Abstract 3517: Epigenetic interactive regulation and synergistic action of Trichostatin A, 5-aza-2′-deoxycytidine and Cisplatin in ovarian cancer

Abstract

Abstract Objective: To investigate the relationship between histone modification, DNA methylation and DNA damage repair response that occur in platinum resistant ovarian cancer cell lines treated with epigenetic modifiers in combination with low dose chemotherapy to develop new approaches for chemotherapy resistant ovarian cancer. Materials and Methods: We selected two common epigenetic modifiers Trichostatin A (TSA), a histone deacetylase inhibitor and 5-aza-2′-deoxycytidine (decitabine), a demethylating agent which were evaluated alone and in combination with low dose Cisplatin for their tumorigencity in SCID mice and their spheroid formation in serum-free medium with two ovarian cancer cell lines SKOV3 and Hey. We also measured the effect of these drugs on tumor suppression pathways, AKT pathway, and expression of cadherins as well as histone modification. Results: All combinations of TSA, decitabine and Cisplatin inhibited both tumorigenicity and spheroid formation in both cell lines with Hey exhibiting more resistance to treatment. E-cadherin expression was suppressed in SKOV3 cells while N-caderin expression was suppressed in Hey cells with both TSA and Cisplatin and decitabine and Cisplatin. In the Hey cell line, p53 expression was increased by sequential treatment with low dose decitabine and low dose cisplatin and by low dose TSA and low dose cisplatin. The profiling of histone code revealed distinctly different chromatin regulation between Hey cells and SKOV3 cells. The expression patterns and characteristics of cell adhesion, mutiple-drug transporter, apoptosis are distinctly different in these two ovarian cancer cell lines, which may be due to the different origins and stages of these cell lines. Conclusions: The combinations of decitabine, TSA and Cisplatin suppressed the formation and growth of xenograft and tumor spheroid, altered the molecular mechanism of cell adhesion, chemosensitivity, and chromatin modification which may provide a new and promising treatment strategy for chemoresistant ovarian 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 3517. doi:10.1158/1538-7445.AM2011-3517