Abstract 835: Fisetin enhances the efficacy of cabazitaxel chemotherapy in prostate metastatic and multidrug- resistant cancer cells

Abstract

Abstract Natural compounds that target microtubules and disrupt the normal function of the mitotic spindle have proven to be the drug of choice for cancer chemotherapeutic in clinics. The development of primary and acquired drug resistance to chemotherapy, however, remains a significant clinical concern. Microtubule targeting agents are typically susceptible to drug resistance that is mediated by P-gp, a broad-spectrum efflux pump that removes these compounds from cells, thus counteracting their anticancer effects. Cabazitaxel, a semi-synthetic derivative of natural Taxanes, well known microtubule-stabilizing agents, has been approved for the treatment of metastatic prostate cancer (PCa); however, most patients progress and become chemoresistant, which remains a major challenge in the management of advanced PCa. The development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance could provide more effective therapeutic options for PCa patients. Here, we investigated whether fisetin, a dietary flavonoid, could sensitize PCa cells and a P-gp-overexpressing NCI/ADR-RES, a well-known multidrug-resistant cancer cell line to cabazitaxel treatment. The effect of fisetin in enhancing the response of cancer cells to cabazitaxel chemotherapy was evaluated in several cancer cells. Fisetin exhibited an anti-proliferative effect by enhancing tubulin polymerization and mitotic arrest, which ultimately led to apoptotic cell death. Fisetin increased the expression of microtubule-associated proteins MAP-2 and MAP-4 and the PC-3 and DU-145 cells were enriched in acetylated alpha tubulin, an indication of stabilization of microtubules. Also, fisetin inhibited the migration of PC-3 cell in scratch wound assay. Further, we examined the susceptibility of NCI/ADR-RES cells to fisetin treatment. Fisetin (10-80 µM) induced apoptosis in a dose and time dependent manner. Treatment of cells with a combination of fisetin (10-80 µM) and cabazitaxel (10-120 nM) significantly retarded the growth of PC-3, C4-2, 22Rv1 and multidrug-resistant cancer cells when compared to vehicle control or cabazitaxel or fisetin alone treated cells. Moreover, we found that activation and cleavage of Caspase-3 and PARP are significantly enhanced in cells treated with combination of fisetin and cabazitaxel than with\ each agent alone. This response was also associated with increase in the expression of pro-apoptotic protein Bax and down-regulation of anti-apoptotic Mcl-1. These findings highlight the novel effect of fisetin as a microtubule-stabilizing agent with poor susceptibility to P-gp and provide the first evidence supporting that fisetin could be further developed for sensitizing resistant cancer cells and used as an adjuvant with cabazitaxel for therapy of PCa and potentially other cancer types. Citation Format: Eiman Mukhtar, Vaqar Mustafa Adhami, Hasan Mukhtar. Fisetin enhances the efficacy of cabazitaxel chemotherapy in prostate metastatic and multidrug- resistant cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 835. doi:10.1158/1538-7445.AM2014-835