The Effect of Medroxyprogesterone Acetate On Cytotoxicity of Vinblastine in Renal Cell Carcinoma Cell Lines

Lee, Dong Hyeon; Chung, Byung Ha; Hong, Sung Joon

Abstract

Inadequate effectiveness of anticancer drug in treating renal cell carcinoma has been attributed to the overexpression of multidrug resistance gene (MDR1) and its product, membrane-bound P-glycoprotein. P-glycoprotein is known to actively pump out intracellular drug, which results in low intracellular anticancer drug concentration. Progesterone, which has been used in patients with advanced renal cell carcinoma is found to cause a three to four-fold increase in vinblastine accumulation in the P-glycoprotein-expressing murine macrophage-like cell line.We have studied to evaluate the MDR modulating action of medroxyprogesterone acetate (MPA) in renal cell carcinoma cell lines also with tamoxifen and verapamil. A-498 of a high mdrl expressed cell line and Caki-2 of a low mdrl expressed cell line were each placed in 96 multiwell plates. Vinblastine, in concentration from 0.01 ug/ml to 10 ug/ml was added to each well and verapamil, from 0.1 uM to 10 uM, MPA, from 2.5 uM to 25 uM, or tamoxifen, from 0.1 uM to 10 uM was also added. The in vitro chemosensitivity of two renal cell carcinoma cell lines (Caki-2 and A498) to vinblastine was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol bromide(MTF) colorimetric assay. Growth of Caki-2 cells is inhibited by low doses of vinblastine(IC50: 0.27 ug/ml), but A-498 cells are highly resistant to the drug, with ICs0 value of 0.47 ug/ml. The chemosensitivity of the A-498 cells is increased in response to 5 uM MPA, 1 uM verapamil and 2 uM tamoxifen, which are known to partially reverse the MDR phenotype in other resistant tumors. The effective concentration of MPA for MDR reversal is in clinically achievable concentration but one of verapamil is not. The chemosensitivity of Caki-2 cells does not change according to MDR modulating agents. .MPA is an effective MDR modulating agents to enhance the cytotoxicity of vinblastine in renal cell carcinoma cell line showing P-glycoprotein expression. It suggests that combination therapy of MPA and vinblastine is better than monotherapy with MPA or vinblastine alone.