Enhanced Therapeutic Effect on Androgen-Independent Prostate Cancer by Depsipeptide (FK228), a Histone Deacetylase Inhibitor, in Combination with Docetaxel

Objectives: To study whether a histone deacetylase inhibitor, FK228, can enhance therapeutic efficacies of other chemotherapeutic agents against androgen-independent prostate cancer (AIPCa) and to explore any possible early biomarker for predicting drug response. Methods: The therapeutic effects of FK228-based combinations on three AIPCa cell lines (PC-3, DU145, and C4-2) were evaluated by synergisms of cytotoxicity. Cell cycle analysis and Western blot assay were used to study the underlying mechanisms of drug action and search for any potential surrogate biomarker. In addition, we investigated the in vivo antitumor effects of the FK228/docetaxel combination using the PC-3 xenograft model. Results: FK228/docetaxel surpassed other FK228-based combinations by achieving more synergism of cytotoxicity. FK228 enhanced the therapeutic effect of docetaxel against AIPCa by exhibiting markedly enhanced and prolonged inhibitory effects in vitro and better tumor regression in vivo by inducing apoptosis. It appears that p21^WAF1 induction consistently correlates with single or combination treatment. Conclusions: The results of our study have shown that FK228 is able to enhance the therapeutic effect of docetaxel against AIPCa. FK228 appears to be a promising second-line option in combination with docetaxel. The p21^WAF1 protein level can be used as a surrogate biomarker to predict and monitor the therapeutic response.