HISTONE DEACETYLASE INHIBITOR, ROMIDEPSIN (FK228) IMPROVES ANTITUMOR EFFECTS OF DOCETAXEL AND CISPLATIN IN MODELS OF AGGRESSIVE PROSTATE CANCER

Background: Once castration resistance is documented and secondary hormone therapy is ineffective, standard treatment of metastatic prostate cancer is with docetaxel (first-line) and platinum derivatives (second-line). Aim: We investigated the cytotoxicity and biology of the histone deacetylase inhibitor Romidepsin (FK228), as well as its capacity to restore sensitivity to docetaxel or cisplatin in hormone-refractory prostate cancer cells. Results: Romidepsin inhibited HDAC activity, produced acetylation of the histone proteins and induced dose-dependent apoptosis that was associated with prominent G sub(2)/M arrest, decrease in S-phase population, increase in p21 protein expression, and down-modulation of cyclins B1 and D1. FK228 led to up-regulation of cleaved caspase-3 and PARP. BCL2 antagonists, such as HA-14-1, enhanced the effects of FK228 in these prostate cancer models. In vivo, FK228 (0.8 mg/kg i.p.) reduced tumor proliferation and induced apoptosis in both xenografts, up-modulating the expression of p16 super(INKA), BAX, BAK, p21 super(WAF1), and p27 super(KIP1), and inhibiting the activation of AKT and the expression of cyclin D1, BCL-2 and BCL-XL. Combined FK228 and chemotherapeutic agent (docetaxel and cisplatin) exposure resulted in strong synergistic apoptosis in all cell lines (combination indices ranged between 0.19 and 0.6). Furthermore, compared to either agent alone, FK228/docetaxel and FK228/cisplatin combinations resulted in increased caspase cleavage and histone hyperacetylation. In vivo, this agent caused tumor growth delay without complete regression in xenograft systems. FK228 sensitized PC3 and 22rv1 xenografts to docetaxel and cisplatin treatments. These combinations were also tolerable in mice and superior to the use of either agent alone. Conclusion: As docetaxel and platinum derivatives are the standard first- and second-line chemotherapy for hormone-refractory prostate cancer, the development of chemotherapy-based combination therapies is of great interest for this disease stage. Our results provide a rationale for clinical trials on combination treatments with FK228 in patients with hormone-refractory and chemoresistant prostate tumors.