Abstract

New treatments are needed for cholangiocarcinoma, an aggressive cancer with a poor prognosis. Combination of statins and bisphosphonates may be useful in treating cancer through influencing the mevalonate pathway. We studied the synergistic effects of simvastatin and alendronate against cholangiocarcinoma cells, looking first at cytotoxic, apoptotic and anti-migratory effects, then possible mechanisms of action. Individually, both simvastatin and alendronate increased cholangiocarcinoma cell death and the combination was more effective. Additionally, the combination treatment inhibited colony formation, reduced protein-related cell proliferation, NF-κB and cyclin D1, and increased p53 protein-related cell death. Apoptosis was induced by the combination treatment through activation of early apoptotic cells and stimulation of the caspase 3 enzyme. The combination treatment also decreased cancer cell migration by suppressing matrix metalloproteinases, metalloproteinase-2 and metalloproteinase-9 levels. Finally, the combination treatment reduced Rac1 protein expression in the mevalonate pathway. Our study shows that a combination of simvastatin plus alendronate has a direct anticancer and anti-migratory effect on cholangiocarcinoma cells in vitro. Mevalonate inhibitors could be used as therapeutic options for cholangiocarcinoma and perhaps, as chemotherapy-sensitizing agents.