Inhibitors of APE1 redox and ATM synergistically sensitize osteosarcoma cells to ionizing radiation by inducing ferroptosis.

Autor: Xiao H; Department of Clinical Laboratory Medicine, Southwest Hospital, Army Medical University, Chongqing 400038, China; Department of Clinical Hematology, College of Pharmacy, Army Medical University, Chongqing 400038, China; Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China., Jiang N; Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China., Zhang H; Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China., Wang S; Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China., Pi Q; Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China., Chen H; Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China., He X; Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China., Luo W; Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China., Lu Y; Department of Occupational Health, College of Preventive Medicine, Army Medical University, Chongqing 400038, China. Electronic address: everlightlu@163.com., Deng Y; Department of Clinical Laboratory Medicine, Southwest Hospital, Army Medical University, Chongqing 400038, China; Department of Clinical Hematology, College of Pharmacy, Army Medical University, Chongqing 400038, China. Electronic address: youcai.deng@tmmu.edu.cn., Zhong Z; Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China; Department of Oncology, The Fifth People's Hospital of Chongqing, Chongqing 400062, China. Electronic address: zhongzhaoyang08@hotmail.com.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Sep 30; Vol. 139, pp. 112672. Date of Electronic Publication: 2024 Jul 19.
DOI: 10.1016/j.intimp.2024.112672
Abstrakt: The resistance of osteosarcoma (OS) to ionizing radiation (IR) is an obstacle for effective patient treatment. Apurinic/apyrimidinic endonuclease-reduction/oxidation factor 1 (APE1/Ref-1) is a multifunctional protein with DNA repair and reduction/oxidation (redox) activities. We previously revealed the role of APE1 in OS radioresistance; however, whether the redox activity of APE1 is involved in OS radioresistance is unclear. APE1 regulates the activation of ataxia-telangiectasia mutated (ATM), an initiator of DNA damage response that mediates radioresistance in other cancers. The role of APE1 redox activity and ATM activation in OS radioresistance is unknown. Our study revealed that IR increased APE1 expression and ATM activation in OS cells, and APE1 directly regulated ATM activation by its redox activity. The combined use of an APE1 redox inhibitor and ATM inhibitor effectively sensitized OS cells to IR in vitro and in vivo. Mechanistically, the increased radiosensitization of OS cells by the combined use of the two inhibitors was mediated by increased ferroptosis. Co-treatment with the two inhibitors significantly decreased expression of the common targeted transcription factor P53 compared with single inhibitor treatment. Collectively, APE1 redox activity, ATM activation and their crosstalk play important roles in the resistance of OS to irradiation. Synergetic inhibition of APE1 redox activity and ATM activation sensitized OS cells to IR by inducing ferroptosis, which provides a promising strategy for OS radiotherapy.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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