Abstract 621: Combined treatment of fisetin and cabazitaxel significantly inhibits tumor growth and metastasis of prostate cancer cells

Drugs that affect microtubule dynamics are among the most effective anticancer agents in routine clinical use. However, the effectiveness of these drugs has been impaired by severe side effects and subsequent development of drug resistance. Continued investigation into the development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance may provide more effective therapeutic options for cancer patients. Considering these facts we believe that natural agents from dietary sources could offer a safe and effective alternative to existing repertoire of microtubule-targeting agents in combination with standard of care. In line with this we have observed that fisetin is a microtubule stabilizing agent and significantly affects microtubule dynamics. We hypothesized that fisetin will enhance the efficacy of cabazitaxel in advanced and metastatic human PCa cells both in vitro and in vivo. We determined the effect of fisetin alone and in combination with cabazitaxel on in vitro and in vivo in a subcutaneous xenograft mouse model. Human prostate cancer PC-3M-luciferase cells (3×103) were injected into 24 athymic nude mice. Two weeks post cell implantation, mice were divided into four groups of 6 animals, and then treated with fisetin (20 mg/kg; 3 times/week), cabazitaxel (5 mg/kg; once/week), combination of fisetin (20 mg/kg; 3 times/week) and cabazitaxel (5 mg/kg; once/week), or vehicle (control) via intraperitoneal route for 8 weeks. Tumor growth of live mice was monitored manually and by IVIS™ imaging system. Combination treatment with fisetin and cabazitaxel significantly (p = 0.0008) inhibited the growth of tumors compared to control and individual treatment groups. We observed only 2.7 fold increase in tumor volume in the combination group over three weeks, while cabazitaxel or fisetin alone resulted in 5 fold increase, and tumor in the control group increased by 7 folds. In addition, we also observed that treatment with fisetin and cabazitaxel alone resulted in 10% and 12% inhibition in tumor growth respectively. However, combination of fisetin and cabazitaxel resulted in 71% inhibition in tumor growth. We next tested the effect of the combination in vitro using PC-3M-luciferase cells. We observed significant inhibition in the protein expression of Ki-67 and PCNA and metastatic markers MMP9 and MMP2 in the combination group compared with each agent alone. In addition, PC-3M-luciferase cells treated with fisetin (20 μM) for 48 hours and then treated with cabazitaxel (5nM) significantly inhibited the migration, invasion and proliferation of these cells. The combination resulted in significant reduction in the effective dose of cabazitaxel. Taken together, these results suggest that fisetin can be used in combination with cabazitaxel to inhibit tumor growth and metastasis of advanced human prostate cancer. Citation Format: Eiman Mukhtar, Vaqar M. Adhami, Imtiaz A. Siddiqui, Hasan Mukhtar. Combined treatment of fisetin and cabazitaxel significantly inhibits tumor growth and metastasis of prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 621.