Abstract 4142: The effects of SBHA on Notch 1 expression and platinum sensitivity in ovarian cancer cells

Abstract

Abstract Objective: Despite advances in radical surgical debulking and intraperitoneal chemotherapy, ovarian cancer remains the most deadly gynecologic malignancy. The Notch signaling pathway plays an important role in cellular differentiation, proliferation, and apoptosis. We have previously found Notch 1 intracellular domain (NICD) to be highly expressed in the most platinum resistant ovarian cancer cell lines. Recent evidence has shown that histone deacetylase inhibitors (HDACi's) decrease platinum resistance in oral squamous cell cancers. In addition, the HDACi suberoyl bis-hydroxamic acid (SBHA) has been found to modify Notch 1 expression in other cancers. We hypothesized that SBHA would reduce ovarian cancer cell proliferation through inhibition of the Notch 1 signaling pathway and help sensitize ovarian cancer cells to platinum. Methods: Following treatment with SBHA, NICD expression in the ovarian carcinoma cell lines OVCAR3, SKOV3, and CaOV3 was analyzed by Western blot. The effects of SBHA and cisplatin on ovarian cancer cell growth were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) growth assay. Results: NICD expression by Western blot was consistently reduced in all 3 cell lines following treatment with SBHA. Dose-dependent growth inhibition of ovarian cancer cells was demonstrated with SBHA treatment. Furthermore, the addition of SBHA to cisplatin resulted in additional reduction of NICD and further growth suppression in SKOV3, the most platinum resistant cell line tested. Conclusions: SBHA treatment of ovarian cancer cells led to decreased NICD expression and dose dependent growth reduction in ovarian cancer cells. In addition, we found that SBHA in combination with platinum further reduced NICD expression and growth in SKOV3 cells. These findings provide a compelling argument for further study into the role that Notch 1 signaling may be playing in platinum resistance and ovarian cancer. 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 4142.