Abstract 4769: Combinatorial effect of thermally targeted p21 polypeptide and bortezomib in prostate cancer

Abstract

Abstract Prostate cancer is the most common non-skin malignancy in men and is responsible for more deaths than any other type of cancer, except lung cancer. Most cases of prostate cancer are androgen dependent. However, during androgen ablation therapy androgen-independent prostate cancer (AIPC) cells are selected via multiple mechanisms. Since, AIPC cells are immune to androgen deprivation their appearance represents a major obstacle in the treatment of prostate cancer. Several mechanisms used by prostate cancer cells require proteasome function among which is androgen receptor recycling as well as degradation of NK-KB inhibitor IKB. Bortezomib, a FDA-approved proteosome inhibitor for the treatment of multiple myeloma was shown to induce growth arrest and apoptosis in many tumor types including AIPC, where it was shown to have a modest effect as a single treatment regime. Previously in our laboratory, Bac-ELP-p21 was found to inhibit the proliferation of SKOV3 ovarian cancer cells and induce S-phase arrest as well as apoptosis. Driven by the need for new therapeutic means for AIPC, we investigated the inhibitory effects of the p21 mimetic peptide on the growth of the androgen independent prostate cancer cell lines PC3 and DU145 as well as its potential to be used as a combination therapy with Bortezomib. For our prostate cancer research, we have further optimized the delivery system in order to get higher yields of purified protein as well as better temperature response. The redesigned p21-ELP1-Bac polypeptide retained its ability to enter both PC3 and DU145 cells and localize into the nucleus, which was confirmed using confocal microscopy and flow cytometry, respectively. Using MTS assay, we have shown that the IC50 value of both Bortezomib and the p21 mimetic peptide decreased by 1.5 and 4.5 times, respectively, when those two drugs were used in combination in both PC3 and DU145 prostate cancer cell lines. Furthermore, the combination treatment lead to an increase in phosphatidylserine exposure in both cell lines observed using flow cytometry after staining with Alexa 488 Annexin and propidium iodide. Using a BrdU incorporation assay combined with PI staining, we found that treatment with p21-ELP-Bac after treatment with Bortezomib caused an increase in the G1 phase of arrested cells in both cell lines. The thermally responsive macromolecular carrier combines the advantages of thermal targeting to the tumor site with targeting of a specific molecular pathway. Our results show that small molecule proteosomal inhibition combined with p21-ELP-Bac represents a promising AIPC treatment that can be further utilized with other therapeutic peptides. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4769. doi:1538-7445.AM2012-4769