|Title:||Pravastatin attenuates carboplatin-induced cardiotoxicity via inhibition of oxidative stress associated apoptosis||Authors:||Cheng C.-F.
|Issue Date:||2008||Journal Volume:||13||Journal Issue:||7||Start page/Pages:||883-894||Source:||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 μM 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 μM) 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. ? 2008 Springer Science+Business Media, LLC.
|ISSN:||1360-8185||DOI:||10.1007/s10495-008-0214-9||SDG/Keyword:||acetylcysteine; carboplatin; caspase 3; caspase 9; cytochrome c; hydroxymethylglutaryl coenzyme A reductase inhibitor; pravastatin; protein bcl xl; protein kinase B; animal cell; animal experiment; animal model; animal tissue; apoptosis; article; cardiomyopathy; cardiotoxicity; cell protection; controlled study; cytotoxicity; DNA fragmentation; drug antagonism; enzyme activity; heart left ventricle function; heart muscle cell; histopathology; immunohistochemistry; leukopenia; male; mouse; nonhuman; oxidative stress; priority journal; protein expression; Animals; Antineoplastic Agents; Apoptosis; Carboplatin; Cardiomyopathies; Carrier Proteins; Caspases; Cells, Cultured; Enzyme Activation; Heart; In Situ Nick-End Labeling; Leukopenia; Male; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; Oxidative Stress; Pravastatin; Proto-Oncogene Proteins c-akt; Rats; Reactive Oxygen Species; Mus; Rattus
|Appears in Collections:||醫學系|
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