Regulation of Drug Sensitivity by Functional Status of P53 in Human Prostate Cancer
Abstract
Effective treatment of prostate cancer requires a better understanding of drug resistance mechanism and better therapeutic strategy. We previously found that flutamide, and anti-androgen commonly used in the treatment of prostate cancer, was a substrate of MRPl, a transmembrane phosphoprotein. During this grant period we further characterized the properties of flutamide transport by MRPl. We demonstrated that transport of flutamide and hydroxyflutamide by MRPl was ATP-dependent, further strengthening the conclusion that flutamide and its active metabolite hydroxyflutamide were transported by MRPl. In addition, our preliminary data showed that nilutamide, a flutamide derivative that is currently used as second line hormone therapy for prostate cancer, was not a substrate of MRPl, suggesting that nilutamide may still be used in the treatment of prostate cancer with the overexpression of MRPl. Using the ELISA assay established in our laboratory, we screened a set of structurally related compounds for their activity of stabilizing p53. Among the compounds tested, we found that promazine, chlorpromazine and trans-flupenthixol were able to stabilize p53. In our LVCaP cell model that harbors a temperature-sensitive p53 mutant, the compounds that possess p53-stabilizing effect appear to be effective in sensitizing drug resistant cells to chemotherapeutic drugs.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA418093
Entities
People
- Jin-ming Yang
- William N. Hait