Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells. Cancer Res 2016 Jul 01;76(13):3904-15
Date
05/25/2016Pubmed ID
27216187Pubmed Central ID
PMC4930686DOI
10.1158/0008-5472.CAN-15-2534Scopus ID
2-s2.0-84977588183 (requires institutional sign-in at Scopus site) 163 CitationsAbstract
Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogues (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP(+)). In particular, the analogue Mito-Met10, synthesized by attaching TPP(+) to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells, Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in nontransformed control cells. Moreover, Mito-Met10 potently triggered G1 cell-cycle phase arrest in PDAC cells, enhanced their radiosensitivity, and more potently abrogated PDAC growth in preclinical mouse models, compared with Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including aggressive cancers like PDAC in great need of more effective therapeutic options. Cancer Res; 76(13); 3904-15. ©2016 AACR.
Author List
Cheng G, Zielonka J, Ouari O, Lopez M, McAllister D, Boyle K, Barrios CS, Weber JJ, Johnson BD, Hardy M, Dwinell MB, Kalyanaraman BAuthors
Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMichael 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
Bryon D. Johnson PhD Adjunct Professor in the Medicine 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
AnimalsApoptosis
Blotting, Western
Carcinoma, Pancreatic Ductal
Cell Cycle
Cell Proliferation
Chemoradiotherapy
Humans
Hypoglycemic Agents
Metformin
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria
Pancreatic Neoplasms
Radiation-Sensitizing Agents
Signal Transduction
Superoxides
Tumor Cells, Cultured
Xenograft Model Antitumor Assays