Anticancer efficacy of the combination of low-dose cisplatin and trichostatin A or 5-aza-2’-deoxycytidine in ovarian cancer cells.

Abstract

e15563 Background: We investigated the combination of low dose cisplatin with histone deacetylase inhibitor trichostatin A and methyl transferase inhibitor 5-aza-2’-deoxycytidine to determine if these agents could improve the sensitivity of ovarian cancer cell lines to cisplatin. The goal was to improve efficacy and decrease the toxicity of conventional chemotherapy in human ovarian cancer. Methods: Two chemoresistant ovarian cancer cell lines HEY, SKOV3 and one immortalized cell line IOSE were were treated with increasing doses of each drug alone and in combination to determine optimal cytotoxicity at the lowest dose. Markers of adhesion, metastasis, proliferation, self renewal, and measures of epigenetic regulation were measured. Spheroids, treated with single and combination drugs, were measured for cell viability. SCID mice were injected with pretreated cells and with untreated cells and then treated sequentially. Results: TSA or 5-aza-2’-deoxycytidine combined with Cisplatin had a marked reduction in E-cadherin and N-cadherin (adhesion and migration), proliferation protein Akt and Akt-1, self-renewal markers Oct4/Nanog/Sox2, and the drug transporter ABCG2. DNA methylase, DNMT3a/3b, histone deacetylase HDAC1/2 and histone demethylase LSD1, measures of epigenetic regulation, were suppressed with combined treatment. Histone methylation markers H3K4 and H3K9 were regulated differentially, with the trimethyled-H3K9 significantly suppressed, suggesting bivalent chromatin regulation. Cisplatin/TSA suppressed spheroid formation, growth, and viability. Cisplatin/TSA suppressed tumorigenesis in SCID mice when cells were pretreated. Animals treated after tumor formation with epigenetic modifiers followed by cisplatin achieved significant tumor regression, suggesting that both approaches enhance anticancer effects. Conclusions: Our research suggests the combination of low dose cisplatin with epigenetic modifiers administered together or sequentially may be promising treatments for ovarian cancer with reduced toxicity and may reverse platinum resistance.