Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer

被引：67

作者：

Boukalova, Stepana ^{[1
]}

Stursa, Jan ^{[2
]}

Werner, Lukas ^{[2
,3
]}

Ezrova, Zuzana ^{[1
]}

Cerny, Jiri ^{[1
]}

Bezawork-Geleta, Ayenachew ^{[4
]}

Pecinova, Alena ^{[5
]}

Dong, Lanfeng ^{[4
]}

Drahota, Zdenek ^{[5
]}

Neuzil, Jiri ^{[1
,4
]}

机构：

[1] Czech Acad Sci, Inst Biotechnol, Vestec, Czech Republic

[2] Inst Chem Technol, Prague, Czech Republic

[3] Univ Hosp Hradec Kralove, Biomed Res Ctr, Hradec Kralove, Czech Republic

[4] Griffith Univ, Sch Med Sci, Southport, Qld, Australia

[5] Czech Acad Sci, Inst Physiol, Prague, Czech Republic

来源：

MOLECULAR CANCER THERAPEUTICS | 2016年 / 15卷 / 12期

基金：

澳大利亚研究理事会;

关键词：

ELECTRON-TRANSPORT CHAIN; SUCCINATE; GROWTH; RISK; INHIBITION; CELLS; SUPPRESSION; MECHANISMS; APOPTOSIS; SURVIVAL;

D O I：

10.1158/1535-7163.MCT-15-1021

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：2875 / 2886

页数：12

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