Mitochondria-derived reactive oxygen species play an important role in Doxorubicin-induced platelet apoptosis

• Published in: International journal of molecular sciences 2015-05, Vol.16 (5), p.11087-11100
• Main Authors: Wang, Zhicheng, Wang, Jie, Xie, Rufeng, Liu, Ruilai, Lu, Yuan
• Format: Article
• Language: English
• Subjects: Adult; Antibiotics, Antineoplastic - pharmacology; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; Blood platelets; Blood Platelets - cytology; Blood Platelets - drug effects; Blood Platelets - metabolism; Cardiolipins - metabolism; Caspase 3 - metabolism; Cytochromes c - metabolism; doxorubicin; Doxorubicin - pharmacology; Female; Humans; Lipid Peroxidation - drug effects; Male; Malondialdehyde - metabolism; Membrane Potential, Mitochondrial - drug effects; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Oxidative Stress - drug effects; Oxygen; Platelet Aggregation - drug effects; Platelet Glycoprotein GPIb-IX Complex - metabolism; platelets; reactive oxygen species; Reactive Oxygen Species - metabolism; von Willebrand Factor - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms160511087

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.