Effect of Verapamil and Cyclosporin A on Cytotoxic Effect of Vinblastine upon Human Renal Cell Carcinoma Cell Lines

Kim, Hyeong Gon; Kim, Hyeon Hoe; Lee, Chongwook

Abstract

It is well known that renal cell carcinoma shows poor responses upon chemotherapy, and a multidrug-resistance has been suggested as one of the possible mechanisms of their resistances to chemotherapeutics of renal cell carcinoma as well as other malignancies. In our previous study, MDR was expressed relatively high in A-498 cell line, low in Caki-2 cell line. From these observation A-498 was selected as the MDR positive cell line and Caki-2 as the MDR negative cell line and then a study was performed to evaluate the effect of verapamil and cyclosporin A on the cytotoxicity of vinblastine, which are known as the most effective chemotherapeutic agent on human renal cell carcinoma, upon these cell lines. And we tried to evaluate the effect of combination of verapamil and cyclosporin A on the cytotoxicity of vinblastine. Verapamil, in concentration of 0.1 uM, did not enhance the anticancer effect of vinblastine on A-498 cells but with the concentration of 1uM and 10uM, it decreased IC50 of vinblastine from 0.4 ug/ml when only vinblastine was used to 0.05 and 0.08, showing the dose modification effect of 8.40 and 5.25 respectively (p<0.05, by Mann Whitney test) Cyclosporin A, in all the concentration of 0.3, 1, 3uM, also decreased IC of vinblastine on A-498 cells to 0.08, 0.05, 0.08 ug/ml respectively, showing the dose modification effect of 5.25 to 8.40 (p<0.05, by Mann Whiney test). In caki-2 cells in which MDR1 and p-glycoprotein expression were barely detected, verapamil and cyclosporin A did not show any effect upon the cytotoxicity of vinblastine. Combination of 0.3uM of cyclosporin A and 0.1uM or 1uM of verapamil did not resistance modulating agents to enhance the cytotoxicity of vinblastine in renal cell carcinoma with enhanced multidrug resistance, but the combination of these drugs did not show any synergistic effect. And further studies including in vivo study and combination of cyclosporin A are needed before clinical trials to improve chemotherapeutic effect upon renal cell carcinoma.