Regulation of Drug Sensitivity by Functional Status of p53 in Human Prostate Cancer

摘要

Mulidrug resistance protein MRP1 is overexpressed in advanced stage and grade human prostate cancer and is negatively regulated by p53. We found that antiandrogen flutamide is affected by MRP1 expression. There were significant differences between the sensitive and MRP1-overexpressing cells in efflux and accumulation. Intracellular glutathione depletion with buthionine sulfoximine or energy depletion using 2-deoxy-D-glucose/sodium azide restored flutamide accumulation to that of parental cells. These studies indicate that flutamide and hydroxyflutamide are transported by MRP1 and that these findings may contribute to our understanding of resistance to hormone refractory prostate cancer. We also determined the effect of compounds that alter p53 function on MRP1 expression. We found that chlorpromazine, promazine, and trans- flupenthixol caused a 2-3 fold increase in wild-type p53 conformation and CP- 31398 increased wild-type p53 conformation 6-10-fold. Promazine and chlorpromazine increased p21 in a dose-dependent manner. LVCap cells exposed to CP-31398 showed a 5-fold increase in p21 and 10-fold decrease in MRP1. These data suggest that CP-31398 is an effective inducer of p21 expression and MRP1 repression in the prostate cancer cells and that compounds with similar structures and greater activity can be identified.