Resveratrol induces cell cycle arrest and apoptosis with docetaxel in prostate cancer cells via a p53/ p21 WAF1/CIP1 and p27 KIP1 pathway

// Santosh Kumar Singh 1 , Saswati Banerjee 1 , Edward P. Acosta 2 , James W. Lillard 1 , Rajesh Singh 1 1 Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA 2 Department of Pharmacology & Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA Correspondence to: Rajesh Singh, email: rsingh@msm.edu Keywords: cell cycle, resveratrol, docetaxel, p21, p53 Received: December 10, 2016      Accepted: January 24, 2017      Published: February 13, 2017 ABSTRACT Resveratrol (RES) is the most effective natural products used for the treatment of a variety of cancers. In this study, we tested the effect of RES in enhancing the efficacy of docetaxel (DTX) treatment in prostate cancer (PCa) cells. The C4-2B and DU-145 cell lines were treated with RES, DTX and combination followed by evaluating the apoptosis and cell cycle progression. The combined drug treatment up-regulates the pro-apoptotic genes ( BAX, BID , and BAK ), cleaved PARP and down regulates the anti-apoptotic genes ( MCL-1, BCL-2, BCL-XL ) promoting apoptosis. In C4-2B cells the combination up regulated the expression of p53 , and cell cycle inhibitors (p21 WAF1/CIP1, p27 KIP ), which, in turn, inhibited the expression of CDK4, cyclin D1, cyclin E1 and induced hypo-phosphorylation of Rb thus blocking the transition of cells in the G 0 /G 1 to S phase. In contrast, the synergistic effect was not profound in DU145 due to its lesser sensitivity to DTX. The suppression of cyclin B1 and CDK1 expression in both cell lines inhibits the further progression of cells in G 2 /M phase. The current study demonstrates that combination treatment blocks the cell cycle arrest by modulation of key regulators and promotes apoptosis via p53 dependent and independent mechanism in PCa.