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Original Article
The Synergistic Effect of PARP Inhibitors and Irinotecan in Small Cell Lung Cancer Cells
Songji Oh1,2orcid , Soyeon Kim1, Bhumsuk Keam1,3, Jeonghwan Youk1,3, Tae Min Kim1,3, Dong-Wan Kim1,2,3, Miso Kim1,3orcid

DOI: https://doi.org/10.4143/crt.2024.728 [Accepted]
Published online: January 7, 2025
1Cancer Research Institute, Seoul National University, Seoul, Korea
2Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, Korea
3Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
Corresponding author:  Miso Kim
Tel: 82-2-2074-4035 Email: misokim@snu.ac.kr
Received: 1 August 2024   • Accepted: 6 January 2025
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Purpose
This study focused on combining irinotecan with Poly (ADP-ribose) polymerase (PARP) inhibitors to explore the potential for novel combination therapeutics in small cell lung cancer (SCLC).
Materials and Methods
We selected 10 different SCLC cell lines with diverse mutational backgrounds in DNA damage response (DDR) pathway genes to evaluate the efficacy of the combination of three PARP inhibitors and irinotecan. After the cells were exposed to the drugs for seven days, cell viability was measured, and a combination index was calculated. Apoptotic signaling was assessed via western blot, and DNA damage was evaluated using an alkaline comet assay.
Results
We assessed the synergistic effects of PARP inhibitors and irinotecan in in vitro SCLC models, which revealed increased sensitivity, particularly in cells harboring BRCA mutations. However, even in cells lacking mutations in DNA damage response pathway genes, the combination of the two drugs exhibited a synergistic effect. When treated with 50 nM irinotecan, the IC50 fold changes for PARP inhibitors were: olaparib, 1649 ± 4049; talazoparib, 25 ± 34.21; venadaparib, 336 ± 596.01. This combination enhanced apoptosis signaling and increased p-chk1 and p-p53 protein levels. Additionally, the treatment of PARP inhibitor with irinotecan increased DNA damage, as visualized by the alkaline comet assay.
Conclusion
This study provides preclinical evidence of the potential clinical benefits of combining irinotecan with PARP inhibitors in SCLC. Further clinical investigations are warranted to validate these findings for the development of more effective and personalized therapeutic strategies for SCLC patients.

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