Despite advances in screening and treatment, prostate cancer (PCa) remains a leading cause of death among American men. A wide range of novel therapies have been introduced for treatment of PCa which lead to dramatic regression of the primary tumor. However, responses are often short-lived due to the development of resistant cancer cells. Cabazitaxel, a microtubule targeting agent, is approved for treatment of metastatic hormone-refractory PCa in patients pretreated with docetaxel. However, toxicity and resistance are associated with cabazitaxel treatment. Therefore, an effective approach that can achieve long-term improvement is urgently needed for the management of PCa. One of the strategies proposed for overcoming resistance is combination therapy. Natural dietary substances have received considerable attention as chemoprevention and chemotherapeutic agents because of their unique property that allows them to interact with multiple targets in cancer cells. Fisetin, a small molecule, has emerged as one of the natural agent with enormous potential in cancer chemoprevention and chemotherapy. This study was designed to investigate the effect of a combination of fisetin and cabazitaxel to achieve maximum therapeutic benefits, reduce dose and toxicity, and to minimize or delay the induction of drug resistance. We observed that treatment of PCa cells with fisetin (20-80 μM) for 24-48 hours and then cabazitaxel (20-80 nM) for 24 hours significantly retarded the growth of PCa cells when compared to cabazitaxel or fisetin alone. The combination resulted in 80% inhibition of cell growth when compared to cabazitaxel (30%) or fisetin alone (18%). In addition, the combination (fisein, 20μM, cabazitaxel 5 nM) treatment significantly inhibited colony formation compared to each agent alone. We next implanted 22Rν1 cells for determining the effects of fisetin, cabazitaxel and their combination. A total of 24 athymic nude male mice (6-8) weeks of age were injected subcutaneously with 1×106 22Rν1 cells. Two weeks later, tumor bearing mice were randomly divided into four groups (n = 6) and treated with fisetin (20 mg/kg; 3 times/week), cabazitaxel (5 mg/kg; once/week), and combination of fisetin (20 mg/kg; 3 times/week) and cabazitaxel (5 mg/kg; once/week), or vehicle (control) via intraperitoneal route. We observed that treatment with fisetin alone resulted in 14% inhibition of tumor growth; cabazitaxel treatment alone resulted in 36% inhibition whereas combination treatment with fisetin and cabazitaxel resulted in 53% inhibition of tumor growth compared with the control group. Tissue staining with proliferation marker Ki67 confirmed the in-vivo effect of fisetin and cabazitzxel on inhibition of cell proliferation. This study potentiates the benefit of combination of fisetin and cabazitaxel that could eliminate rapidly proliferating and resistant cells in PCa and possibly other cancer types.

Citation Format: Eiman Mukhtar, Vaqar Mustafa Adhami, Mario Sechi, Hasan Mukhtar. Fisetin enhances the efficacy of cabazitaxel: an in vitro and in vivo study in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2531. doi:10.1158/1538-7445.AM2015-2531

©2015 American Association for Cancer Research.
2015