Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

Objective.: To characterize the molecular pathways involved in apoptosis following administration of histone deacetylase inhibitors to Type I and II endometrial cancer cells. Methods.: Ark2, Ishikawa, and AN3 cell lines representing both Type I and II endometrial cancers were treated with various concentrations of oxamflatin and HDAC inhibitor-1. Cell apoptosis was determined by flow cytometry, nuclear staining, Western blotting, and mitochondrial membrane potential assays. Results.: Compared to controls, there was a 95% reduction in the growth of Ark2 cells following administration of histone deacetylase inhibitors and this response was dose-dependent. These agents also caused profound morphologic changes and loss of mitochondrial membrane potentials consistent with the induction of apoptosis. Cleavage of PARP, caspase-9, and caspase-8 was detected, confirming the activation of apoptotic cascades in endometrial carcinoma cells. This effect was present in both serous and endometrioid cell types. Conclusion.: Our results suggest that oxamflatin and HDAC inhibitor-1 have potent cytotoxicity in endometrial cancer cells by inducing cell apoptosis. Histone deacetylase inhibitors are promising agents for the treatment of both Type I and II endometrial carcinoma.