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. 2025 Aug;182(15):3594-3611.
doi: 10.1111/bph.70037. Epub 2025 Apr 7.

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

Subhankar Bose  1   2 , Priyanka Saha  1 , Md Tanjim Alam  1 , Bilash Chatterjee  1   2 , Mrinmoy Sarkar  1 , Amit Kumar Dixit  3 , Deepak Kumar  4 , Rakesh Kumar Pathak  5 , Prem Prakash Tripathi  6 , Amit Kumar Srivastava  1   2
Affiliations

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

Subhankar Bose et al. Br J Pharmacol. 2025 Aug.

Abstract

Background and purpose: Chemoresistance and tumour 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 targeting Pol ƞ -mediated TLS with high in vivo efficacy remains a challenge.

Experimental approach: The small molecule was identified through in silico screening. Pol η inhibitory potential of the identified small molecule was validated by a fluorescent-based reporter strand displacement assay. Flow cytometry was conducted to analyse the CD44 + CD117 + cancer stem-like cell (CSC) population and live-dead cell population. Xenograft mouse models were used to test the CSC sensitising potential.

Key results: We screened and identified chrysin as a small-molecule inhibitor that sensitises ovarian cancer stem-like cells to cisplatin treatment by inhibiting Pol ƞ -mediated TLS. Chrysin effectively inhibits Pol ƞ expression, mitigates cancer stem-like cell enrichment and enhances 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 haematological toxicity and suppresses tumour growth in human ovarian cancer xenografts.

Conclusions and implications: 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.

Keywords: cancer stem‐like cells (CSCs); chemoresistance; chrysin; mutagenesis; translesion DNA synthesis (TLS).

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