Molecular mechanism mediating cytotoxic activity of cabazitaxel in docetaxel-resistant human prostate cancer cells

Abstract

Background/Aim: Cabazitaxel is known to be effective in patients with castration-resistant prostate cancer (CRPC) showing resistance to docetaxel. The objective of this study was to investigate the molecular mechanism mediating cytotoxic activity of cabazitaxel in docetaxelresistant human CRPC cells. Materials and Methods: Parental human CRPC cell line PC3 (PC3/P) was continuously exposed to increasing doses of docetaxel, and a cell line resistant to docetaxel, PC3/R, was developed. Phenotypic differences between these cell lines were investigated. Results: There were no significant differences in sensitivity to cabazitaxel between PC3/P and PC3/R. In PC3/P, both docetaxel and cabazitaxel markedly inhibited the phosphorylation of AKT serine/threonine kinase 1 (AKT) and p44/42 mitogen-activated protein kinase (MAPK). In PC3/R, however, phosphorylation of AKT and p44/42 MAPK were maintained following treatment with docetaxel, whereas treatment with cabazitaxel resulted in the marked downregulation of phosphorylation of AKT but not that of p44/42 MAPK. Furthermore, additional treatment of PC3/R with a specific inhibitor of AKT significantly enhanced the cytotoxic activity of docetaxel but not that of cabazitaxel. Growth of PC3/R in nude mice after treatment with cabazitaxel was significantly inhibited compared with that after treatment with docetaxel. Conclusion: Antitumor activity of cabazitaxel in docetaxel-resistant CRPC cells was explained, at least in part, by the inactivation of persistently phosphorylated AKT even after treatment with docetaxel.