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  3. Dihydroartemisinin elicits immunogenic death through ferroptosis-triggered ER stress and DNA damage for lung cancer immunotherapy

Dihydroartemisinin elicits immunogenic death through ferroptosis-triggered ER stress and DNA damage for lung cancer immunotherapy

  • Phytomedicine. 2023 Jan 31;112:154682. doi: 10.1016/j.phymed.2023.154682.
Ning Han 1,  Zi-Yi Yang 2,  Zhong-Xiong Xie 3,  Hua-Zhen Xu 4,  Ting-Ting Yu 2,  Qi-Rui Li 2,  Liu-Gen Li 2,  Xing-Chun Peng 5,  Xiao-Xin Yang 6,  Jun Hu 2,  Xiang Xu 2,  Xiao Chen 4,  Mei-Fang Wang 7,  Tong-Fei Li 8
Affiliations

Affiliations

  • 1 Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of hand Microsurgery, Dongfeng Hospital Affiliated to Hubei University of Medicine, Shiyan, Hubei, 442000, China.
  • 2 Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China.
  • 3 Department of hand Microsurgery, Dongfeng Hospital Affiliated to Hubei University of Medicine, Shiyan, Hubei, 442000, China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Donghu Avenue No.185, Wuhan 430072, China.
  • 5 Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of hand Microsurgery, Dongfeng Hospital Affiliated to Hubei University of Medicine, Shiyan, Hubei, 442000, China.
  • 6 School Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China.
  • 7 Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China. Electronic address: wmfpps02@hotmail.com.
  • 8 Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China. Electronic address: Litongfeihappy@163.com.
PMID: 36739636 DOI: 10.1016/j.phymed.2023.154682
Abstract

Background: The immunosuppressive microenvironment of lung Cancer serves as an important endogenous contributor to treatment failure. The present study aimed to demonstrate the promotive effect of DHA on immunogenic cell death (ICD) in lung Cancer as well as the mechanism.

Methods: The lewis lung Cancer cells (LLC), A549 cells and LLC-bearing mice were applied as the lung Cancer model. The Apoptosis, Ferroptosis assay, western blotting, immunofluorescent staining, qPCR, comet assay, flow cytometry, confocal microscopy, transmission electron microscopy and immunohistochemistry were conducted to analyze the functions and the underlying mechanism.

Results: An increased Apoptosis rate and immunogenicity were detected in DHA-treated LLC and tumor grafts. Further findings showed DHA caused lipid peroxide (LPO) accumulation, thereby initiating Ferroptosis. DHA stimulated cellular endoplasmic reticulum (ER) stress and DNA damage simultaneously. However, the ER stress and DNA damage induced by DHA could be abolished by Ferroptosis inhibitors, whose immunogenicity enhancement was synchronously attenuated. In contrast, the addition of exogenous iron ions further improved the immunogenicity induced by DHA accompanied by enhanced ER stress and DNA damage. The enhanced immunogenicity could be abated by ER stress and DNA damage inhibitors as well. Finally, DHA activated immunocytes and exhibited excellent anti-cancer efficacy in LLC-bearing mice.

Conclusions: In summary, the current study demonstrates that DHA triggers Ferroptosis, facilitating the ICD of lung Cancer thereupon. This work reveals for the first time the effect and underlying mechanism by which DHA induces ICD of Cancer cells, providing novel insights into the regulation of the immune microenvironment for Cancer Immunotherapy by Chinese medicine phytopharmaceuticals.

Keywords

Cancer immunotherapy; DNA damage response (DDR); Dihydroartemisinin (DHA); Endoplasmic reticulum stress (ER stress); Ferroptosis; Immunogenic cell death (ICD).

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