Effect of the multidrug resistance protein on the transport of the antiandrogen flutamide.

摘要: Prostate cancer is the most common noncutaneous malignancy of American men. Although it can be initially treated with androgen deprivation therapy, tumors that relapse become resistant to future hormonal manipulation. We previously found multidrug resistance protein (MRP), MRP1, overexpressed in advanced stage and grade human prostate negatively regulated by p53. In this study, we sought determine whether cellular accumulation antiandrogen flutamide, a drug commonly used treatment cancer, affected MRP1 expression. There were significant differences between wild-type MRP1-overexpressing cells efflux flutamide hydroxyflutamide, its active metabolite. contrast, transport dihydrotestosterone was not MRP1. Treating leukotriene D4, known substrate, or VX-710, an modulator, restored hydroxyflutamide accumulation. Finally, intracellular glutathione depletion buthionine sulfoximine energy using 2-deoxy-d-glucose/sodium azide parental while incubating at 4°C abolished MRP1-mediated transport. summary, these studies indicate but are transported findings may contribute our understanding hormone refractory cancer.