Abstract A206: Chk1 protects normal cells from HDAC inhibitor-induced cell death.

Histone deacetylase inhibitors (HDACi) are a new class of selective anti-cancer agents that inhibit zinc-dependent histone deacetylases. HDACi in clinical trials have shown anti-cancer activity at well-tolerated doses. The mechanisms of resistance to HDACi are important in developing these agents for cancer therapy. We previously showed that vorinostat induces DNA damage in both transformed and normal cells. Normal cells can repair the DNA damage, while transformed cells cannot and undergo apoptosis and death. This study found Chk1, a component of the G2 checkpoint, protects normal cells from HDACi-induced cell death. Culture with HDAC inhibitor plus Chk1 inhibitor (UCN-01, AZD7762 or CHIR124) killed normal cells, while there was no cell death in culture of normal cells with HDAC inhibitor alone. Chk1 inhibitor also increased cell death of transformed cells cultured with HDACi. In culture with both HDACi and Chk1 inhibitor, mitotic abnormalities which included loss of sister chromatid cohesion and chromosomal disruption were observed in normal and transformed cells. These findings show that intact Chk1 is important for the resistence of normal cells to HDACi and suggest that combined treatment of HDACi with Chk1 inhibitor may cause substantial toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A206.