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J Cancer 2024; 15(3):699-713. doi:10.7150/jca.90371 This issue Cite

Research Paper

Radiosensitization of Osteosarcoma Cells Using the PARP Inhibitor Olaparib Combined with X-rays or Carbon Ions

Meng Dong^1,2,3,*, Hongtao Luo^2,4,5,*, Ruifeng Liu^2,4,5, Jinhua Zhang^2,4, Zhen Yang^2,6, Dandan Wang^1,2, Yuhang Wang^1,2, Junru Chen^1,2, Yuhong Ou^1,2, Qiuning Zhang^2,4,5,✉, Xiaohu Wang^1,2,4,5,✉

1. The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
2. Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
3. Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, China
4. Department of Postgraduate, University of Chinese Academy of Sciences, Beijing, China
5. Heavy Ion Therapy Center, Lanzhou Heavy Ions Hospital, Lanzhou, China
6. Gansu University of Chinese Medicine, Lanzhou, China
* Meng Dong and Hongtao Luo contributed equally to this study.

✉ Corresponding authors: Xiaohu Wang, Ph.D., The First School of Clinical Medicine, Lanzhou University, Lanzhou, China; Postal address: No.1, Donggang west road, Chenguan district, Lanzhou 730000, PR China; Email: xhwanggansucom; TEL numbers: +86 139 0940 7551; Fax: +86-931-4969316; and Qiuning Zhang, Ph.D., Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China; Postal address: No.1, Yanxia road, Chenguan district, Lanzhou 730030, PR China; Email: zhangqnac.cn; TEL numbers: +86 139 1988 7479; Fax: +86-931-4969316. More

Abstract

Objective: Osteosarcomas are derived from bone-forming mesenchymal cells that are insensitive to radiation. This study aimed to investigate the radiosensitization of osteosarcoma cells (U2OS and K7M2) using the PARP inhibitor olaparib combined with X-rays or carbon ions (C-ions).

Methods: The effect of olaparib on the proliferation of osteosarcoma cells after irradiation was assessed using CCK-8 and clone formation assays. Cells were treated with olaparib and/or radiation and the effects of olaparib on the cell cycle and apoptosis were analysed by flow cytometry after 48h. Immunofluorescence was used to stain the nuclei, γ-H2AX, 53BP1, and Rad51 proteins, and the number of γ-H2AX, 53BP1, and Rad51 foci was observed under a fluorescence microscope. The effect of olaparib combined with radiation on double-stranded DNA breaks in osteosarcoma cells was evaluated.

Results: At the same radiation dose, olaparib reduced the proliferation and colony formation ability of irradiated osteosarcoma cells (P < 0.05). Olaparib monotherapy induced minimal apoptotic effects and G₂/M phase arrest in osteosarcoma cells and irradiation alone induced moderate apoptosis and G₂/M phase arrest. However, radiation combined with olaparib significantly increased the percentage of apoptotic cells and G2/M phase arrest in osteosarcoma cells (P < 0.05). Immunofluorescence experiments showed that compared to the radiation group, the formation of γ-H2AX and 53BP1 foci was significantly increased in the combined group (P < 0.05). The expression levels of Rad51 foci in the irradiated group were higher than those in the control group (P < 0.05). However, the number of Rad51 foci in the combined group was significantly decreased (P < 0.05).

Conclusion: The PARP inhibitor olaparib combined with irradiation (X-rays or C-ions) enhanced the radiosensitivity of osteosarcoma cell lines (U2OS and K7M2). Our findings provide a potential theoretical basis for the clinical application of olaparib in overcoming radiation resistance in osteosarcoma.

Keywords: osteosarcoma, PARP inhibitor, olaparib, X-rays, carbon ion, radiosensitization

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