Olaparib synergically exacerbates the radiation-induced intestinal apoptosis in mice

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. © 2024, The Author(s) under exclusive licence to The Korean Society of Toxicogenomics and Toxicoproteomics.