Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo

Suberoylanilide hydroxamic acid (SAHA) is the prototype of a family of hybr id polar compounds that induce growth arrest in transformed cells and show promise for the treatment of cancer. SAHA induces differentiation and/or ap optosis in certain transformed cells in culture and is a potent inhibitor o f histone deacetylases, In this study, we examined the effects of SAHA on t he growth of human prostate cancer cells in culture and on the growth of th e CWR22 human prostate xenograft in nude mice. SAHA suppressed the growth o f the LNCaP, PC-3, and TSU-Prl cell lines at micromolar concentrations (2.5 -7.5 mu M). SAHA induced dose-dependent cell death in the LNCaP cells. In m ice with transplanted CWR22 human prostate tumors, SAHA (25, 50, and 100 mg /kg/day) caused significant suppression of tumor growth compared with mice receiving vehicle alone; treatment with 50 mg/kg/day resulted in a 97% redu ction in the mean final tumor volume compared with controls. At this dose, there was no detectable toxicity as evaluated by weight gain and necropsy e xamination. Increased accumulation of acetylated core histones was detected in the CWR22 tumors within 6 h of SAHA administration. SAHA induced prosta te-specific antigen mRNA expression in CWR22 prostate cancer cells, resulti ng in higher levels of serum prostate-specific antigen than predicted from tumor volume alone. The results suggest that hydroxamic acid-based hybrid p olar compounds inhibit prostate cancer cell growth and may be useful, relat ively nontoxic agents for the treatment of prostate carcinoma.