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Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies

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Abstract

Metformin, one of the most widely prescribed antidiabetic drugs in the world, is being repurposed as a potential drug in cancer treatment. Epidemiological studies suggest that metformin exerts anticancer effects in diabetic patients with pancreatic cancer. However, at typical antidiabetic doses the bioavailability of metformin is presumably too low to exert antitumor effects. Thus, more potent analogs of metformin are needed in order to increase its anticancer efficacy. To this end, a new class of mitochondria-targeted metformin analogs (or mito-metformins) containing a positively-charged lipophilic triphenylphosphonium group was synthesized and tested for their antitumor efficacy in pancreatic cancer cells. Results indicate that the lead compound, mito-metformin10, was nearly 1000-fold more potent than metformin in inhibiting mitochondrial complex I activity, inducing reactive oxygen species (superoxide and hydrogen peroxide) that stimulate redox signaling mechanisms, including the activation of adenosinemonophosphate kinase and inhibition of proliferation of pancreatic cancer cells. The potential use of the low-temperature electron paramagnetic resonance technique in assessing the role of mitochondrial complexes including complex I in tumor regression in response to metformin and mito-metformins in the in vivo setting is discussed.

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Funding

This work was supported by a grant from NIH (U01 CA178960) to M.D. and B.K. A.S. was supported by a grant from Polish National Science Centre No. 2015/18/E/ST4/00235.

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Authors and Affiliations

  1. Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA

    Balaraman Kalyanaraman, Gang Cheng & Jacek Zielonka

  2. CNRS, Institut de Chimie Radicalaire (ICR), Aix-Marseille Univ, UMR 7273, Marseille, 13013, France

    Micael Hardy & Olivier Ouari

  3. Institute of Applied Radiation Chemistry Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, Lodz, 90-924, Poland

    Adam Sikora

  4. Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA

    Michael B. Dwinell

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  1. Balaraman Kalyanaraman
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Correspondence to Balaraman Kalyanaraman.

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Kalyanaraman, B., Cheng, G., Hardy, M. et al. Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies. Cell Biochem Biophys 75, 311–317 (2017). https://doi.org/10.1007/s12013-017-0796-3

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