Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer
Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer
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DOI：
10.1158/1535-7163.mct-15-1021
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发表时间：
2016-12-01
影响因子：
5.7
通讯作者：
Neuzil, Jiri
中科院分区：
文献类型：
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作者：
Boukalova, Stepana;Stursa, Jan;Neuzil, Jiri
胰腺癌是最难治疗的肿瘤疾病之一。二甲双胍是一种广泛用于治疗2型糖尿病的处方药，目前正作为治疗胰腺癌的药物进行试验，尽管其疗效较低。为了将二甲双胍运送到其分子靶点线粒体复合体I(CI)，我们用线粒体载体三苯基膦基团标记了该试剂。线粒体靶向二甲双胍(MitoMet)被发现比亲本化合物杀死一组胰腺癌细胞的效率高三到四个数量级。呼吸评估证明CI是MitoMet的分子靶点，这一点得到了分子模拟的证实。MitoMet还有效地抑制了三种小鼠模型的胰腺肿瘤。我们认为，这种新型的线粒体靶向制剂在临床上具有很高的吸引力，它有可能极大地改善胰腺癌患者的黯淡前景。(C)2016年AACR。
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.