Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells.
Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells.
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二甲双胍的线粒体靶向类似物在胰腺癌细胞中表现出增强的抗增殖和放射增敏作用。
DOI：
10.1158/0008-5472.can-15-2534
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Kalyanaraman B
中科院分区：
文献类型：
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作者：
Cheng G;Zielonka J;Ouari O;Lopez M;McAllister D;Boyle K;Barrios CS;Weber JJ;Johnson BD;Hardy M;Dwinell MB;Kalyanaraman B
二甲双胍(Met)是一种被批准的抗糖尿病药物，最近有证据表明它具有明显的化学预防作用，目前正在探索将其用于癌症治疗。MET是一种弱阳离子药物，以线粒体为靶标在肿瘤细胞中诱导细胞毒效应，尽管效果不是很好。我们假设，通过连接一个带正电荷的亲脂取代基来增加其线粒体靶向潜力将增强Met的抗肿瘤活性。为了解决这个问题，我们合成了一组含有三苯基膦阳离子(TPP+)的不同烷基链长的线粒体靶向Met类似物(Mito-Mets)。特别是，通过10碳脂肪族侧链将TPP+连接到Met合成的类似物Mito-Met10，在抑制胰腺导管腺癌(PDAC)细胞增殖方面比Met强近1000倍。值得注意的是，在PDAC细胞中，Mito-Met10有效地抑制线粒体复合体I，刺激超氧化物和AMPK的激活，但对未转化的对照细胞没有影响。此外，与Met相比，Mito-Met10有效地触发了PDAC细胞的G1期停滞，增强了其放射敏感性，并更有效地抑制了临床前小鼠模型中的PDAC生长。总而言之，我们的发现表明，改善Met的线粒体靶向如何增强其抗癌活性，包括在急需更有效治疗选择的侵袭性癌症中，如PDAC。
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 analogs (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP+). In particular, the analog 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 non-transformed 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 to Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including in aggressive cancers like PDAC in great need of more effective therapeutic options.