Abstract LB-55: Histone deacetylase inhibitor causes DNA damage and apoptosis by downregulation of repair enzymes in cancer but not normal cells: Basis of resistance of normal cells to HDACi

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and many non-histone proteins, affecting gene expression, cell cycle progression, cell migration and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here we show that the HDACi, SAHA (Suberoylanilide hydroxamic acid, vorinostat), induces DNA DSB (double strand break) in normal (HFS) and cancer (LNCaP, A549) cells, but normal cells in contrast to cancer cells repair the DSB despite continued culture with SAHA. In transformed cells, H2AX levels increased with continued culture with SAHA, while in normal cells, this marker of DNA DSB tended to decrease with time. To define the capacity of normal and transformed cells for repair of SAHA induced DNA DSB, cells were cultured for 24hr with SAHA, washed and continued culture without HDACi. In normal cells, the H2AX was undetectable by 2hr (presumably reflecting repair of DNA DSB), while persisting in transformed for duration of culture (presumably reflecting failure to repair DNA DSB) with consequent transformed cell death. Further, we found that SAHA suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, Tip60 and PP2A, in cancer (LNCaP, A549) but not in normal cells (HFS). These findings indicate that the HDACi induces DNA damage in cancer and normal cells, but normal cells have the capacity to repair the DNA DSB, while cancer cells do not owing in part at least to suppression of DNA DSB repair proteins. This selective action of SAHA in inducing transformed cell death points to potential effective therapeutic strategies for combination therapy with HDACi with agents that suppress DNA damage repair proteins. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-55.