Faculty Collaboration Database

Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies. Cell Biochem Biophys 2017 Dec;75(3-4):311-317

Date

04/22/2017

Pubmed ID

28429253

Pubmed Central ID

PMC5680142

DOI

10.1007/s12013-017-0796-3

Scopus ID

2-s2.0-85018513016 (requires institutional sign-in at Scopus site)   20 Citations

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.

Author List

Kalyanaraman B, Cheng G, Hardy M, Ouari O, Sikora A, Zielonka J, Dwinell MB

Authors

Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Micael Joel Hardy PhD Visiting Assistant Professor in the Biophysics department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Cell Line, Tumor
Cell Proliferation
Electron Spin Resonance Spectroscopy
Electron Transport Complex I
Humans
Hydrogen Peroxide
Metformin
Mitochondria
Oxidation-Reduction
Pancreatic Neoplasms
Reactive Oxygen Species
Signal Transduction