Abstract 2623: ST3595, a new histone deacetylase (HDAC) inhibitor endowed with a peculiar mechanism of action

Abstract

Abstract The novel hydroxamic acid-based compound ST3595, was identified within an in vitro screening for its inhibitory activity on histone deacetylase's (HDAC's) (Pisano C. et al., Clin Cancer Res 2010, 16 (15): 3944-53; Dalla Valle S et al., Eur J Med Chem 2009, 44 (5): 1900-12). With aim to define its antitumor potential, we investigated the in vivo activity of ST3595 in a variety of tumor models. In addition, we performed a comparative study of ST3595 and vorinostat (SAHA) to better understand the cellular/molecular basis of the antiproliferative activity. In in vivo experiments, ST3595, delivered orally or i.p. at well-tolerated doses (100 mg/kg) induced a significant tumor growth inhibition (ranging from 57 to 87%) in a variety of human tumor xenografts (H460 non-small cell lung, HCT116 colon and A2780 ovarian carcinoma). In in vitro studies, ST3595 exhibited arrest of H460 cells (wt p53) in S phase associated with a large extent of apoptosis. Under conditions producing comparable antiproliferative effects, treatment with vorinostat resulted in a G2/M arrest with a marginal induction of apoptosis. In HT29 cells (mutant p53) ST3595 caused arrest in S and G2/M phases with apoptosis induction, whereas vorinostat induced G1 accumulation without evidence of apoptosis, thus suggesting only antiproliferative effects. To explore the basis of the different cellular effects, we investigated the modulation of various factors implicated in DNA damage response and repair, cell cycle control and regulation of apoptosis. In H460 cells, we found that, in contrast to vorinostat, ST3595 was an effective inducer of p53 acetylation, supporting a role of this p53 modification in the proapoptotic activity of ST3595. In addition, in contrast to vorinostat, ST3595 strongly affected the expression of critical proteins involved in cell cycle control and DNA damage response. In particular, ST3595 induced activation and phosphorylation of H2AX, and of the checkpoint kinases chk1 and chk2, thus supporting an interference of the HDAC inhibitor in the processes controlling DNA integrity. In the light of the use of broad-specificity HDAC inhibitors in cancer therapy and in combination with other antitumor agents, the ability of ST3595 to modulate DNA damage response and it proapoptotic efficacy may have relevant implications in enhancing antitumor activity of well-established cytotoxic agents. Preclinical studies of ST3595 with genotoxic agents support this interpretation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2623. doi:10.1158/1538-7445.AM2011-2623