Inhibition of DNA polymerase eta-mediated translesion DNA synthesis by small molecule sensitizes ovarian cancer stem-like cells to chemotherapy

Abstract

Abstract Chemoresistance and tumor relapse pose significant challenges in achieving successful chemotherapy outcomes. Targeting DNA polymerase eta (Pol ƞ) mediated-mutagenic translesion DNA synthesis (TLS) has emerged as a promising strategy for improving chemotherapy. However, the identification of small molecule inhibitors specifically targeting Pol η-mediated TLS with high in vivo efficacy remains a challenge. In this study, we screened and identified chrysin as a small-molecule inhibitor that sensitizes ovarian cancer stem-like cells (CSLCs) to cisplatin treatment by inhibiting Pol ƞ-mediated TLS. Chrysin effectively inhibits Pol ƞ expression, enhancing cisplatin-induced cell death both in vitro and in vivo. Furthermore, chrysin treatment reduces spontaneous and cisplatin-induced mutagenesis. Pre-treatment with chrysin attenuates cisplatin-induced hematological toxicity and suppresses tumor growth in ovarian cancer human xenografts. These results establish chrysin as a novel class of TLS inhibitors and highlight its potential as a chemotherapy adjuvant for overcoming chemoresistance and improving treatment outcomes in ovarian cancer.