Abstract
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.
Highlights
Prostate cancer (PCa) is one of the most commonly diagnosed malignant tumors in men and the second leading cause of cancer-related deaths in Western countries [1]
Previous reports showed that androgen ablation affected the expression level of p-glycoprotein (ABCB1), Myxovirus resistanse A (MxA), and Y-box binding protein-1 (YB-1) in prostate cancer cell [25,26,27,28,29]
These results indicated that the expressions of ABCB1, YB-1 or MxA expression were not responsible for the different sensitivity in prostate cancer cells
Summary
Prostate cancer (PCa) is one of the most commonly diagnosed malignant tumors in men and the second leading cause of cancer-related deaths in Western countries [1]. One of the most troublesome aspects of PCa is that androgen-dependent PCa inevitably progresses to highly aggressive and life-threatening castration-resistant prostate cancer (CRPC) after androgen ablation therapy [2, 3]. Docetaxel has been approved by the U.S Food and Drug Administration, leading to regulatory approval of this cytotoxic drug to treat patients with CRPC [3, 4]. Cabazitaxel showed activity in both docetaxel-sensitive and docetaxel-resistant cancers in preclinical testing and in clinical trials, providing the rationale for further clinical development in cancers such as metastatic CRPC [5]
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