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Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

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TLDR
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.

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HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer

TL;DR: Rational therapeutic combinations seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment.
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Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer.

TL;DR: The current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment is reviewed and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC are reviewed.
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A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan.

TL;DR: In this article, a review of the literature that has investigated the effects of metformin on aging, healthspan, and lifespan in humans as well as other species is presented.
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Metformin: Is it a drug for all reasons and diseases?

TL;DR: Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people in the US as discussed by the authors .
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Therapeutic Potential of Metformin in COVID-19: Reasoning for Its Protective Role.

TL;DR: In this article, the authors discuss the multifaceted ability of metformin to control blood glucose levels and possibly attenuate endothelial dysfunction, inhibit viral entry and infection, and modify inflammatory and immune responses during SARS-CoV-2 infections.
References
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Journal ArticleDOI

Role of AMP-activated protein kinase in mechanism of metformin action

TL;DR: It is reported that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed.
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TSC2 mediates cellular energy response to control cell growth and survival.

TL;DR: It is described that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway and its phosphorylation by AMPK protect cells from energy deprivation-induced apoptosis.
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AMPK phosphorylation of raptor mediates a metabolic checkpoint.

TL;DR: AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor, uncovering a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.
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Metformin and reduced risk of cancer in diabetic patients

TL;DR: It is hypothesised that metformin use in patients with type 2 diabetes may reduce their risk of cancer and tested this hypothesis using record linkage databases developed in Tayside, Scotland: a diabetes clinical information system (DARTS) and a database of dispensed prescriptions (MEMO).
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Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain

TL;DR: It is concluded that the drug's pharmacological effects are mediated, at least in part, through a time-dependent, self-limiting inhibition of the respiratory chain that restrains hepatic gluconeogenesis while increasing glucose utilization in peripheral tissues.
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