title: Cisplatin induces platelet apoptosis through the ERK signaling pathway.
abstract: 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.
authors.affiliation: School of Biological Science and Medical Engineering, Beijing University of Aeronautics and Astronautics, Beijing.
authors.forename: Weilin
authors.initials: W
authors.lastname: Zhang
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Changgeng
authors.initials: C
authors.lastname: Ruan
authors.forename: Kesheng
authors.initials: K
authors.lastname: Dai
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D053148:Caspase 3; D002945:Cisplatin