Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (13), p.3904-3915
• Main Authors: Cheng, Gang, Zielonka, Jacek, Ouari, Olivier, Lopez, Marcos, McAllister, Donna, Boyle, Kathleen, Barrios, Christy S, Weber, James J, Johnson, Bryon D, Hardy, Micael, Dwinell, Michael B, Kalyanaraman, Balaraman
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - radiation effects; Blotting, Western; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - radiotherapy; Cell Cycle - drug effects; Cell Cycle - radiation effects; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Chemical Sciences; Chemoradiotherapy; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Metformin - chemistry; Metformin - pharmacology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria - drug effects; Mitochondria - pathology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - radiotherapy; Radiation-Sensitizing Agents - chemistry; Radiation-Sensitizing Agents - pharmacology; Signal Transduction; Superoxides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-2534

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.