Effects of Simvastatin in Combination with Anticancer Drugs on Proliferation and Migration in Cholangiocarcinoma Cells

Abstract

Developing new treatment options for cholangiocarcinoma is necessary because of the adverse drug reactions and drug resistance problems associated with current chemotherapeutics. Therefore, this study examined cytotoxic, apoptotic and antimigratory effects of simvastatin used in combination with anticancer drugs (5-fluorouracil and cisplatin) against human cholangiocarcinoma cells and investigated the underlying molecular mechanism (s) of action. Proliferation, apoptosis and migration of cholangiocarcinoma cells were determined by sulforhodamine B, flow cytometry, colony formation, reactive oxygen species formation, caspase 3 activity, wound healing and western blotting. We observed that the two test statins, simvastatin and atorvastatin, enhanced 5-fluorouracil and cisplatin cytotoxicity against cholangiocarcinoma cells, simvastatin showed the higher effects than atorvastatin. Further, simvastatin plus 5-fluorouracil and cisplatin decreased colony formation and in combination induced p21 and reduced cyclin D1 protein. Furthermore, combination treatment augmented the apoptosis of cholangiocarcinoma cell through stimulating reactive oxygen species generation and caspase 3 activity as well as upregulating caspase 3 levels. Simvastatin also potentiated antimigratory effect of anticancer drugs via reduction in matrix metalloproteinase 9 levels. Accordingly, the combination of simvastatin with anticancer drugs could be considered a novel strategy to expand treatment options for cholangiocarcinoma.