Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions.
Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions.
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DOI：
10.1371/journal.pone.0081162
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Doetsch PW
中科院分区：
文献类型：
--
作者：
Marullo R;Werner E;Degtyareva N;Moore B;Altavilla G;Ramalingam SS;Doetsch PW
顺铂是治疗多种类型肿瘤的最有效和最广泛使用的抗癌剂之一。顺铂的细胞毒性作用被认为主要是通过核DNA加合物的产生介导的，如果不修复，则由于DNA复制和转录阻断而导致细胞死亡。然而，顺铂诱导核DNA（nDNA）损伤的能力本身并不足以解释其高度的有效性，也不足以解释其对正常有丝分裂后组织的毒性作用。在体内暴露于顺铂后，在几种组织中观察到氧化损伤，表明氧化应激在顺铂诱导的剂量限制性毒性的发病机制中的作用。然而，顺铂诱导的ROS产生的机制及其对顺铂在正常细胞和癌细胞中的细胞毒性的贡献仍然知之甚少。通过采用一组正常细胞系和癌细胞系以及芽殖酵母酿酒酵母作为模型系统，我们表明，暴露于顺铂诱导了细胞依赖性ROS反应，显著增强了由nDNA损伤引起的细胞毒性作用。ROS的产生不依赖于顺铂诱导的nDNA损伤的量，并且作为蛋白质合成受损的结果发生在线粒体中。顺铂诱导的线粒体功能障碍在确定其细胞毒性作用方面的贡献在细胞之间变化，并取决于线粒体氧化还原状态、线粒体DNA完整性和生物能量功能。因此，通过操纵这些细胞参数，我们能够增强顺铂在癌细胞中的细胞毒性。这项研究提供了一个新的机制洞察顺铂诱导的细胞杀伤，并可能导致设计新的治疗策略，以提高抗癌药物的疗效。
Cisplatin is one of the most effective and widely used anticancer agents for the treatment of several types of tumors. The cytotoxic effect of cisplatin is thought to be mediated primarily by the generation of nuclear DNA adducts, which, if not repaired, cause cell death as a consequence of DNA replication and transcription blockage. However, the ability of cisplatin to induce nuclear DNA (nDNA) damage per se is not sufficient to explain its high degree of effectiveness nor the toxic effects exerted on normal, post-mitotic tissues. Oxidative damage has been observed in vivo following exposure to cisplatin in several tissues, suggesting a role for oxidative stress in the pathogenesis of cisplatin-induced dose-limiting toxicities. However, the mechanism of cisplatin-induced generation of ROS and their contribution to cisplatin cytotoxicity in normal and cancer cells is still poorly understood. By employing a panel of normal and cancer cell lines and the budding yeast Saccharomyces cerevisiae as model system, we show that exposure to cisplatin induces a mitochondrial-dependent ROS response that significantly enhances the cytotoxic effect caused by nDNA damage. ROS generation is independent of the amount of cisplatin-induced nDNA damage and occurs in mitochondria as a consequence of protein synthesis impairment. The contribution of cisplatin-induced mitochondrial dysfunction in determining its cytotoxic effect varies among cells and depends on mitochondrial redox status, mitochondrial DNA integrity and bioenergetic function. Thus, by manipulating these cellular parameters, we were able to enhance cisplatin cytotoxicity in cancer cells. This study provides a new mechanistic insight into cisplatin-induced cell killing and may lead to the design of novel therapeutic strategies to improve anticancer drug efficacy.
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影响因子：
5.8
作者：
Hour TC;Lai YL;Kuan CI;Chou CK;Wang JM;Tu HY;Hu HT;Lin CS;Wu WJ;Pu YS;Sterneck E;Huang AM
通讯作者：
Huang AM
影响因子：
2.8
作者：
Campbell, KCM;Rybak, LP;Hughes, L
通讯作者：
Hughes, L
影响因子：
3.8
作者：
DEKONING, P;NEIJT, JP;GISPEN, WH
通讯作者：
GISPEN, WH
影响因子：
4.7
作者：
LEE, KB;PARKER, RJ;REED, E
通讯作者：
REED, E
影响因子：
2.9
作者：
CICCARELLI, RB;SOLOMON, MJ;LIPPARD, SJ
通讯作者：
LIPPARD, SJ