Abstract
Resistance to cisplatin (CDDP) in ovarian cancer (OVCA) arises from the dysregulation of tumor suppressors and survival signals. During genotoxic challenge, these factors can be influenced by secondary agents that facilitate the induction of apoptosis. Piceatannol is a natural metabolite of the stilbene resveratrol found in grapes and is converted from its parent compound by the enzyme CYP1BA1 p450. It has been hypothesized to exert specific effects against various cellular targets; however, its ability to influence CDDP resistance in cancer cells has not been investigated to date. Here, we show that piceatannol is a potent enhancer of CDDP sensitivity in OVCA, and this effect is achieved through the modulation of several major determinants of chemoresistance. Piceatannol enhances p53-mediated expression of the pro-apoptotic protein NOXA, increases XIAP degradation via the ubiquitin-proteasome pathway, and enhances caspase-3 activation. This response is associated with an increase in Drp1-dependent mitochondrial fission, leading to more effective induction of apoptosis. In vivo studies using a mouse model of OVCA reveal that a number of these changes occur in association with a greater overall reduction in tumor weight when mice are treated with both piceatannol and CDDP, in comparison to treatment with either agent alone. Taken together, these findings demonstrate the potential application of piceatannol to enhance CDDP sensitivity in OVCA, and it acts on p53, XIAP, and mitochondrial fission.