of vemurufenib with metformin has synergistic anti-cancer effects which was evaluated through MTT assay (cytotoxicity), colony formation assay (antiproliferation evaluation) and suppressed the progression of ATC cells growth by inducing significant apoptosis, proven by Annexin V-FITC assay (Early Apoptosis Detection). Downregulation of ERK signaling, upregulation of AMPK pathway and precision in epithelial-mesenchymal transition (EMT) pathway which were assessed by RT-PCR and Western blot provide the evidence that the combination of drugs involved in the precision of altered molecular signaling Further our results suggest that Metformin act as a demethylating agent in anaplastic thyroid cancer cells by inducing the expression of NIS and TSHR. Our study for the first time explored cAMP signaling in ATC wherein cAMP signaling is downregulated due to decrease in intracellular cAMP level upon metformin treatment.
    CONCLUSION: To conclude, our findings demonstrate novel therapeutic targets and treatment strategies for undifferentiated ATC.
    Keywords:  Anaplastic thyroid cancer; Cyclic AMP signaling; Metformin; Thyroid stimulating hormone receptor; Vemurafenib
    DOI:  https://doi.org/10.1007/s11033-021-06762-7
  36. Pharm Biol. 2021 Dec;59(1): 1480-1489
    Saikosaponin D: review on the antitumour effects, toxicity and pharmacokinetics.
    Piao Zhou, Wei Shi, Xiao-Yan He, Quan-Yu Du, Fei Wang, Jing Guo.
       CONTEXT: Bupleuri Radix, the dried root of Bupleurum chinense DC and Bupleurum scorzonerifolium Willd (Apiaceae), is an important medicinal herb widely used to treat cancers for hundreds of years in Asian countries. As the most antitumour component but also the main toxic component in Bupleuri Radix, saikosaponin D (SSD) has attracted extensive attention. However, no summary studies have been reported on the antitumour effects, toxicity and pharmacokinetics of this potential natural anticancer substance.
    OBJECTIVE: To analyse and summarise the existing findings regarding to the antitumour effects, toxicity and pharmacokinetics of SSD.
    MATERIALS AND METHODS: We collected relevant information published before April 2021 by conducting a search of literature available in various online databases including PubMed, Science Direct, CNKI, Wanfang database and the Chinese Biological Medicine Database. Bupleurum, Bupleuri Radix, saikosaponin, saikosaponin D, tumour, toxicity, and pharmacokinetics were used as the keywords.
    RESULTS: The antitumour effects of SSD were multi-targeted and can be realised through various mechanisms, including inhibition of proliferation, invasion, metastasis and angiogenesis, as well as induction of cell apoptosis, autophagy, and differentiation. The toxicological effects of SSD mainly included hepatotoxicity, neurotoxicity, haemolysis and cardiotoxicity. Pharmacokinetic studies demonstrated that SSD had the potential to alter the pharmacokinetics of some drugs for its influence on CYPs and P-gp, and the oral bioavailability and actual pharmacodynamic substances in vivo of SSD are still controversial.
    CONCLUSIONS: SSD is a potentially effective and relatively safe natural antitumour substance, but more research is needed, especially in vivo antitumour effects and pharmacokinetics of the compound.
    Keywords:  Bupleuri Radix; cytotoxicity; mechanisms; metabolism; phytochemicals; saikosaponins; tumour
    DOI:  https://doi.org/10.1080/13880209.2021.1992448
  37. Elife. 2021 Oct 28. pii: e67476. [Epub ahead of print]10
    6-Phosphogluconate dehydrogenase (6PGD), a key checkpoint in reprogramming of regulatory T cells metabolism and function.
    Saeed Daneshmandi, Teresa Cassel, Richard M Higashi, Teresa W-M Fan, Pankaj Seth.
      Cellular metabolism has key roles in T cells differentiation and function. CD4+ T helper-1 (Th1), Th2, and Th17 subsets are highly glycolytic while regulatory T cells (Tregs) use glucose during expansion but rely on fatty acid oxidation for function. Upon uptake, glucose can enter pentose phosphate pathway (PPP) or be used in glycolysis. Here, we showed that blocking 6-phosphogluconate dehydrogenase (6PGD) in the oxidative PPP resulted in substantial reduction of Tregs suppressive function and shifts toward Th1, Th2, and Th17 phenotypes which led to the development of fetal inflammatory disorder in mice model. These in turn improved anti-tumor responses and worsened the outcomes of colitis model. Metabolically, 6PGD blocked Tregs showed improved glycolysis and enhanced non-oxidative PPP to support nucleotide biosynthesis. These results uncover critical role of 6PGD in modulating Tregs plasticity and function, which qualifies it as a novel metabolic checkpoint for immunotherapy applications.
    Keywords:  6PGD; cell biology; glucose; immunoregulation; metabolism; mouse; pentose phosphate pathway; regulatory T cell
    DOI:  https://doi.org/10.7554/eLife.67476
  38. Mol Ther Oncolytics. 2021 Dec 17. 23 107-123
    Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis.
    Dan Liu, Xing Jin, Guanzhen Yu, Mingsong Wang, Lei Liu, Wenjuan Zhang, Jia Wu, Fengying Wang, Jing Yang, Qin Luo, Lili Cai, Xi Yang, Xisong Ke, Yi Qu, Zhenye Xu, Lijun Jia, Wen-Lian Chen.
      Metabolic reprogramming is a core hallmark of cancer and is key for tumorigenesis and tumor progression. Investigation of metabolic perturbation by anti-cancer compounds would allow a thorough understanding of the underlying mechanisms of these agents and identification of new anti-cancer targets. Here, we demonstrated that the administration of oleanolic acid (OA) rapidly altered cancer metabolism, particularly suppressing the purine salvage pathway (PSP). PSP restoration significantly opposed OA-induced DNA replication and cell proliferation arrest, underscoring the importance of this pathway for the anti-cancer activity of OA. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and 5'-nucleotidase (5'-NT), two metabolic enzymes essential for PSP activity, were promptly degraded by OA via the lysosome pathway. Mechanistically, OA selectively targeted superoxide dismutase 1 (SOD1) and yielded reactive oxygen species (ROS) to activate the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/macroautophagy pathway, thus eliciting lysosomal degradation of HGPRT and 5'-NT. Furthermore, we found that the PSP was overactivated in human lung and breast cancers, with a negative correlation with patient survival. The results of this study elucidated a new anti-cancer mechanism of OA by restraining the PSP via the SOD1/ROS/AMPK/mTORC1/macroautophagy/lysosomal pathway. We also identified the PSP as a new target for cancer treatment and highlighted OA as a potential therapeutic agent for cancers with high PSP activity.
    Keywords:  5′-nucleotidase; hypoxanthine-guanine phosphoribosyltransferase; lysosomal degradation; macroautophagy; oleanolic acid; purine salvage pathway; superoxide dismutase 1
    DOI:  https://doi.org/10.1016/j.omto.2021.08.013
  39. Front Pharmacol. 2021 ;12 720777
    Targeted Lipid Nanoparticles Encapsulating Dihydroartemisinin and Chloroquine Phosphate for Suppressing the Proliferation and Liver Metastasis of Colorectal Cancer.
    Jianqing Peng, Qin Wang, Jia Zhou, Shuli Zhao, Pan Di, Yan Chen, Ling Tao, Qianming Du, Xiangchun Shen, Yi Chen.
      Antimalarial drugs Dihydroartemisinin (DHA) and chloroquine phosphate (CQ) exhibit evident anti-cancer activity, particularly as combination therapy. DHA and CQ combination therapy has been proved to exhibit higher cytotoxic effect in tumor cells and lower toxicity to normal cells than combination of artemisinin derivatives (ARTs) and anticancer chemotherapy drugs. However, different physiochemical properties of DHA and CQ, leading to distinctive in vivo outcomes, considerably limited their synergistic effect in cancer treatment. Herein, we developed a lipid nanoparticle (LNP) for co-delivery of DHA and CQ to inhibit proliferation and metastasis of colorectal cancer. Considering the beneficial effects of acid/reactive oxide species (ROS)-sensitive phospholipids and targeting ligands for colorectal cancer cells, an RGD peptide-modified pH/ROS dual-sensitive LNP loaded with DHA and CQ (RLNP/DC) was prepared. It exhibited optimal cytotoxicity and suppression of invasion and metastasis in HCT116 cells in vitro, attributable to irreversible upregulation of intracellular ROS levels, downregulation of VEGF expression, and upregulation of paxillin expression. A mouse model of orthotopic metastasis of colorectal cancer was established to evaluate anti-proliferation and anti-metastasis effects of RLNP/DC in vivo. Thus, an optimized nanoplatform for DHA and CQ combination therapy was developed in this study that offered potential antitumor efficacy against colorectal cancer.
    Keywords:  ROS; chloroquine phosphate; colorectal cancer; dihydroartemisinin; lipid nanoparticles; liver metastasis
    DOI:  https://doi.org/10.3389/fphar.2021.720777
  40. Lipids Health Dis. 2021 Oct 25. 20(1): 143
    High density lipoproteins and oxidative stress in breast cancer.
    Gabriele Mazzuferi, Tiziana Bacchetti, Md Obaidul Islam, Gianna Ferretti.
      Breast cancer is one of the main leading causes of women death. In recent years, attention has been focused on the role of lipoproteins, alterations of cholesterol metabolism and oxidative stress in the molecular mechanism of breast cancer. A role for high density lipoproteins (HDL) has been proposed, in fact, in addition to the role of reverse cholesterol transport (RCT), HDL exert antioxidant and anti-inflammatory properties, modulate intracellular cholesterol homeostasis, signal transduction and proliferation. Low levels of HDL-Cholesterol (HDL-C) have been demonstrated in patients affected by breast cancer and it has been suggested that low levels of HDL-C could represent a risk factor of breast cancer. Contrasting results have been observed by other authors. Recent studies have demonstrated alterations of the activity of some enzymes associated to HDL surface such as Paraoxonase (PON1), Lecithin-Cholesterol Acyltransferase (LCAT) and Phospholipase A2 (PLA2). Higher levels of markers of lipid peroxidation in plasma or serum of patients have also been observed and suggest dysfunctional HDL in breast cancer patients. The review summarizes results on levels of markers of oxidative stress of plasma lipids and on alterations of enzymes associated to HDL in patients affected by breast cancer. The effects of normal and dysfunctional HDL on human breast cancer cells and molecular mechanisms potentially involved will be also reviewed.
    Keywords:  Breast cancer; Cholesterol; High-density lipoprotein; Lipoprotein; Oxidative stress
    DOI:  https://doi.org/10.1186/s12944-021-01562-1
  41. Biomed Res Int. 2021 ;2021 8972074
    Effects of Curcumin on Aging: Molecular Mechanisms and Experimental Evidence.
    Afsane Bahrami, Fabrizio Montecucco, Federico Carbone, Amirhossein Sahebkar.
      Aging is characterized by a progressive inability to maintain homeostasis, self-repair, renewal, performance, and fitness of different tissues throughout the lifespan. Senescence is occurring following enormous intracellular or extracellular stress stimuli. Cellular senescence serves as an antiproliferative process that causes permanent cell cycle arrest and restricts the lifespan. Senescent cells are characterized by terminal cell cycle arrest, enlarged lysosome, and DNA double-strand breaks as well as lipofuscin granularity, senescence-associated heterochromatin foci, and activation of DNA damage response. Curcumin, a hydrophobic polyphenol, is a bioactive chemical constituent of the rhizomes of Curcuma longa Linn (turmeric), which has been extensively used for the alleviation of various human disorders. In addition to its pleiotropic effects, curcumin has been suggested to have antiaging features. In this review, we summarized the therapeutic potential of curcumin in the prevention and delaying of the aging process.
    DOI:  https://doi.org/10.1155/2021/8972074
  42. Drug Deliv Transl Res. 2021 Oct 30.
    Harnessing nanomedicine for enhanced immunotherapy for breast cancer brain metastases.
    Christine P Carney, Nikhil Pandey, Anshika Kapur, Graeme F Woodworth, Jeffrey A Winkles, Anthony J Kim.
      Brain metastases (BMs) are the most common type of brain tumor, and the incidence among breast cancer (BC) patients has been steadily increasing over the past two decades. Indeed, ~ 30% of all patients with metastatic BC will develop BMs, and due to few effective treatments, many will succumb to the disease within a year. Historically, patients with BMs have been largely excluded from clinical trials investigating systemic therapies including immunotherapies (ITs) due to limited brain penetration of systemically administered drugs combined with previous assumptions that BMs are poorly immunogenic. It is now understood that the central nervous system (CNS) is an immunologically distinct site and there is increasing evidence that enhancing immune responses to BCBMs will improve patient outcomes and the efficacy of current treatment regimens. Progress in IT for BCBMs, however, has been slow due to several intrinsic limitations to drug delivery within the brain, substantial safety concerns, and few known targets for BCBM IT. Emerging studies demonstrate that nanomedicine may be a powerful approach to overcome such limitations, and has the potential to greatly improve IT strategies for BMs specifically. This review summarizes the evidence for IT as an effective strategy for BCBM treatment and focuses on the nanotherapeutic strategies currently being explored for BCBMs including targeting the blood-brain/tumor barrier (BBB/BTB), tumor cells, and tumor-supporting immune cells for concentrated drug release within BCBMs, as well as use of nanoparticles (NPs) for delivering immunomodulatory agents, for inducing immunogenic cell death, or for potentiating anti-tumor T cell responses.
    Keywords:  Blood–brain barrier; Breast cancer brain metastases; Immune checkpoint inhibitors; Immunotherapy; Nanoimmunotherapies; Nanoparticles; Nanotechnology
    DOI:  https://doi.org/10.1007/s13346-021-01039-9
  43. Phytother Res. 2021 Oct 25.
    Curcumin and its derivatives in cancer therapy: Potentiating antitumor activity of cisplatin and reducing side effects.
    Asal Jalal Abadi, Sepideh Mirzaei, Mahmood Khaksary Mahabady, Farid Hashemi, Amirhossein Zabolian, Fardin Hashemi, Pourya Raee, Shahin Aghamiri, Milad Ashrafizadeh, Amir Reza Aref, Michael R Hamblin, Kiavash Hushmandi, Ali Zarrabi, Gautam Sethi.
      Curcumin is a phytochemical isolated from Curcuma longa with potent tumor-suppressor activity, which has shown significant efficacy in pre-clinical and clinical studies. Curcumin stimulates cell death, triggers cycle arrest, and suppresses oncogenic pathways, thereby suppressing cancer progression. Cisplatin (CP) stimulates DNA damage and apoptosis in cancer chemotherapy. However, CP has adverse effects on several organs of the body, and drug resistance is frequently observed. The purpose of the present review is to show the function of curcumin in decreasing CP's adverse impacts and improving its antitumor activity. Curcumin administration reduces ROS levels to prevent apoptosis in normal cells. Furthermore, curcumin can inhibit inflammation via down-regulation of NF-κB to maintain the normal function of organs. Curcumin and its nanoformulations can reduce the hepatoxicity, neurotoxicity, renal toxicity, ototoxicity, and cardiotoxicity caused by CP. Notably, curcumin potentiates CP cytotoxicity via mediating cell death and cycle arrest. Besides, curcumin suppresses the STAT3 and NF-ĸB as tumor-promoting pathways, to enhance CP sensitivity and prevent drug resistance. The targeted delivery of curcumin and CP to tumor cells can be mediated nanostructures. In addition, curcumin derivatives are also able to reduce CP-mediated side effects, and increase CP cytotoxicity against various cancer types.
    Keywords:  apoptosis; chemoresistance; cisplatin; combination cancer chemotherapy; curcumin; side effects
    DOI:  https://doi.org/10.1002/ptr.7305
  44. PLoS Genet. 2021 Oct;17(10): e1009871
    Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.
    Jiwon Jeong, Jongbin Lee, Ji-Hyung Kim, Chunghun Lim.
      Kohlschütter-Tönz syndrome (KTS) manifests as neurological dysfunctions, including early-onset seizures. Mutations in the citrate transporter SLC13A5 are associated with KTS, yet their underlying mechanisms remain elusive. Here, we report that a Drosophila SLC13A5 homolog, I'm not dead yet (Indy), constitutes a neurometabolic pathway that suppresses seizure. Loss of Indy function in glutamatergic neurons caused "bang-induced" seizure-like behaviors. In fact, glutamate biosynthesis from the citric acid cycle was limiting in Indy mutants for seizure-suppressing glutamate transmission. Oral administration of the rate-limiting α-ketoglutarate in the metabolic pathway rescued low glutamate levels in Indy mutants and ameliorated their seizure-like behaviors. This metabolic control of the seizure susceptibility was mapped to a pair of glutamatergic neurons, reversible by optogenetic controls of their activity, and further relayed onto fan-shaped body neurons via the ionotropic glutamate receptors. Accordingly, our findings reveal a micro-circuit that links neural metabolism to seizure, providing important clues to KTS-associated neurodevelopmental deficits.
    DOI:  https://doi.org/10.1371/journal.pgen.1009871
  45. ACS Appl Mater Interfaces. 2021 Oct 29.
    Intravesical Mucoadhesive Hydrogel Induces Chemoresistant Bladder Cancer Ferroptosis through Delivering Iron Oxide Nanoparticles in a Three-Tier Strategy.
    Ao Qi, Chunyang Wang, Shaobin Ni, Yuyang Meng, Tengda Wang, Ziqi Yue, Kaiqi Yang, Yuqian Li, Zhe Cheng, Pengyu Guo, Cheng Zhang.
      Bladder cancer (BCa) is the most costly solid tumor owing to its high recurrence. Relapsed cancer is known to acquire chemoresistant features after standard intravesical chemotherapy. This cancer state is vulnerable to ferroptosis, which occurs when lipid peroxides generated by iron metabolism accumulate to lethal levels. Increasing the labile iron pool (LIP) by iron oxide nanoparticles (IONPs) promises to inhibit chemoresistant BCa (CRBCa), but systemically administered IONPs do not sufficiently accumulate at the tumor site. Therefore, their efficacy is weakened. Here, we present a three-tier delivery strategy through a mucoadhesive hydrogel platform conveying hyaluronic acid-coated IONPs (IONP-HA). When instilled, the hydrogel platform first adhered to the interface of the tumor surface, sustainably releasing IONP-HA. Subsequently, the tumor stiffness and interstitial fluid pressure were reduced by photothermal therapy, promoting IONP-HA diffusion into the deep cancer tissue. As CRBCa expressed high levels of CD44, the last delivery tier was achieved through antibody-mediated endocytosis to increase the LIP, ultimately inducing ferroptosis. This three-tiered strategy delivered the IONPs stepwise from anatomical to cellular levels and increased the iron content by up to 50-fold from that of systematic administration, which presents a potential regimen for CRBCa.
    Keywords:  chemoresistant bladder cancer; ferroptosis; intravesical therapy; iron oxide nanoparticles; three-tier delivery strategy
    DOI:  https://doi.org/10.1021/acsami.1c14944
  46. J Photochem Photobiol B. 2021 Oct 11. pii: S1011-1344(21)00212-8. [Epub ahead of print]225 112333
    Titaniumdioxide mediated sonophotodynamic therapy against prostate cancer.
    Mehran Aksel, Ömer Kesmez, Adem Yavaş, Mehmet Dinçer Bilgin.
      In this study, we aimed to investigate of antitumor efficiency of titanium dioxide mediated photodynamic (PDT), sonodynamic (SDT), and sonophotodynamic (SPDT) therapies with a possible mechanism against the PC3 prostate cancer cell line. SPDT is a new approach to cancer treatment that combines sonodynamic and photodynamic therapies. On the other hand, Titanium dioxide (TiO2) has been used in many applications in pharmaceutical products and cosmetics, industrial products, and medicines. TiO2 nanoparticles will be useful for the treatment of cancer with PDT and SDT as the sensitizers in medicine. In this study, TiO2 nanoparticles were used for an in vitro comparison between the PDT, SDT, SPDT damages on prostate cancer cell lines. For this purpose, the cells were incubated in RPMI-1640 media with various concentrations of TiO2 and subjected to 0,5 W/cm2 ultrasound and/or 0,5 mJ/cm2 light irradiation. The prostate cancer cells were irradiated with light and exposed with the US and both for SPDT in the presence and/or absence of TiO2. Cell viability was measured using by MTT test after treatments. Investigate to apoptosis mechanism, Propidium iodide and Hoechst 33342 staining were used and the results showed that apoptotic cell bodies were increased compared with other groups. According to western blot analyses, caspase-3, caspase-8, PARP, and Bax levels were decreased after treatments, whereas the expression levels of caspase-9 were increased. Biochemical results showed that after treatments MDA levels were increased while SOD, CAT, GSH levels were decreased. In conclusion, TiO2-mediated SPDT may provide a promising approach for prostate cancer therapy and might play a key role in the apoptotic mechanism of these treatments.
    Keywords:  PC3; Photodynamic therapy; Prostate cancer; Sonodynamic therapy; Sonophotodynamic therapy; Titanium dioxide
    DOI:  https://doi.org/10.1016/j.jphotobiol.2021.112333
  47. Biol Trace Elem Res. 2021 Oct 27.
    Induction of Iron Stress in Hepatocellular Carcinoma Cell Lines by Siderophore of Aspergillus nidulans Towards Promising Anticancer Effect.
    Azmi Khan, Pratika Singh, Archana Chaudhary, Rizwanul Haque, Prashant Singh, Arun Kumar Mishra, Abhijit Sarkar, Amrita Srivastava.
      Hepatocellular carcinoma is among the leading causes of cancer-related deaths worldwide and needs efficient and feasible approach of treatment. Present study focuses on exploring the anticancer activity of a secondary metabolite called siderophore of Aspergillus nidulans against hepatocellular carcinoma cell line HepG2. These small peptides are produced by microorganisms including fungi for scavenging iron from its surroundings. Fungi including Aspergillus spp. are known to produce siderophores under iron-limited conditions. Siderophores have high affinity towards iron and are classified into various types. In the present study, siderophore isolated and purified from fungal cultures was confirmed to be of hydroxamate type by chrome azurol sulfonate and Atkin's assay. HPLC analysis confirmed purity while LC-ESI-MS revealed that the siderophore is triacetyl fusigen. Cancerous cells, HepG2, grown under siderophore treatment showed inhibition in growth and proliferation in a dose- and time-dependent manner. Reduction in viability and metabolic activity was evident upon treatment as seen in trypan blue, MTT and WST assay. Fluorescent staining using PI and DAPI confirmed the same while DCFDA staining revealed increased reactive oxygen species production which might have led to cell death and deterioration. Such increase in ROS has been correlated with iron accumulation by assessing intracellular iron level through ICP-MS. To assess the effect of siderophore treatment on normal cells, WRL-68, same assays were carried out but the effect was mostly non-significant up to 48 h. Thus, present work suggests that an optimum dose of siderophore purified from A. nidulans culture might prove a useful anticancer agent.
    Keywords:  Anticancer; Aspergillus nidulans; Hepatocellular carcinoma; Iron; Siderophore
    DOI:  https://doi.org/10.1007/s12011-021-02980-z
  48. Cell Rep. 2021 Oct 26. pii: S2211-1247(21)01350-4. [Epub ahead of print]37(4): 109880
    ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.
    Jillian Hattaway Luttman, Jacob P Hoj, Kevin H Lin, Jiaxing Lin, Jing Jin Gu, Clay Rouse, Amanda G Nichols, Nancie J MacIver, Kris C Wood, Ann Marie Pendergast.
      Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced ABL signaling is associated with a poor prognosis in lung adenocarcinoma patients. Here we show that ABL kinase allosteric inhibitors impair mitochondrial integrity and decrease oxidative phosphorylation. To identify metabolic vulnerabilities that enhance this phenotype, we utilized a CRISPR/Cas9 loss-of-function screen and identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and target of statin therapies, as a top-scoring sensitizer to ABL inhibition. Combination treatment with ABL allosteric inhibitors and statins decreases metastatic lung cancer cell survival in vitro in a synergistic manner. Notably, combination therapy in mouse models of lung cancer brain metastasis and therapy resistance impairs metastatic colonization with a concomitant increase in animal survival. Thus, metabolic combination therapy might be effective to decrease metastatic outgrowth, leading to increased survival for lung cancer patients with advanced disease.
    Keywords:  ABL kinases; HMGCR; brain metastasis; lung adenocarcinoma; statins; therapy resistance
    DOI:  https://doi.org/10.1016/j.celrep.2021.109880
  49. Front Cell Dev Biol. 2021 ;9 731393
    The Relationship Between Mesenchymal Stem Cells and Tumor Dormancy.
    Linxian Zhao, Kai Zhang, Hongyu He, Yongping Yang, Wei Li, Tongjun Liu, Jiannan Li.
      Tumor dormancy, a state of tumor, is clinically undetectable and the outgrowth of dormant tumor cells into overt metastases is responsible for cancer-associated deaths. However, the dormancy-related molecular mechanism has not been clearly described. Some researchers have proposed that cancer stem cells (CSCs) and disseminated tumor cells (DTCs) can be seen as progenitor cells of tumor dormancy, both of which can remain dormant in a non-permissive soil/niche. Nowadays, research interest in the cancer biology field is skyrocketing as mesenchymal stem cells (MSCs) are capable of regulating tumor dormancy, which will provide a unique therapeutic window to cure cancer. Although the influence of MSCs on tumor dormancy has been investigated in previous studies, there is no thorough review on the relationship between MSCs and tumor dormancy. In this paper, the root of tumor dormancy is analyzed and dormancy-related molecular mechanisms are summarized. With an emphasis on the role of the MSCs during tumor dormancy, new therapeutic strategies to prevent metastatic disease are proposed, whose clinical application potentials are discussed, and some challenges and prospects of the studies of tumor dormancy are also described.
    Keywords:  anti-tumor treatment; cancer stem cells (CSCs); disseminated tumor cells (DTCs); mesenchymal stem cells (MSCs); tumor dormancy
    DOI:  https://doi.org/10.3389/fcell.2021.731393
  50. Photodiagnosis Photodyn Ther. 2021 Oct 20. pii: S1572-1000(21)00406-3. [Epub ahead of print] 102585
    Targeting glioblastoma stem cells: the first steps of photodynamic therapy.
    Lechner Rodríguez Aguilar, María Laura Vilchez, Laura N Milla Sanabria.
      Glioblastoma is one of the most malignant type of brain cancer. Numerous evidence suggests that within gliomas there is a small subpopulation of cells with the capacity for self-renewal, called glioma stem cells. These cells could be responsible for tumorigenesis, chemo and radioresistance, and finally for the recurrence of the tumor. Fluorescence-guided resection of photosensitizers have improved the results of treatment against this disease, prolonging the survival of patients by a few months. Also, clinical trials have reported improvements in the therapeutic response after photodynamic therapy. Thus far, there are few published works that show the response of glioblastoma stem-like cells to photodynamic therapy. Here, we present a brief review exclusively commenting on the therapeutic approaches to eliminate glioblastoma cancer stem cells and on the research publications about this topic of glioblastoma stem cells in relation to photodynamic therapy. It is our hope that this review will be useful to provide an overview about what is known to date on the topic and to promote the generation of new ideas for the eradication of glioblastoma stem cells by photodynamic treatment.
    Keywords:  Cancer stem cells; Glioblastoma; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.pdpdt.2021.102585
  51. Biomaterials. 2021 Oct 22. pii: S0142-9612(21)00581-0. [Epub ahead of print]279 121224
    Multistage targeted "Photoactive neutrophil" for enhancing synergistic photo-chemotherapy.
    Yurui Xu, Xiaomin Zhang, Getian Hu, Xiaotong Wu, Yuanyuan Nie, Heming Wu, Desheng Kong, Xinghai Ning.
      Cell-based drug delivery system holds a great promise in anticancer treatment, due to its potential of maximizing therapeutic efficacy while minimizing adverse effects. However, current cell system can only deliver drugs in tumor lesions, but lack an ability to target subcellular locus of therapeutic actions, thereby compromising anticancer efficacy. Herein, we bioengineered living neutrophils as a novel type of "Photoactive neutrophil" (PAN) with capabilities of self-amplified multistage targeting and inflammation response for enhancing mitochondria-specific photo-chemotherapy. PAN encapsulated multifunctional nanocomplex (RA/Ce6) of RGD-apoptotic peptide conjugate (RA) decorated liposomal photosensitizer Ce6, and could overcome tumor barriers to selectively release RA/Ce6 within tumor. Consequently, RA/Ce6 actively entered cancer cells and accumulated in mitochondria to trigger combined photodynamic therapy (PDT) and RA-induced mitochondrial membrane disruption, resulting in enhanced therapeutic effects. Importantly, PAN exhibited inflammation amplified tumor targeting after PDT, and initiated combined photo-chemotherapy to suppress tumor growth without adverse effects, leading to prolonged mice survival. Therefore, PAN represents the first multistage targeted cell therapy, and brings new insights into cancer treatment.
    Keywords:  Bioengineered neutrophil; Combined treatment; Mitochondrial specificity; Multistage targeting; Photo-chemotherapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2021.121224
  52. J Colloid Interface Sci. 2021 Sep 29. pii: S0021-9797(21)01625-8. [Epub ahead of print]606(Pt 2): 1950-1965
    Reactive oxygen species / photothermal therapy dual-triggered biomimetic gold nanocages nanoplatform for combination cancer therapy via ferroptosis and tumor-associated macrophage repolarization mechanism.
    Yawen Wei, Zhihua Wang, Jie Yang, Rui Xu, Huizi Deng, Siyu Ma, Tianxu Fang, Jun Zhang, Qi Shen.
      With the continuous development of cancer nanotechnology, an important trend in the research is to combine the broad application prospects of functional nanomaterials with recent biological discoveries and technological advances. Herein, a cancer cell membrane-camouflaged gold nanocage loading doxorubicin (DOX) and l-buthionine sulfoximine (BSO) (denoted as m@Au-D/B NCs) was constructed as an innovative nanoplatform to confer promising cancer combination therapy by evoking effective ferroptosis and immune responses. Briefly, the loading of BSO and DOX could induce ferroptosis through simultaneous effective glutathione (GSH) consumption and reactive oxygen species (ROS) accumulation. Gold nanocages (AuNCs) with distinct anti-tumor application performance was utilized as ideal nanocarrier for drug loading, evoking photothermal effects and photochemical catalysis to generate more ROS under near-infrared (NIR) irradiation. Moreover, m@Au-D/B NCs-mediated photothermal therapy (PTT) combined with ROS production could repolarize the tumor-associated macrophages (TAMs) from pro-tumor (M2) phenotype to anti-tumor (M1) phenotype, thus improving tumor-suppressive immune environment and then promoting the activation of effector cells and release of pro-inflammatory cytokines, in which the antitumor responses were evoked robustly in a methodical approach. The anti-tumor effects in vivo implied that m@Au-D/B NCs could significantly inhibit tumor growth without severe toxicity. Hence, this homotypic targeting nanosystem could offer an auspicious anticancer access by triggering combination cancer therapy via ferroptosis and tumor-associated macrophage repolarization mechanism.
    Keywords:  ferroptosis; homotypic targeting; photothermal therapy (PTT); tumor-associated macrophage repolarization (TAMs)
    DOI:  https://doi.org/10.1016/j.jcis.2021.09.160
  53. J Biomed Nanotechnol. 2021 Sep 01. 17(9): 1806-1811
    Evaluation of Apigenin Inhibiting Lactate Dehydrogenase Activity Based on CdTe Quantum Dots Fluorescence.
    Xiangling Ren, Meijia Liu, Ming Tang, Longfei Tan, Changhui Fu, Qiong Wu, Hongbo Li, Yi Chen, Lufeng Chen, Xianwei Meng.
      Lactate dehydrogenase (LDH) is one of key enzymes in glucose metabolism pathway, which plays a critical role in cell metabolism. Inhibition of LDH can inhibit glycolysis process, thereby inhibiting the occurrence and development of tumor cells. Two kinds of LDH inhibitors, apigenin and emodin, were obtained by testing the IC50 of several natural products in LDH enzyme reaction. The IC50 of apigenin was about 1/3 of LDH inhibitor sodium oxalate. A new method to evaluate the performance of LDH inhibitors based on CdTe QDs was established at the same time, which provides a new idea for research on LDH enzyme inhibitors.
    DOI:  https://doi.org/10.1166/jbn.2021.3158
  54. Front Bioeng Biotechnol. 2021 ;9 755727
    Polymeric Nanoparticles for Mitochondria Targeting Mediated Robust Cancer Therapy.
    Yajing Sun, Qingshan Yang, Xue Xia, Xiaozhe Li, Weimin Ruan, Meng Zheng, Yan Zou, Bingyang Shi.
      Despite all sorts of innovations in medical researches over the past decades, cancer remains a major threat to human health. Mitochondria are essential organelles in eukaryotic cells, and their dysfunctions contribute to numerous diseases including cancers. Mitochondria-targeted cancer therapy, which specifically delivers drugs into the mitochondria, is a promising strategy for enhancing anticancer treatment efficiency. However, owing to their special double-layered membrane system and highly negative potentials, mitochondria remain a challenging target for therapeutic agents to reach and access. Polymeric nanoparticles exceed in cancer therapy ascribed to their unique features including ideal biocompatibility, readily design and synthesis, as well as flexible ligand decoration. Significant efforts have been put forward to develop mitochondria-targeted polymeric nanoparticles. In this review, we focused on the smart design of polymeric nanosystems for mitochondria targeting and summarized the current applications in improving cancer therapy.
    Keywords:  cancer therapy; drug delivery; mitochondria; nanoparticles; polymers
    DOI:  https://doi.org/10.3389/fbioe.2021.755727
  55. Nanoscale. 2021 Oct 26.
    Mitochondria targeted composite enzyme nanogels for synergistic starvation and photodynamic therapy.
    Zheng Luo, Xiaotong Fan, Ying Chen, Xiyu Lai, Zibiao Li, Yun-Long Wu, Chaobin He.
      Mitochondria, as the energy factory of cells, often maintain a high redox state, and play an important role in cell growth, development and apoptosis. Therefore, the destruction of mitochondrial redox homeostasis has now become an important direction for cancer treatment. Here, we design a mitochondrial targeting composite enzyme nanogel bioreactor with a circulating supply of O2 and H2O2, which is composed of mitochondrial target triphenylphosphine (TPP), natural enzymes glucose oxidase (GOX) and catalase (CAT), and protoporphyrin IX (PpIX). The nanogel can effectively increase the stability of the natural enzymes, and its size of about 65 nm makes them close in space, which greatly improves their cascade catalytic efficiency and safety. Under the action of target TPP, the system can accurately target the mitochondria of breast cancer 4T1 cells, catalyze intracellular glucose to generate H2O2 through GOX, and H2O2 is further used as a catalytic substrate for CAT to generate O2. This O2 can not only further improve the catalytic efficiency of GOX, but also provide raw materials for the production of ROS in PDT, which can effectively destroy the mitochondria of cancer cells, thereby causing tumor cell apoptosis. Compared with GOX alone, thanks to the close spatial position of the composite enzymes, the composite enzyme nanogel can quickly consume the highly oxidative H2O2 produced by GOX, thereby showing better safety to normal cells. In addition, the composite enzyme group under light showed excellent antitumor effects by combining starvation therapy and PDT under adequate oxygen supply in animal experiments. In general, this composite enzyme nanogel system with good stability, high safety and excellent cascade catalytic efficiency opens a new way for the development of safe and efficient cancer therapeutics.
    DOI:  https://doi.org/10.1039/d1nr06214j
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