Abstract
Metformin is one of the most commonly prescribed medications for the treatment of type 2 diabetes. Numerous reports have suggested potential anti-cancerous and cancer preventive properties of metformin, although these findings vary depending on the intrinsic properties of the tumor, as well as the systemic physiology of patients. These intriguing studies have led to a renewed interest in metformin use in the oncology setting, and fueled research to unveil its elusive mode of action. It is now appreciated that metformin inhibits complex I of the electron transport chain in mitochondria, causing bioenergetic stress in cancer cells, and rendering them dependent on glycolysis for ATP production. Understanding the mode of action of metformin and the consequences of its use on cancer cell bioenergetics permits the identification of cancer types most susceptible to metformin action. Such knowledge may also shed light on the varying results to metformin usage that have been observed in clinical trials. In this review, we discuss metabolic profiles of cancer cells that are associated with metformin sensitivity, and rationalize combinatorial treatment options. We use the concept of bioenergetic flexibility, which has recently emerged in the field of cancer cell metabolism, to further understand metabolic rearrangements that occur upon metformin treatment. Finally, we advance the notion that metabolic fitness of cancer cells increases during progression to metastatic disease and the emergence of therapeutic resistance. As a result, sophisticated combinatorial approaches that prevent metabolic compensatory mechanisms will be required to effectively manage metastatic disease.
Highlights
Reviewed by: Bin Zheng, Harvard Medical School, United States Daniel Rotroff, Cleveland Clinic, United States Federica Barbieri, Università di Genova, Italy
We use the concept of bioenergetic flexibility, which has recently emerged in the field of cancer cell metabolism, to further understand metabolic rearrangements that occur upon metformin treatment
Completed clinical trials have varied in outcome depending on trial design, cancer type, stage of cancer, timing of metformin treatment, and combinatorial therapies or treatments given in addition to metformin
Summary
Edited by: Frederic Bost, Centre National de la Recherche Scientifique (CNRS), France. Studies have been developed to investigate potential anti-cancer roles of metformin in nondiabetic patients given the increasing literature supporting its action in cancers, as well as the fact that metformin is associated with less hypoglycemic episodes than other diabetic medications [19]. One randomized trial of metformin combinatorial treatment with standard of care chemotherapy showed no benefit in advanced pancreatic cancer [21], despite large meta-analysis showing significant survival in metformin treated pancreatic patients [22]. These studies highlight a need for more rigorous planning of clinical trials that focus more on potential predictive biomarkers [23]. The current available data support continued efforts toward examining the potential therapeutic role of metformin in various cancers, both in diabetic and non-diabetic patients
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