Abstract
Abstract Objectives: Epithelial ovarian cancer (EOC) is the second most common female pelvic reproductive organ cancer in the United States, and carries the highest mortality in this category in the Western world. The progression free survival and overall survival depend greatly on tumor sensitivity to a platinum chemotherapy. Once platinum resistance is encountered, response rates of only 6-30% are achieved. Triapine, a novel small-molecule drug developed in our laboratory, potently inhibits the activity of ribonucleotide reductase involved in the key step of DNA synthesis and replication. Given that triapine caused profound disruption of dNTP levels and S phase progression, we examined the effects of triapine on the repair of replication-associated DSBs and on the sensitivity of platinum resistant EOC to DNA damaging and platinum therapy. Methods: Cell sensitivity to varying ratios of treating drug combinations (triapine/6-thio-guanine alone, triapine/6-thioguanine with cisplatin, carboplatin, doxorubicin, or paclitaxel) was carried out by clonogenic survival assays using multiple EOC cells lines (A2780, CP70, CAOV-3, IGROV-1, BG-1, PEO1, PEO4, SKOV-3). Colonies were stained and counted to determine % survival. DNA replication was determined by EdU incorporation into DNA using flow cytometry and confocal microscopy. Results: Treatment with triapine leads to synergistic sensitization of BRCA wild-type EOC cells to platinum drugs. The degree of sensitization by triapine is more pronounced toward the lower concentrations of platinum drugs, at which DNA replication is still ongoing. Platinum drugs induce DNA double strand breaks (DSBs) and Rad51 foci in BRCA wild type EOC cells. Triapine attenuates formation of Rad51 foci, a marker of DSB repair, in these cells. For EOC cells that are highly platinum resistant, combination of triapine and 6-thioguanine is required to achieve significant sensitization to platinum drugs. Conclusions: Platinum drugs induce replication-associated DSBs and Rad51-dependent repair in BRCA wild-type EOC cells. Triapine inhibits Rad51-dependent repair of DSBs and therefore sensitizes BRCA wild-type EOC cells to platinum drugs. The mechanism by which 6-thioguanine enhances the effects of triapine is currently being investigated. Our findings indicate for the first time that triapine and 6-thioguanine can be used in combination with platinum agents to target BRCA wild-type and platinum-resistant EOC. Citation Format: Elena S. Ratner, Margaret Whicker, Z. Ping Lin, Alan C. Sartorelli. Triapine sensitizes chemoresistant ovarian cancer cells to platinum therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4490. doi:10.1158/1538-7445.AM2013-4490
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