The Mechanisms Of Simvastatin On Apoptosis And Autophagy In Human OCM-1Cells

Choroidal melanoma is the most common primary intraocularmalignancy in adults, and is associated with high mortality.Currently,choroidal melanoma is chemoresistant and there is no routineadjuvant chemotherapy for it. The tumor has a predilection for lightlypigmented individuals, blue eyes, and blonde hair. The etiology isunknown.The size of choroidal malignant melanoma (CMM)Represents the most important indicator of vital prognosis and survivalrate.Even if enucleation is performed in due course, half of the patientswho undergo surgical treatment for CMM die from complications ofsubsequent metastasis. So, it is necessary to look for an effective way totreat the choroidal malignant melanoma.Simvastatin, one of the3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors, is currently widely used safe and welltolerated therapeutic agent for treating hypercholesterolemia,atherosclerosis,coronary heart disease and stroke. In addition to its lipid-lowering effects,simvastatin also may have a potential role in the prevention and treatmentof cancer. However, the efficacy and the molecular mechanism ofsimvastatin on choroidal melanoma progression have yet to beclarified.Given the need for alternative therapeutic strategies, these findings inparallel with limited knowledge about simvastatin’s influence onchoroidal melanoma prompted us to evaluate its potential therapeuticoptions for choroidal melanoma. The objective of this study was to determine whether simvastatin exerts anticancer effects in choroidalmelanoma cell lines (OCM-1cells) and the mechanism by whichsimvastatin exerts these effects.Therefore,in this study, we investigated the effects of simvastatin onOCM-1cells growth, apoptosis and cycle.Simvastatin showed aninhibitory effects on OCM-1cells viability in dose-dependent (2-10μM)and time-dependent (24-72h) manner. Further study suggested thatsimvastatin-induced inhibition OCM-1cells proliferation was associatedwith G1phase arrest, decreased protein and mRNA expression ofproliferation marker cyclin D1, cyclin E, cyclin dependent kinase (CDK)2and increased expression of CDK inhibitory protein P21. In addition,simvastatin resulted in an increase in levels of reactive oxygen species (ROS)in OCM-1cells and simvastatin significantly triggered apoptosis and autophgyin OCM-1cells, which was characterized by increased chromatincondensation,increased MDC recruitment to autophagosomes in the cytoplasmof cells,activation of caspase-9and cleaved-caspase-3,increased expressionmitochondrion-related apoptosis protein of P53, Bax,increased expressionautophgy-related protein LC-3and decreased expression of Bcl2and iASPP.Collectively, our study demonstrated that simvastatin can efficientlyinhibit proliferation and induce apoptosis and autophagy in OCM-1cells.