title: Mitochondria-derived reactive oxygen species play an important role in Doxorubicin-induced platelet apoptosis.
abstract: Doxorubicin (DOX) is an effective chemotherapeutic agent; however; its use is limited by some side effects; such as cardiotoxicity and thrombocytopenia. DOX-induced cardiotoxicity has been intensively investigated; however; DOX-induced thrombocytopenia has not been clearly elucidated. Here we show that DOX-induced mitochondria-mediated intrinsic apoptosis and glycoprotein (GP)Ibα shedding in platelets. DOX did not induce platelet activation; whereas; DOX obviously reduced adenosine diphosphate (ADP)- and thrombin-induced platelet aggregation; and impaired platelet adhesion on the von Willebrand factor (vWF) surface. In addition; we also show that DOX induced intracellular reactive oxygen species (ROS) production and mitochondrial ROS generation in a dose-dependent manner. The mitochondria-targeted ROS scavenger Mito-TEMPO blocked intracellular ROS and mitochondrial ROS generation. Furthermore; Mito-TEMPO reduced DOX-induced platelet apoptosis and GPIbα shedding. These data indicate that DOX induces platelet apoptosis; and impairs platelet function. Mitochondrial ROS play a pivotal role in DOX-induced platelet apoptosis and GPIbα shedding. Therefore; DOX-induced platelet apoptosis might contribute to DOX-triggered thrombocytopenia; and mitochondria-targeted ROS scavenger would have potential clinical utility in platelet-associated disorders involving mitochondrial oxidative damage.
authors.affiliation: Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China. ahwzc@126.com.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China. Jiewang2015@126.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Blood Engineering Laboratory, Shanghai Blood Center, Shanghai 200051, China. xierufeng555@163.com.
authors.forename: Rufeng
authors.initials: R
authors.lastname: Xie
authors.affiliation: Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China. liuruilai88@163.com.
authors.forename: Ruilai
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China. yuanlu@hsh.stn.sh.cn.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D002308:Cardiolipins; D019038:Platelet Glycoprotein GPIb-IX Complex; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D014841:von Willebrand Factor; D008315:Malondialdehyde; D004317:Doxorubicin; D045304:Cytochromes c; D053148:Caspase 3
keywords: apoptosis; doxorubicin; mitochondria; platelets; reactive oxygen species