Tanida Satoshi, Mizoshita Tsutomu, Ozeki Keiji, Tsukamoto Hironobu, Kamiya Takeshi, Kataoka Hiromi, Sakamuro Daitoku, Joh Takashi
Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho, Nagoya, Aichi 467-8601, Japan.
Int J Surg Oncol. 2012;2012:862879. doi: 10.1155/2012/862879. Epub 2012 Jun 12.
Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. Cisplatin forms inter- and intrastrand crosslinked DNA adducts and its cytotoxicity is mediated by propagation of DNA damage recognition signals to downstream pathways involving ATR, p53, p73, and mitogen-activated protein kinases, ultimately resulting in apoptosis. Cisplatin resistance arises through a multifactorial mechanism involving reduced drug uptake, increased drug inactivation, increased DNA damage repair, and inhibition of transmission of DNA damage recognition signals to the apoptotic pathway. In addition, a new mechanism has recently been revealed, in which the oncoprotein c-Myc suppresses bridging integrator 1 (BIN1), thereby releasing poly(ADP-ribose)polymerase 1, which results in increased DNA repair activity and allows cancer cells to acquire cisplatin resistance. The present paper focuses on the molecular mechanisms of cisplatin-induced apoptosis and of cisplatin resistance, in particular on the involvement of BIN1 in the maintenance of cisplatin sensitivity.
顺铂是治疗晚期胃癌最重要且有效的化疗药物。顺铂会形成链间和链内交联的DNA加合物，其细胞毒性是通过将DNA损伤识别信号传递至涉及ATR、p53、p73和丝裂原活化蛋白激酶的下游通路来介导的，最终导致细胞凋亡。顺铂耐药性的产生是通过多因素机制，包括药物摄取减少、药物失活增加、DNA损伤修复增加以及DNA损伤识别信号向凋亡通路的传递受到抑制。此外，最近还揭示了一种新机制，即癌蛋白c-Myc抑制桥连整合器1（BIN1），从而释放聚（ADP-核糖）聚合酶1，这导致DNA修复活性增加，并使癌细胞获得顺铂耐药性。本文重点关注顺铂诱导凋亡和顺铂耐药性的分子机制，特别是BIN1在维持顺铂敏感性中的作用。
