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Olaparib synergically exacerbates the radiation-induced intestinal apoptosis in mice

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Abstract

Background

Olaparib, a poly [ADP-ribose] polymerase (PARP) inhibitor, is used in cancer treatment and in other diseases and achieves local cancer control in combination with radiotherapy.

Objectives

We investigated the effects of olaparib on irradiation-induced intestinal damage using both in vitro and in vivo model systems. In particular, we evaluated how olaparib affects irradiation-induced cytotoxicity in intestinal epithelial (IEC-6) cell line and intestinal damage in mice subjected to abdominal radiation.

Results

Using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays to evaluate radiation-induced cytotoxicity and the loss of cell viability, we found that olaparib pretreatment significantly exacerbated radiation-induced effects. Olaparib therapy increased protein expression related to radiation-induced DNA damage. Administering per oral olaparib (100 mg/kg) to adult mice from − 2 to 0 days before radiation exposure (10 or 15 Gy) significantly accelerated intestinal damage. Measurements of the small intestinal villi length and number of crypts were collected through histological investigations. The irradiation group showed shorter crypt survival and jejunal villi height than the sham-irradiated group. In addition, through the TUNEL assay, we were able to confirm an increased apoptotic rate of enterocytes in the group pretreated with olaparib before 10 Gy of irradiation compared with the dose-matched irradiation group.

Conclusion

In radiation-exposed mice, olaparib therapy significantly reduced indicators such as the length of the small intestinal villi and number of crypts. Administering olaparib before radiation aggravated the radiation-induced damage to the jejunum and exacerbated intestinal apoptosis. Olaparib in combination with radiotherapy should be used cautiously in patients with cancer.

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Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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Acknowledgements

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Funding

This work was supported by the National Research Foundation (Grant No. NRF-2020R1A2C10042721440982119420104) funded by the Ministry of Science and ICT, Republic of Korea.

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Authors and Affiliations

  1. College of Veterinary Medicine and BK21FOUR Program, Chonnam National University, Gwangju, Republic of Korea

    Sohee Jeong, Jeongmin Lee, Changjong Moon, In Sik Shin, Joong Sun Kim & Sohi Kang

  2. Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Republic of Korea

    Jun Hong Park

  3. Division of Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea

    Yeonghoon Son & Hae-June Lee

  4. Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju, Republic of Korea

    Sohi Kang

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  1. Sohee Jeong
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Contributions

JSK and SK designed the study, and supervised the data collection. SJ and JL performed the animal studies and histological evaluation. YS performed the cell studies and molecular biological evaluation. SJ, JL, YS, and HJL draft the manuscript. JHL, CM, and ISS analyzed the data. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Joong Sun Kim or Sohi Kang.

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Conflict of interest

Sohee Jeong declares that she has no conflict of interest. Jeongmin Lee declares that she has no conflict of interest. Jun Hong Park declares that he has no conflict of interest. Yeonghoon Son declares that he has no conflict of interest. Hae-June Lee declares that she has no conflict of interest. Changjong Moon declares that he has no conflict of interest. In Sik Shin declares that he has no conflict of interest. Joong Sun Kim declares that he has no conflict of interest. Sohi Kang declares that she has no conflict of interest.

Ethical approval

The procedures and protocols were in accordance with the Institutional Animal Care and Use Committee of the Chonnam National University (Approval No. CNU IACUC-YB-2022–129) while minimizing the number and suffering of animals.

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Jeong, S., Lee, J., Park, J.H. et al. Olaparib synergically exacerbates the radiation-induced intestinal apoptosis in mice. Mol. Cell. Toxicol. (2024). https://doi.org/10.1007/s13273-023-00421-7

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