cerivastatin and Rhabdomyosarcoma--Embryonal

The aim of this study was to determine the effects of α-cyano-4-hydroxycinnamic acid (CHC), a lactate efflux inhibitor, and citrate, an alkaline reagent, on statin-induced muscle injury using a human prototypic embryonal rhabdomyosarcoma cell line (RD) as a model of in vitro skeletal muscle and on statin-induced muscle damage in an in vivo study. Statin-induced reduction of cell viability and apoptosis was measured by the 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay and caspase assay. In an in vivo study, plasma creatine phosphokinase (CPK) level was examined in cerivastatin-treated rats. CHC increased growth inhibition of RD cells induced by cerivastatin, a lipophilic statin, but not these induced by pravastatin, a hydrophilic statin. On the other hand, citrate suppressed cerivastatin-, simvastatin- and atorvastatin-induced reduction of cell viability and caspase activation in RD cells. Moreover, citrate prevented cerivastatin-induced increase in CPK concentration in a concentration-dependent manner. This is first study to evaluate CHC or citrate-induced exacerbation or improvement of statin-induced muscle damage.

Topics: Animals; Apoptosis; Caspase 1; Cell Line, Tumor; Cell Survival; Cells, Cultured; Citric Acid; Coumaric Acids; Creatine Kinase; Humans; Hydrogen-Ion Concentration; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Muscle, Skeletal; Pyridines; Rats; Rats, Wistar; Rhabdomyosarcoma, Embryonal

Although HMG-CoA reductase inhibitors such as statins are the most widely used cholesterol-lowering agents, there is a risk of myopathy or rhabdmyolysis occurring in patients taking these drugs. It has been reported that a number of lipophilic statins cause apoptosis in various cells, but it is still not clear whether intracellular acidification is involved in statin-induced apoptosis. There have been few studies aimed at identifying compounds that suppress statin-induced myotoxicity. In the present study, we examined the relationship between cerivastatin-induced apoptosis and intracellular acidification and the effect of bicarbonate on cerivastatin-induced apoptosis using an RD cell line as a model of in vitro skeletal muscle. Cerivastatin reduced the number of viable cells and caused dramatic morphological changes and DNA fragmentation in a concentration-dependent manner. Moreover, cerivastatin-induced apoptosis was associated with intracellular acidification and caspase-9 and -3/7 activation. On the other hand, bicarbonate suppressed cerivastatin-induced pH alteration, caspase activation, morphological change and reduction of cell viability. Accordingly, bicarbonate suppressed statin-induced apoptosis. The strategy to combine statins with bicarbonate can lead to reduction in the chance of the severe adverse events including myopathy or rhabdmyolysis.

Topics: Apoptosis; Biological Transport; Caspase 3; Caspase 7; Caspase 9; Cell Line, Tumor; Cell Shape; Cell Survival; DNA Fragmentation; Dose-Response Relationship, Drug; Enzyme Activation; Fluorobenzenes; Humans; Hydrogen-Ion Concentration; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscle, Skeletal; Protective Agents; Pyridines; Pyrimidines; Rhabdomyolysis; Rhabdomyosarcoma, Embryonal; Rosuvastatin Calcium; Sodium Bicarbonate; Sulfonamides