@article {WATANABE3753, author = {HIROMITSU WATANABE and ASUKA KAWAKAMI and RYO SATO and KYOHEI WATANABE and YUTO MATSUSHITA and HIDEAKI MIYAKE}, title = {Molecular Mechanism Mediating Cytotoxic Activity of Cabazitaxel in Docetaxel-resistant Human Prostate Cancer Cells}, volume = {41}, number = {8}, pages = {3753--3758}, year = {2021}, doi = {10.21873/anticanres.15167}, publisher = {International Institute of Anticancer Research}, 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 docetaxel-resistant 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 down-regulation 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.}, issn = {0250-7005}, URL = {https://ar.iiarjournals.org/content/41/8/3753}, eprint = {https://ar.iiarjournals.org/content/41/8/3753.full.pdf}, journal = {Anticancer Research} }