Molecular events are associated with resistance to vinblastine in bladder cancer

Abstract

Bladder cancer occurs in the majority of cases in males, which represents the fourth highest incident cancer in men and tenth in women. It is associated with a high rate of recurrence, and prognosis is poor once the cancer metastasizes to distant sites. Transitional cell cancer (TCC) is the most predominant histological type. Bladder cancer is highly chemosensitive. However, the presence of acquired drug resistance is one of the primary impediments to the success of chemotherapy. To differentiate and delineate the molecular events, we developed drug resistant human transitional bladder cancer T24 cells (DRC) by treating cells with the increasing concentration of vinblastine. We found that DRC was resistant to vinblastine in comparison to parental T24 cells. We analyzed the contributory factors that may be involved in the development of resistance. As expected, expression of permeability glycoprotein (P-gp) was up-regulated in DRC. In addition, levels of Caveolin-1 (Cav-1), Fatty acid synthase (FASN) and Cytochrome P450 (CYP450) were elevated in DRC. Downregulation of these proteins by respective specific pharmacological inhibitors and/or by siRNAs resensitized cells to vinblastine. These results suggested that differential levels of P-gp, Cav-1 and FASN except CYP450 play a major role in acquired resistant phenotype in bladder cancer.