Metformin: Multi-faceted protection against cancer
Open Access
- 24 December 2011
- journal article
- review article
- Published by Impact Journals, LLC in Oncotarget
- Vol. 2 (12), 896-917
- https://doi.org/10.18632/oncotarget.387
Abstract
Sonia Del Barco1,2,*, Alejandro Vazquez-Martin2,3,*, Sílvia Cufí2,3, Cristina Oliveras-Ferraros2,3, Joaquim Bosch-Barrera1,2, Jorge Joven4, Begoña Martin-Castillo2,5, Javier A. Menendez2,3 1 Medical Oncology, Catalan Institute of Oncology, Girona (Catalonia, Spain) 2 Girona Biomedical Research Institute, Girona (Catalonia, Spain) 3 Unit of Translational Research, Catalan Institute of Oncology, Girona (Catalonia, Spain) 4 Centre de Recerca Biomèdica, Hospital Universitari Sant Joan de Reus, Institut d’Investigaciò Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus (Catalonia, Spain) 5 Unit of Clinical Research, Catalan Institute of Oncology, Girona (Catalonia, Spain) * Denotes equal contribution Received: December 19, 2011; Accepted: December 23, 2011; Published: December 24, 2011; Keywords: Diabetes, cancer, metformin, cancer stem cells, senescence Correspondence: Javier A. Menendez, email: // <![CDATA[ mail("jmenendez","iconcologia",2,"") // ]]> // <![CDATA[ $('.header-date').hide(); $('#titleAuthors').hide(); $('#abstractHeader').hide(); // ]]> Abstract The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin’s molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin’s primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics.Keywords
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