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Ref Type Journal Article
PMID (27216187)
Authors Cheng G, Zielonka J, Ouari O, Lopez M, McAllister D, Boyle K, Barrios CS, Weber JJ, Johnson BD, Hardy M, Dwinell MB, Kalyanaraman B
Title Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells.
Journal Cancer research
Vol 76
Issue 13
Date 2016 Jul 01
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MitoMet-10 MitoMet-10 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
MitoMet-10 MitoMet-10 is a mitochondria-targeted analog of Metformin with increased potency, which may decrease tumor cell proliferation and increase sensitivity to radiotherapy (PMID: 27216187).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown pancreatic cancer not applicable MitoMet-10 Preclinical Actionable In a preclinical study, MitoMet-10 decreased tumor growth in mouse models of pancreatic cancer (PMID: 27216187). 27216187
Unknown unknown pancreatic ductal adenocarcinoma not applicable MitoMet-10 + Radiotherapy Preclinical Actionable In a preclinical study, MitoMet-10 increased the radiosensitivity of pancreatic ductal adenocarcinoma cells in culture (PMID: 27216187). 27216187
Unknown unknown pancreatic ductal adenocarcinoma not applicable MitoMet-10 Preclinical Actionable In a preclinical study, MitoMet-10 inhibited mitochondrial function and proliferation of pancreatic ductal adenocarcinoma cells in culture, and demonstrated increased potency compared to metformin (PMID: 27216187). 27216187