Faculty Collaboration Database

Mitochondria-targeted metformins: anti-tumour and redox signalling mechanisms. Interface Focus 2017 Apr 06;7(2):20160109

Date

04/07/2017

Pubmed ID

28382202

Pubmed Central ID

PMC5311906

DOI

10.1098/rsfs.2016.0109

Scopus ID

2-s2.0-85013194895 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

Reports suggest that metformin exerts anti-cancer effects in diabetic individuals with pancreatic cancer. Thus, metformin is currently being repurposed as a potential drug in cancer treatment. Studies indicate that potent metformin analogues are required in cancer treatment because of the low bioavailability of metformin in humans at conventional antidiabetic doses. We proposed that improved mitochondrial targeting of metformin by attaching a positively charged lipophilic triphenylphosphonium group will result in a new class of mitochondria-targeted metformin analogues with significantly enhanced anti-tumour potential. Using this approach, we synthesized various mitochondria-targeted metformin analogues with different alkyl chain lengths. Results indicate that the antiproliferative effects increased with increasing alkyl chain lengths (100-fold to 1000-fold). The lead compound, mito-metformin₁₀, potently inhibited mitochondrial respiration through inhibition of complex I, stimulation of superoxide and hydrogen peroxide formation and activation of AMPK. When used in combination with ionizing radiation, mito-metformin₁₀ acted as a radiosensitizer of pancreatic cancer cells. Because of the 1000-fold-higher potency of mitochondria-targeted metformin₁₀, therapeutically effective plasma concentrations likely can be achieved in cancer patients.

Author List

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

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