Pharmacological ascorbate induces 'BRCAness' and enhances the effects of Poly(ADP-Ribose) polymerase inhibitors against BRCA1/2 wild-type ovarian cancer.

Pharmacological ascorbate induces 'BRCAness' and enhances the effects of Poly(ADP-Ribose) polymerase inhibitors against BRCA1/2 wild-type ovarian cancer. Oncol Lett. 2020 Apr;19(4):2629-2638 Authors: Ma Y, Chen P, Drisko JA, Khabele D, Godwin AK, Chen Q Abstract The promise of poly(ADP-ribose) polymerase inhibitors (PARPis) in the management of epithelial ovarian cancer (EOC) is hampered by the limited clinical activity against BRCA wild-type or homologous recombination-proficient EOC. In order to decrease the resistance and increase the efficacy of PARPis, combination treatments of pharmacological ascorbate and PARPis in preclinical BRCA wild-type EOC models were investigated. The cytotoxicity of pharmacological ascorbate, olaparib and veliparib in a panel of BRCA1/2 wild-type EOC cell lines were measured using MTT assays. Poly(ADP-ribose) levels were quantified using chemiluminescent ELISA. The expression of proteins involved in DNA damage and DNA double-strand breaks (DSBs) repair pathways were assessed by western blotting. The in vivo efficacy of pharmacological ascorbate, olaparib and their combination was evaluated in an intraperitoneal xenograft mouse model of BRCA1/2 wild-type EOC. Pharmacological ascorbate induced H2O2-dependent cytotoxicity in BRCA1/2 wild-type EOC cells. SHIN3 and OVCAR5 cells were resistant to olaparib and veliparib treatment; however, the combination of ascorbate with olaparib or veliparib significantly ...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research