Abstract 2491: Biphasic effect of psoralidin on cell cycle regulatory markers in hormone refractory prostate cancer

Abstract

Abstract Cell cycle deregulation has been strongly associated with the pathogenesis of prostate cancer (PCa). Overexpression of cell cycle regulatory proteins (cyclin D1-25%, cyclin A-35% and cyclin B-75%) have been reported in clinical PCa samples when compared to normal prostate tissue. Based on this, we rationalized that downregulation of cell cycle regulatory molecules may play an important role in chemoprevention/therapy of PCa. We previously published that psoralidin; a natural compound effectively suppresses PCa growth both in vitro and in vivo. Hence, in this study we determined whether psoralidin alters cell cycle regulatory proteins in PCa cells. To determine this we performed cell cycle analysis using PI staining and also studied the expression patterns and activity of various cell cycle regulatory markers using Western blot analysis and kinase assays respectively in two hormone refractory prostate cancer (HRPC) cells (PC-3 and DU-145) following treatment with or without psoralidin in dose dependent manner. Psoralidin has biphasic effect on PCa cells where at a lower concentration (40µM) caused a G0/G1 cell cycle arrest whereas at a higher concentration (60µM) caused a G2/M cell cycle arrest. Psoralidin at lower concentration induced expression of cyclin dependent kinase inhibitors (p27, p57, p21, p16) in PC-3 and DU-145 cells whereas at higher concentration upregulation of p18 was observed in both HRPC cells. Additionally, we found that at lower concentration cyclins (E & E2 and H) and cdks (6 and 9) are downregulated whereas at higher concentration psoralidin downregulated expression of cyclins (D1, A, E & E2, B1, D3 and H) and cdks (6, 7, 2 and 9) in both HRPC cells. At lower concentration psoralidin inhibits expression of cdc-2 and cdc-25B whereas at higher concentration cdc-2, −25A and −25B are downregulated in both PC-3 and DU-145 cells. Also, psoralidin inhibited phosphorylation of Rb at both lower and higher concentration in HRPC cells causing irreversible cell cycle arrest resulting in the induction of apoptosis. These results clearly highlight the potential of psoralidin as a therapeutic agent for PCa. Currently, we are investigating the effect of psoralidin on cell cycle markers using both xenograft and TRAMP models. The outcome of our study may enable bringing psoralidin to the mainstream of medicine for prevention and/or therapy for PCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2491.