Abstract 2029: Interactions between a selenophene compound and DNA polymerase eta.

Abstract

Abstract D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is a selenophene compound that has potent toxicity to various types of cancer cells but not for normal cells. More importantly, in vivo xenograft animal studies have also shown that D-501036 is a promising anticancer compound. Mechanistic studies indicated that D-501036 induces DNA double strand breaks in a dose dependent manner and blocks cell cycle progression at S-phase. D-501036 forms DNA adducts and the amount of DNA adducts increased with the concentration of D-501036. Therefore, we examined several DNA replication/repair mechanisms for their potential relationship with D-501036. Interestingly, we observed that D-501036 suppressed the expression of DNA lesion bypass polymerase η (pol η) more than 70% in both time and dose dependent manners in the ovarian Ovcar-4 cancer cells. Pol η is the key enzyme to replicate across UV induced cyclobutane pyrimidine dimers (CPD) in DNA. Genetic defects in the pol η encoding gene result in a disease called Xeroderma Pigmentosum variant (XP-V). In addition to its biological function, biochemical studies have shown that pol η can also efficiently bypass cisplatin intrastrand crosslinked guanosines (Pt-GG). In consistence with the biochemical studies, cellular studies have shown that the expression of pol η reduces the cytotoxicity of cisplatin in Ovcar-4 cells. These results suggested that pol η plays an important role in modulating the cellular sensitivity to cisplatin. Although cisplatin is an important therapeutic agent for the treatment of ovarian cancer but the development of resistance against cisplatin has been a major drawback. Given that D-501036 suppresses the expression of pol η, we performed a cytotoxicity study using the combination of D-501036 and cisplatin. Our results indicated that D-501036 can potentiate the sensitivity of Ovcar-4 cells to cisplatin more than 1,000- fold. Together, our results suggested that D-501036 is a promising compound that can be used to enhance the activity of cisplatin for the treatment of ovarian cancer. Further studies are undergoing to determine the mechanisms of action of D-501036, the information obtained will facilitate the development of new compounds to improve the treatment for ovarian cancer. Citation Format: Anne Rietz, Yih-wen Chen, Kai-Ming Chou. Interactions between a selenophene compound and DNA polymerase eta. [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 2029. doi:10.1158/1538-7445.AM2013-2029