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

  • Balaraman Kalyanaraman
  • Gang Cheng
  • Micael Hardy
  • Olivier Ouari
  • Adam Sikora
  • Jacek Zielonka
  • Michael B. Dwinell
Original Paper

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.

Keywords

Modified metformin Reactive oxygen species Redox signaling Mitochondrial metabolism Pancreatic cancer 

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Balaraman Kalyanaraman
    • 1
  • Gang Cheng
    • 1
  • Micael Hardy
    • 2
  • Olivier Ouari
    • 2
  • Adam Sikora
    • 3
  • Jacek Zielonka
    • 1
  • Michael B. Dwinell
    • 4
  1. 1.Department of Biophysics and Free Radical Research CenterMedical College of WisconsinMilwaukeeUSA
  2. 2.CNRS, Institut de Chimie Radicalaire (ICR)Aix-Marseille UnivMarseilleFrance
  3. 3.Institute of Applied Radiation Chemistry Faculty of ChemistryLodz University of Technology, Zeromskiego 116LodzPoland
  4. 4.Department of Microbiology and Molecular GeneticsMedical College of WisconsinMilwaukeeUSA

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