Abstract 1012: Pan HDACs inhibitor ST3595 targets PARP activity and has curative effect in breast BRCA-deficient model when combined with cisplatin treatment.

Abstract

Acetylation is emerging as a major form of post-translational regulation of gene expression beyond histones and the maintenance of chromatin. Acetylation has been found to play a role in many cellular functions including DNA repair, cell division, apoptosis, cell signaling, chaperone activity and in the cytoskeleton. It is now evident that, given the pleiotropic effects of HDAC inhibitors (HDACi), their therapeutic potential is expected to be best exploited through combination with other antitumor agents . Indeed preclinical data with several tumor cell lines have shown synergistic effects when combining HDACi with various DNA damaging agents, suggesting their involvement in the modulation of DNA damage response (Munshi et al. Clin Cancer Res (2005) 11: :4912-4922; Chen et al. Cancer Res 2007, 67: 5318-5327).To increase our understanding on the molecular and pharmacological properties of ST3595 (Zuco et al. PLoS ONE,2011, 6(12)), a novel Pan- HDACs inhibitor, we have investigated its role in modulating the DNA-repair genes expression and how this modulation could eventually be translated into a therapeutical approach. Our studies evidentiated that, besides the modulation of typical pathways associated to HDAC inhibition (i.e. cell cycle control, DNA replication, apoptosis, cell differentiation, etc.) and mainly mediated by acetylation of histones, ST3595 strongly induces the modulation of molecular markers associated with DNA-damage signalling (γ-H2A.X, acetyl-p53Lys373/382, p-Chk1/2, etc.), p53- signalling and response pathways (i.e. MDM2, Bax, Noxa, PUMA, p21, etc.), and ER-stress response (gadd-153, ATF-3, ATF-4, Grp78, Grp34, HERPUD1 et others), in several tumour models. In addition, an extensive TaqMan gene expression analysis in ST3595-treated tumour cells, revealed several target genes, including ATM, gadd45-α, gadd45-β, and some repair enzymes, modulated directly or indirectly by this molecule. Since PARP-1 acts as a DNA damage sensor and has been implicated in multiple DNA repair pathways, including the SSB, DSB, and base excision repair (BER) pathways, we tested ST3595 as putative PARP inhibitor. In these experiments, although ST3595 have a mild direct effect against the enzyme, a very strong inhibitory effect (at low μM dose) was measured in vitro, by means of a specific Poly-ADP-ribosylation (parylation) assay, on HeLa cells. To assess the specificity and the therapeutical relevance of this observation, we investigated the efficacy of ST3595 in two breast cancer models, MDA MB436 (triple negative, BRCA1/2 mutated) compared to MDA MB231 (triple negative). The results from in vitro and in vivo experiments have shown an increased antitumor activity of ST3595 against BRCA1/2 mutated tumor and cured mice, when the drug has been associate to Cisplatin. Citation Format: Claudio Pisano, Marcella Barbarino, Francesca De Paolis, Giorgia Pollastrone, Ilaria Laporta, Assunta Riccio, Alfonsina Porciello, Loredana Vesci, Carmela Melito, Ferdinando Milazzo, Pasquale Deluca. Pan HDACs inhibitor ST3595 targets PARP activity and has curative effect in breast BRCA-deficient model when combined with cisplatin treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1012. doi:10.1158/1538-7445.AM2013-1012