Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer

0469007 - BTÚ 2017 RIV US eng J - Journal Article
Boukalová, Štěpána - Štursa, J. - Werner, L. - Ezrová, Zuzana - Černý, Jiří - Bezawork-Geleta, A. - Pecinová, Alena - Dong, L. - Drahota, Zdeněk - Neužil, Jiří
Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer.
Molecular Cancer Therapeutics. Roč. 15, č. 12 (2016), s. 2875-2886. ISSN 1535-7163. E-ISSN 1538-8514
R&D Projects: GA ČR GA15-02203S; GA MZd(CZ) NV16-31604A; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036 ; RVO:67985823
Keywords : ELECTRON-TRANSPORT CHAIN * RESPIRATORY COMPLEX-II * SUCCINATE
Subject RIV: FD - Oncology ; Hematology; EB - Genetics ; Molecular Biology (FGU-C)
Impact factor: 5.764, year: 2016

Pancreatic cancer isone of the hardest-to-treat types of neoplastic diseases. Metformin, a widely prescribed drug against type 2 diabetes mellitus, is being trialed as an agent against pancreatic cancer, although its efficacy is low. With the idea of delivering metformin to its molecular target, the mitochondrial complex I (CI), we tagged the agent with the mitochondrial vector, triphenylphosphonium group. Mitochondrially targeted metformin (MitoMet) was found to kill a panel of pancreatic cancer cells three to four orders of magnitude more efficiently than found for the parental compound. Respiration assessment documented CI as the molecular target for MitoMet, which was corroborated by molecular modeling. MitoMet also efficiently suppressed pancreatic tumors in three mouse models. We propose that the novel mitochondrially targeted agent is clinically highly intriguing, and it has a potential to greatly improve the bleak prospects of patients with pancreatic cancer. (C) 2016 AACR.
Permanent Link: http://hdl.handle.net/11104/0266913