NSC-3852 synergistically enhances the cytotoxicity of olaparib in oral squamous cell carcinoma.

Abstract

The PARP inhibitor olaparib is an anti-cancer agent based on synthetic lethality that targets poly (ADP-ribose) polymerases. It is used as a therapeutic agent for breast, ovarian, pancreatic, and prostate cancers carrying BRCA1/2 mutations that cause deficiency in homologous recombination. In recent years, acquired resistance to PARP inhibitors has become a clinical problem in PARP inhibitor-treated patients. Meanwhile, the development of molecular targeted drugs for highly malignant oral cancers has not progressed, and effective treatment strategies are needed. In this study, we identified the histone deacetylase inhibitor NSC-3852 as a compound that synergistically enhances the effects of olaparib in oral squamous cell carcinoma cell lines. N-Acetyl-l-cysteine treatment partially recovered cell survival after co-treatment with olaparib and NSC-3852. Moreover, the combination of olaparib and NSC-3852 rapidly upregulated γH2AX at 2 h after treatment, and induced S-phase arrest and apoptosis at 24 h after treatment, suggesting that this combination induced apoptosis through accumulation of massive DNA damage. Taken together, these findings demonstrate that NSC-3852 is a sensitizer of olaparib and suggest that the combination of NSC-3852 and olaparib may be a useful therapeutic strategy for homologous recombination-proficient cancers, including cancers with acquired resistance to olaparib and high-grade oral squamous cell carcinoma.