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VX-680 is one selective small-molecule inhibitor of the Aurora kinases. It has been shown to disrupt motosis and induce apoptosis in a wide variety of tumor cell lines. However, its effect on human cholangiocarcinoma (CCA) cells remains uncharacterized. In the current study, we observed the effects of VX-680 on the human CCA (QBC939 and HCCC-9810) cell line. In cell culture, VX-680 inhibited proliferation and induced apoptosis of tumor cell growth in a dose-dependent and time-dependent manner, and exerted the most effective cytotoxicity against HCCC-9810 cells. The proliferation inhibition rate increased from 5.39 to 51.74%, whereas the apoptosis rate increased from 9.59 to 50.02% when HCCC-9810 cells were cultured with 5 µmol/l VX-680 for 48 h. Immunoblot analysis showed that the expression of phospho-p53(Ser-15) was upregulated after 48 h treatment of the cancer cells with VX-680. This activation in p53 was associated with a decrease in Bcl-2 and an increase in Bax, which led to the expression of its downstream effectors (caspase-9 and caspase-3). We further found that pifithrin-α, a p53 inhibitor, attenuated the anticancer effects of VX-680 and downregulated the expression of apotosis-related proteins (Bax and caspase-9). These results suggest that VX-680 could mediate cell death by acting on a P53/Bax/ caspase-3-dependent pathway in human CCA cells.