The effect of vitamin D3 and ketoconazole combination on VDR-mediated P-gp expression and function in human colon adenocarcinoma cells : implications in drug disposition and resistance

The vitamin D3 metabolite 1,25-dihydroxycholecalciferol (DHC) and analogues derived from it are being investigated as potential agents for the treatment of cancer. Combining ketoconazole (KTZ) with DHC has been recommended to enhance the anticancer activity of DHC. DHC exerts its biological activities through the vitamin D receptor (VDR). VDR is recognized to be a regulator of P-glycoprotein (P-gp), a member of the ABC transporter family well known for its role in multidrug resistance in cancer chemotherapy. We have investigated the effect of DHC and adding KTZ together with DHC on P-gp and VDR expression and the functional consequences of P-gp induction in intestinal human colonic adenocarcinoma cells LS174T cells. DHC increased P-gp expression by two times, and the addition of KTZ further increased the expression to four times. The combination of DHC+KTZ also significantly increased VDR expression, consistent with the enhanced increase in P-gp expression by this combination. The increase in P-gp expression was accompanied by increased P-gp function, as measured by decreased Rh123 accumulation in the LS174T cells. In addition, DHC significantly decreased colchicine cytotoxicity in a dose-sensitive manner, and the addition of KTZ further decreased the colchicine cytotoxicity, indicating the chemo-protective effect of DHC is enhanced by KTZ, consistent with the enhanced expression of P-gp. The results of this study raise the possibility that DHC and the addition of KTZ to DHC treatment may decrease the effectiveness of cancer chemotherapy by promoting P-gp-mediated drug resistance.