Abstract
Abstract The majority of epithelial ovarian carcinomas harbor molecular alterations in DNA-damage response genes. Epithelial ovarian cancers are surprisingly sensitive to DNA-damaging platinum-based (cisplatin or carboplatin) chemotherapy, suggesting that the dependencies of ovarian cancers on impaired DNA-damage response pathways can be harnessed for therapeutic purposes. Our group and others have shown that histone deacetylase (HDAC) inhibitors are promising anti-tumor agents, particularly when combined with DNA-damaging drugs in ovarian cancer cells. In this study, H2AX phosphorylation (pH2Ax), a known histone mark of DNA damage and other histone marks related to DNA damage and repair pathways, including the newly recognized acetylated lysine K56 on histone 3 (H3K56ac) were used to distinguish the biological effects of a unique and diverse panel of clinically utilized and novel HDAC inhibitors. Ovarian cancer cell lines with diverse molecular alterations, including mutations in p53, Brca1, Akt, Ras, and overexpression of MDR1, were utilized in these screens. The HDAC inhibitors that induced the highest levels of pH2Ax produced the greatest anti-tumor effects (growth inhibition and apoptosis). Furthermore, a screen of DNA-damage response histone marks led to the selection of novel HDAC inhibitors that exerted synergistic anti-tumor effects when combined with cisplatin and other DNA-damaging drugs. Taken together, our results support a role of HDAC inhibitors in the treatment of ovarian cancer and suggest that pH2Ax is a potential surrogate biomarker of the efficacy of HDAC inhibitor combination therapy with DNA-damaging agents. 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 2985.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
