Histone deacetylase inhibitor potentiates anticancer effect of docetaxel via modulation of Bcl-2 family proteins and tubulin in hormone refractory prostate cancer cells.

We evaluated the antitumor effects of docetaxel (Sigma®) and histone deacetylase inhibitors in hormone refractory prostate cancer cells, and analyzed the mechanism by which combination treatment induced cell death. We used LNCaP, DU145 and PC3 cells (ATCC®) to evaluate the in vitro apoptotic effects of histone deacetylase inhibitors and their combinations with docetaxel as well as the molecular mechanisms. The DU145 xenograft model was used to evaluate the in vivo efficacy of PXD101 combined with docetaxel. Suberoylanilide hydroxamic acid or PXD101 inhibited the growth of hormone dependent LNCaP cells, and hormone independent DU145 and PC3 cells. It increased sub-G1 population and activated caspase-8, 9 and 3, indicating apoptosis induction. Pretreating DU145 cells with docetaxel followed by histone deacetylase inhibitors showed significant synergistic cytotoxicity compared with that of simultaneous co-treatment or reverse sequential treatment. Pretreatment with docetaxel followed by histone deacetylase inhibitors increased the apoptotic sub-G1 population, caspase activation and tubulin acetylation compared with that of docetaxel alone. Combination treatment decreased Mcl-1 and Bcl-xl, and increased t-Bid, Bik and Bim. Combined docetaxel and PXD101 reduced tumor size with efficacy equivalent to that of a double dose of docetaxel alone in the DU145 xenograft model. These preclinical results indicate that the sequential combination of docetaxel and histone deacetylase inhibitors led to a synergistic increase in the death of hormone refractory prostate cancer cells via intrinsic and extrinsic apoptotic pathways by modulating Bcl-2 family proteins and tubulin in vitro and in vivo. Results suggest that this combination may be a new therapeutic modality in patients with hormone refractory prostate cancer.

Hwang JJ ，Kim YS ，Kim MJ ，Kim DE ，Jeong IG ，Kim CS ... -  《-》

A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl-XL.

Hwang JJ ，Kim YS ，Kim T ，Kim MJ ，Jeong IG ，Lee JH ，Choi J ，Jang S ，Ro S ，Kim CS ... -  《-》

Activity of suberoylanilide hydroxamic Acid against human breast cancer cells with amplification of her-2.

Bali P ，Pranpat M ，Swaby R ，Fiskus W ，Yamaguchi H ，Balasis M ，Rocha K ，Wang HG ，Richon V ，Bhalla K ... -  《CLINICAL CANCER RESEARCH》

Docetaxel followed by castration improves outcomes in LNCaP prostate cancer-bearing severe combined immunodeficient mice.

Tang Y ，Khan MA ，Goloubeva O ，Lee DI ，Jelovac D ，Brodie AM ，Hussain A ... -  《CLINICAL CANCER RESEARCH》

Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models.

Festuccia C ，Gravina GL ，D'Alessandro AM ，Muzi P ，Millimaggi D ，Dolo V ，Ricevuto E ，Vicentini C ，Bologna M ... -  《ENDOCRINE-RELATED CANCER》