Oleanolic acid methyl ester, a novel cytotoxic mitocan, induces cell cycle arrest and ROS-Mediated cell death in castration-resistant prostate cancer PC-3 cells

Abstract

Oleanolic acid derivatives exhibit potent anticancer activities against numerous types of cancer. However, the antitumor activity of oleanolic acid methylester (OAME), an oleanolic acid derivative, against prostate cancer has not been studied. Hence, the present work was conducted to study the anticancer activities of OAME. Viability assay showed that treatment of cancer cells with OAME induced a significant cell death in concentration- and time-dependent manner. Of note, OAME displayed a selective cytotoxicity against cancer cells compared to normal epithelial cells. Cells treated with OAME exhibited cell cycle arrest at both G1 and G2. Apoptotic induction potential of OAME was demonstrated using Annexin V assay, caspase activation, and DNA fragmentation methods Mechanistically, the results revealed that OAME strongly impacted the intrinsic apoptotic pathway in a concentration-dependent manner, as demonstrated by loss of mitochondrial membrane potential and release cytochrome c into the cytosol. ROS scavenger completely abrogated OAME-induced cell death. In vivo, OAME exerted concentration- dependent antiproliferative effect, associated with a significant level of apoptosis, potent antiangiogenic activity, and downregulation of survivin. This study provides significant insight into the therapeutic activities of OAME against prostate cancer in vitro and in vivo, suggesting that OAME might serve as a promising lead compound to treat hormonal-resistant prostate cancer.