Abstract B30: Induction of BRCAness phenotype by curcumin and hydroxyurea in WT BRCA ovarian cancer cells
Authors: Yuehua Mao, Richard D Dinnen, Robert L Fine
Journal: Clinical Cancer Research (2013)

Abstract The field of ovarian cancer therapeutics has recently made a substantial leap forward with the discovery that ovarian cancers with a BRCA mutation can be exploited with “synthetic lethality”. This phenomenon takes advantage of the role of PARP (poly-ADP ribosyl-polymerase), which compensates for the missing or low BRCA protein in these patients with a BRCA germline mutation. PARP activity is essential for these patients to maintain a normal genotype, albeit not completely normal since they developed ovarian cancer mainly because of their BRCA mutation. Thus, in the 5 major mechanisms of DNA repair PARP compensates for missing BRCA1 or BRCA2 in homologous repair, base excision repair and nuclear excision repair. In these patients, if PARP is inhibited, then massive DNA mutations accumulate and are not repaired because PARP ribosylates the areas of cut or damaged DNA to mark the areas needed for repair to occur. The concept of inhibiting PARP in these BRCA mutated tumors is an elegant idea. The caveat here is the BRCA mutant genotype where there is a germline, inactivating mutation in one allele and LOH or somatic mutation of the other allele only occurs in 5-10% of the cancer population. Thus, could there be a way to apply this concept of synthetic lethality to the other 90-95% of the cancer population without BRCA mutations in ovarian cancer patients? We tried to answer that question by testing different agent which could modulate gene expression, and found that curcumin and hydroxyurea, at low concentrations, could sometimes increase the cytotoxicity of alkylating agents which suggests a mechanism involving DNA repair. Four (ovcar-8, TOV21G, PA-1 and UACC1598) out of nine pretreated ovarian cancer cell lines with hydroxyurea or curcumin has synergistically increase apoptosis induced by PARP inhibitor - Olaparid. In the tested Ovcar-8 cancer cell line, Curcumin (5 μM) alone induced 10% apoptosis, hydroxyurea (100 μM) alone induced 17% apoptosis, Olaparid (2.5 μM) alone induced 7% cell death. Curcumin and Olaparid together induce 45% cell death (165% increase), hydroxurea and Olaparid together induced 40% (67% increase). Both curcumin and hydroxyurea decrease BRCA1 and BRCA2 mRNA and protein level in the tested sensitive cell lines. Further study, we found that curcumin prompt epigenetically BRCA1,2 promoter methylation and lead to gene expression shutting down whereas hydroxyurea induced miRNA hsa-miR-17-5p and hsa-miR-182-5p and lead BRCA1 mRNA degradation. This finding suggest If wt BRCA patients with ovarian cancer could be induced into BRCAness, then perhaps a larger percentage than 5-10% could benefit from PARP inhibitors and DNA crosslinkers like mitomycin C. Citation Format: Yuehua Mao, Richard D Dinnen, Robert L Fine. Induction of BRCAness phenotype by curcumin and hydroxyurea in WT BRCA ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B30.