Abstract 2632: SAHA loosens chromatin structure and increases DNA damage in human lung cancer cells induced by arsenic trioxide

Abstract

Abstract The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well-documented. ATO may cause DNA damage through the generation of reactive oxygen intermediates. Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), modulates gene or protein expression via histone dependent or independent pathway that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. The objective of this study is to investigate whether ATO and SAHA could synergistically enhanced cell killing to cancer cells. The present studies showed that combined treatment with ATO and SAHA results in enhanced suppression of non-small cell lung carcinoma (NSCLC) H1299 cells in vitro and in xenograft mouse model. By analyzing the annexin V positive cells, apoptotic cell death is significantly enhanced in combined treatment. At the doses used, ATO does not interfere with the cell cycle progression, whereas SAHA induces the expression of p21WAF1/CIP1 and leads to G1 arrest. By the aid of Comet assay, we demonstrated that ATO induces DNA breaks in H1299 cells, but not SAHA. However, co-treatment with SAHA and ATO significantly increases ATO-induced DNA damage. Moreover, SAHA enhances acetylation of histone H3 and sensitize genomic DNA to DNase I digestion. Our present results suggest that SAHA may result in chromatin relaxation, and lead to cells become more susceptible to ATO for causing DNA damage. Therefore, combination of SAHA with ATO may provide effective approach to treatment of lung cancer. 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 2632. doi:10.1158/1538-7445.AM2011-2632