Cisplatin induces platelet apoptosis through the ERK signaling pathway

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• 作者：Weilin Zhang^a ; ^b ; Lili Zhao^a ; ^b ; Jun Liu^a ; ^b ; Juan Du^a ; ^b ; Zhicheng Wang^a ; ^b ; Changgeng Ruan^b ; Kesheng Dai^b ; ^{kdai@suda.edu.cn}
• 关键词：Cisplatin ; cis-diamminedichloroplatinum II ; MEK ; mitogen-activated protein kinase kinase ; ERK ; extracellular signal-regulated protein kinase ; JNK ; c-Jun N-terminal kinase ; VWF ; von Willebrand factor ; DMSO ; dimethyl sulfoxide ; PMSF ; phenylmethylsulfonyl fl
• 刊名：Thrombosis Research
• 出版年：2012
• 期刊代码：247_00493848
• 类别：med
• 出版时间：July, 2012
• 卷：130
• 期：1
• 页码：81-91
• 文件大小：1399 K

摘要

Cisplatin (cis-diamminedichloroplatinum II) is one of the most widely used anti-tumor agents. However, cisplatin-based chemotherapy is usually accompanied by adverse side effects such as thrombocytopenia, and the mechanism remains unclear. Here we show that cisplatin induced several platelet apoptotic events including up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bcl-X_L, mitochondrial translocation of Bax, mitochondrial inner transmembrane potential depolarization, caspase-3 activation and phosphatidylserine (PS) exposure. Cisplatin dose-dependently induced activation of extracellular signal-regulated protein kinase (ERK) in platelets. Caspase-3 inhibitor z-DEVD-fmk dramatically inhibited cisplatin-induced caspase-3 activation and PS exposure without affecting ERK activation. Blockade of the ERK pathway significantly prevented platelet apoptosis. Furthermore, levels of reactive oxygen species (ROS) and Ca^2 + were significantly elevated by cisplatin, and scavenging of ROS and Ca^2 + obviously inhibited platelet apoptosis induced by cisplatin. In addition, cisplatin did not induce platelet activation, whereas it obviously impaired platelet functions. These data indicate that cisplatin induces platelet apoptosis through the ERK signaling pathway, which might contribute to cisplatin-related haematological toxicity.