title: Pravastatin attenuates carboplatin-induced cardiotoxicity via inhibition of oxidative stress associated apoptosis.
abstract: The objective of this study was to evaluate the cardiac toxicity induced by carboplatin, a second generation platinum-containing anti-cancer drug, and to test whether pravastatin can reduce this cardio-toxicity. In the present study, infusion of carboplatin (100 mg/kg) to mice resulted in decreased survival rates and abnormal cardiac histology, concomitant with increased cardiac apoptosis. In addition, treatment of cultured rat cardiomyocytes with carboplatin (100 muM for 48 h) caused marked apoptosis and increased caspase-3, -9, and cytochrome C, but decreased BCL-XL protein expression, and this was inhibited by reactive oxygen species (ROS) scavenger n-acetylcysteine. Furthermore, pretreatment of cardiomyocytes with pravastatin (20 microM) before carboplatin exposure significantly attenuated apoptosis and decreased caspase-3, -9, cytochrome C activity. Lastly, mice pre-treated with pravastatin before carboplatin treatment showed improved survival rate and cardiac function, with reduced cardiomyocyte apoptosis via activating Akt and restoring normal mitochondrial HAX-1 in heart tissue. In summary, our results show that carboplatin can induce cardiotoxicity in vivo and in cultured cells via a mitochondrial pathway related to ROS production, whereas pravastatin administration can reduce such oxidative stress thus prevented cardiac apoptosis. Therefore, pravastatin can be used as a cytoprotective agent prior to carboplatin chemotherapy.
authors.affiliation: Graduate Institute of Pharmacology & Toxicology and College of Medicine, Tzu Chi University, 701, Chung Yang Road, Section 3, Hualien City, Hualien 970, Taiwan.
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Cheng
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Juan
authors.forename: Jin-Jer
authors.initials: JJ
authors.lastname: Chen
authors.forename: Ying-Chi
authors.initials: YC
authors.lastname: Chao
authors.forename: His-Hsien
authors.initials: HH
authors.lastname: Chen
authors.forename: Wei-Shiung
authors.initials: WS
authors.lastname: Lian
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Lu
authors.forename: Chung-I
authors.initials: CI
authors.lastname: Chang
authors.forename: Ted-H
authors.initials: TH
authors.lastname: Chiu
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016190:Carboplatin / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000517:prevention & control; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; C510653:Hax1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D016190:Carboplatin; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D017035:Pravastatin