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

Amit Srivast, Subhankar Bose, Priyanka Saha, Md Tanjim Alam, Bilash Chatterjee, Mrinmoy Sarkar, Amit Dixit, Deepak Kumar, Prem Tripathi
2023 · doi:10.21203/rs.3.rs-3118868/v1
preprint OA: closed CC-BY-4.0
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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.

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License: CC-BY-4.0