Zhu Zhenzhu, Wang Zenghui, Zhang Changli, Wang Yanjun, Zhang Hongmei, Gan Zhenji, Guo Zijian, Wang Xiaoyong
State Key Laboratory of Pharmaceutical Biotechnology , School of Life Sciences , Nanjing University , Nanjing , P. R. China . Email:
State Key Laboratory of Coordination Chemistry , School of Chemistry and Chemical Engineering , Nanjing University , Nanjing , P. R. China . Email:
Chem Sci. 2019 Jan 22;10(10):3089-3095. doi: 10.1039/c8sc04871a. eCollection 2019 Mar 14.
Mitochondria are potential therapeutic targets for anticancer drugs. A series of mitochondrion-targeted monofunctional platinum complexes, Pt(-PPhCHPy)(NH)Cl (OPT), Pt(-PPhCHPy)(NH)Cl (MPT), and Pt(-PPhCHPy)(NH)Cl (PPT) (PPh = triphenylphosphonium, Py = pyridine), are studied in this article. The antitumor activity and mechanism of action have been investigated and as well as on molecular levels. OPT exhibits higher efficacy than cisplatin against A549 lung cancer cells; furthermore, it shows a strong inhibition towards the growth of non-small-cell lung cancer in nude mice. The DNA binding ability of these complexes follows an order of PPT > OPT > MPT. Cellular uptake and distribution studies show that OPT accumulates mainly in mitochondria, while MPT and PPT accumulate more preferentially in nuclei than in mitochondria. As a result, OPT induces remarkable changes in the ultrastructure and membrane of mitochondria, leading to more radical mitochondrial dysfunctions than cisplatin. The release of cytochrome c from mitochondria is more evident for cells treated with OPT than with cisplatin, though the apoptosis of A549 cells induced by OPT is similar to that induced by cisplatin. Disruption to mitochondrial oxidative phosphorylation and glycolysis is involved in the antitumor mechanism of these compounds. The results indicate that in addition to DNA binding, bioenergetic pathways also play crucial roles in the antitumor activity of mitochondrion-targeted monofunctional platinum complexes.
线粒体是抗癌药物潜在的治疗靶点。本文研究了一系列线粒体靶向单功能铂配合物，即Pt(-PPhCHPy)(NH)Cl（OPT）、Pt(-PPhCHPy)(NH)Cl（MPT）和Pt(-PPhCHPy)(NH)Cl（PPT）（PPh = 三苯基鏻，Py = 吡啶）。研究了它们的抗肿瘤活性及其作用机制，包括在分子水平上的机制。OPT对A549肺癌细胞的疗效高于顺铂；此外，它对裸鼠非小细胞肺癌的生长有强烈抑制作用。这些配合物与DNA的结合能力顺序为PPT > OPT > MPT。细胞摄取和分布研究表明，OPT主要在线粒体中积累，而MPT和PPT在细胞核中的积累比在线粒体中更优先。结果，OPT引起线粒体超微结构和膜的显著变化，导致比顺铂更严重的线粒体功能障碍。与顺铂处理的细胞相比，OPT处理的细胞中线粒体细胞色素c的释放更明显，尽管OPT诱导的A549细胞凋亡与顺铂诱导的相似。线粒体氧化磷酸化和糖酵解的破坏参与了这些化合物的抗肿瘤机制。结果表明，除了与DNA结合外，生物能量途径在靶向线粒体的单功能铂配合物的抗肿瘤活性中也起着关键作用。
