Metformin as a Radiation Modifier; Implications to Normal Tissue Protection and Tumor Sensitization.
TL;DR: The interesting properties of metformin such as radioprotection, radiomitigation and radiosensitization could make it an interesting adjuvant for clinical radiotherapy, as well as an interesting candidate for mitigation of radiation injury after a radiation disaster.
Abstract: BACKGROUND: Nowadays, ionizing radiation is used for several applications in medicine, industry, agriculture, and nuclear power generation. Besides the beneficial roles of ionizing radiation, there are some concerns about accidental exposure to radioactive sources. The threat posed by its use in terrorism is of global concern. Furthermore, there are several side effects to normal organs for patients who had undergone radiation treatment for cancer. Hence, the modulation of radiation response in normal tissues was one of the most important aims of radiobiology. Although, so far, several agents have been investigated for protection and mitigation of radiation injury. Agents such as amifostine may lead to severe toxicity, while others may interfere with radiation therapy outcomes as a result of tumor protection. Metformin is a natural agent that is well known as an antidiabetic drug. It has shown some antioxidant effects and enhances DNA repair capacity, thereby ameliorating cell death following exposure to radiation. Moreover, through targeting endogenous ROS production within cells, it can mitigate radiation injury. This could potentially make it an effective radiation countermeasure. In contrast to other radioprotectors, metformin has shown modulatory effects through induction of several genes such as AMPK, which suppresses reduction/ oxidation (redox) reactions, protects cells from accumulation of unrepaired DNA, and attenuates initiation of inflammation as well as fibrotic pathways. Interestingly, these properties of metformin can sensitize cancer cells to radiotherapy. CONCLUSION: In this article, we aimed to review the interesting properties of metformin such as radioprotection, radiomitigation and radiosensitization, which could make it an interesting adjuvant for clinical radiotherapy, as well as an interesting candidate for mitigation of radiation injury after a radiation disaster. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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TL;DR: In this article, the tumor cells isolated from the primary tumor exploit several mechanisms to maintain their survival including rewiring metabolic demands to use sources available within the new environments, avoiding anoikis cell death when cells are detached from extracellular matrix (ECM), adopting flow mechanic by acquiring platelet shielding and immunosuppression by negating the activity of suppressor immune cells, such as natural killer (NK) cells.
Abstract: Metastasis is the most complex and deadly event. Tumor-stromal interface is a place where invasion of tumor cells in the form of single-cell or collective migration occurs, with the latter being less common but more efficient. Initiation of metastasis relies on the tumor cell cross-talking with stromal cells and taking an epithelial-mesenchymal transition (EMT) in single cells, and a hybrid EMT in collective migratory cells. Stromal cross-talking along with an abnormal leaky vasculature facilitate intravasation of tumor cells, here the cells are called circulating tumor cells (CTCs). Tumor cells isolated from the primary tumor exploit several mechanisms to maintain their survival including rewiring metabolic demands to use sources available within the new environments, avoiding anoikis cell death when cells are detached from extracellular matrix (ECM), adopting flow mechanic by acquiring platelet shielding and immunosuppression by negating the activity of suppressor immune cells, such as natural killer (NK) cells. CTCs will adhere to the interstituim of the secondary organ/s, within which the newly arrived disseminative tumor cells (DTCs) undergo either dormancy or proliferation. Metastatic outgrowth is under the influence of several factors, such as the activity of macrophages, impaired autophagy and secondary site inflammatory events. Metastasis can be targeted by multiple ways, such as repressing the promoters of pre-metastatic niche (PMN) formation, suppressing environmental contributors, such as hypoxia, oxidative and metabolic stressors, and targeting signaling and cell types that take major contribution to the whole process. These strategies can be used in adjuvant with other therapeutics, such as immunotherapy.
102 citations
TL;DR: Molecules under development with the aim of reaching clinical practice and other nonclinical applications are discussed and differentiates radioprotectors and radiomitigators (minimize toxicity even after radiation has been delivered).
Abstract: The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and radiomitigators remain an unsolved problem. Because ionizing radiation-induced cellular damage is primarily attributed to free radicals, radical scavengers are promising as potential radioprotectors. Early development of such agents focused on thiol synthetic compounds, e.g., amifostine (2-(3-aminopropylamino) ethylsulfanylphosphonic acid), approved as a radioprotector by the Food and Drug Administration (FDA, USA) but for limited clinical indications and not for nonclinical uses. To date, no new chemical entity has been approved by the FDA as a radiation countermeasure for acute radiation syndrome (ARS). All FDA-approved radiation countermeasures (filgrastim, a recombinant DNA form of the naturally occurring granulocyte colony-stimulating factor, G-CSF; pegfilgrastim, a PEGylated form of the recombinant human G-CSF; sargramostim, a recombinant granulocyte macrophage colony-stimulating factor, GM-CSF) are classified as radiomitigators. No radioprotector that can be administered prior to exposure has been approved for ARS. This differentiates radioprotectors (reduce direct damage caused by radiation) and radiomitigators (minimize toxicity even after radiation has been delivered). Molecules under development with the aim of reaching clinical practice and other nonclinical applications are discussed. Assays to evaluate the biological effects of ionizing radiations are also analyzed.
67 citations
TL;DR: Targeting ROS/NF-kappaB signalling pathway by resveratrol may have a significant effect on the improvement of hepatic injury induced by phosphine, suggesting it may be a possible candidate for the treatment of phosphine-poisoning.
61 citations
09 Dec 2019
TL;DR: The biology of metformin and its molecular mechanism of action is discussed, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of meetformin as a potential anti-cancer/anti-Tumor agent in breast cancer therapy are discussed, and the future prospects and directions for a better understanding and re-purposing of met formin as an anti- cancer drug in the treatment of breast cancer are outlined.
Abstract: Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer.
52 citations
TL;DR: In this article, the authors investigated how desmoplastic aggregates can influence the functionality of CSCs for promoting a cold pancreatic tumor immunity, which can be an effective strategy for improving responses from cold tumors to immunotherapy.
Abstract: Cold tumors generally show low mutational burden and low infiltration of effector T cells. The pancreas, prostate, ovary, breast, and colon are placed into the category of cold tumors. In such tumors, effector T cells are either excluded from the tumor area or taken away from being in contact with tumor cells. The stromal reaction in the form of desmoplasia is important for the pathogenesis of tumors like the pancreas. Besides acting as a barrier for the penetration of drugs into the tumor area, the dense stroma presumably creates an immunosuppressive tumor microenvironment (TME), which accounts for low responses from tumor to immunotherapy. Cancer stem cells (CSCs) are an important part of the immunosuppressive complex within the TME. The presence of CSCs within the TME is related negatively to the activity of the antitumor immune system. Here, the question is how desmoplastic aggregates can influence the functionality of CSCs for promoting a cold pancreatic tumor immunity? This review is aimed at responding to this question, the disruption of which can be an effective strategy for improving responses from cold tumors to immunotherapy.
50 citations
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TL;DR: The results clearly establish ATM as the major kinase involved in the phosphorylation of H2AX and suggest that ATM is one of the earliest kinases to be activated in the cellular response to double-strand breaks.
1,909 citations
TL;DR: The role of NF-κB in TLR signaling pathways has been discussed in this article, where the authors review recent progress in their understanding of the role and potential implications for molecular medicine.
1,822 citations
TL;DR: In human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of meetformin.
Abstract: Metformin is widely used to reduce the high blood sugar levels caused by diabetes. Recently, several studies have suggested that patients taking metformin who also develop cancer have tumors that grow more slowly than average. As clinical trials have already started to investigate if metformin is an effective anti-cancer treatment, it is important to understand how it might restrict tumor growth. Researchers have proposed two ways that metformin could affect tumors. First, insulin is known to prompt cancer cells to divide, so the slower rate of tumor growth could just be a side-effect of the metformin reducing the amount of insulin in the blood. Alternatively, metformin could target cancer cells more directly by cutting the energy supply produced by their mitochondria. Metformin has been shown to disrupt complex I of the electron transport chain that is used by cells to generate energy. However, it is not known if disrupting complex I would actually stop cells dividing because they can generate energy in other ways. Wheaton, Weinberg et al. have now demonstrated that metformin does target complex I in cancer cells, and that its effects depend on the amount of glucose available for cells to convert, without involving mitochondria, into energy. When there is plenty of glucose, metformin slows down the rate at which cancer cells divide, which slows down tumor growth. When the cells are deprived of glucose, metformin kills the cells instead. Metformin also inhibits the pathways that regulate hypoxia inducible factors (HIFs), which are part of a system that helps cells to survive low-oxygen conditions, a prominent feature of many tumors. This means that metformin may combat cancer more effectively if used alongside other treatments that reduce the availability of both oxygen and glucose inside cells. Metformin could also potentially treat conditions that are linked to overactive HIFs, such as pulmonary hypertension.
863 citations
TL;DR: Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving meetformin, and additional studies to evaluate the potential of met formin as an antitumor agent are warranted.
Abstract: Purpose Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy. Patients and Methods We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using 2 tests of independence and compared pairwise using a binomial test of proportions. Factors predictive of pCR were assessed using a multivariate logistic regression model. Results The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P .02). Pairwise comparisons between the metformin and nonmetformin groups (P .007) and the nonmetformin and nondiabetic groups (P .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use. Conclusion Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.
838 citations
TL;DR: CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor–κB signaling, protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival.
Abstract: The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor-kappaB signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.
666 citations