Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer

Reactive oxygen species (ROS) production induced by taxanes in cancer cells may influence the taxane-induced cell death or the drug resistance. We investigated the correlation between the cytotoxic effect of taxanes and ROS production in human castration-resistant prostate cancer (CRPC) cell lines. Three human prostate cancer cell lines were treated with increasing concentrations of docetaxel or cabazitaxel in vitro. Cabazitaxel showed significantly higher cytotoxic efficacy than docetaxel in human CRPC cells, accompanied by elevated ROS production detected by FACS analysis. To investigate whether cabazitaxel-mediated cell death was caused by the ROS generation induced by cabazitaxel, we treated CRPC cells in the presence of antioxidant NAC. NAC reduced the cytotoxic effect induced by cabazitaxel. We found that ROS elimination by Sestrin-3 (SESN3) was significantly inhibited by cabazitaxel, but not by docetaxel. These results indicate higher sensitivity of human CRPC to cabazitaxel compared to docetaxel involves ROS production through inhibiting the expression of antioxidant enzyme SESN3.