Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Cynaropicrin Induces Reactive Oxygen Species-Dependent Paraptosis-Like Cell Death in Human Liver Cancer Cells

  • Min Yeong Kim (Basic Research Laboratory for the Regulation of Microplastic-Mediated Diseases and Anti‑Aging Research Center, Dong-eui University) ;
  • Hee-Jae Cha (Department of Parasitology and Genetics, Kosin University College of Medicine) ;
  • Su Hyun Hong (Basic Research Laboratory for the Regulation of Microplastic-Mediated Diseases and Anti‑Aging Research Center, Dong-eui University) ;
  • Sung-Kwon Moon (Department of Food and Nutrition, Chung-Ang University) ;
  • Taeg Kyu Kwon (Department of Immunology, School of Medicine, Keimyung University) ;
  • Young-Chae Chang (Research Institute of Biomedical Engineering and Department of Cell Biology, Daegu Catholic University School of Medicine) ;
  • Gi Young Kim (Department of Marine Life Sciences, Jeju National University) ;
  • Jin Won Hyun (Department of Biochemistry, College of Medicine, and Jeju Research Center for Natural Medicine, Jeju National University) ;
  • A-Young Nam (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University) ;
  • Jung-Hyun Shim (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University) ;
  • Yung Hyun Choi (Department of Parasitology and Genetics, Kosin University College of Medicine)
  • Received : 2025.01.20
  • Accepted : 2025.03.04
  • Published : 2025.05.01
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Abstract

Cynaropicrin, a sesquiterpene lactone found in artichoke leaves exerts diverse pharmacological effects. This study investigated whether cynaropicrin has a paraptosis-like cell death effect in human hepatocellular carcinoma Hep3B cells in addition to the apoptotic effects reported in several cancer cell lines. Cynaropicrin-induced cytotoxicity and cytoplasmic vacuolation, a key characteristic of paraptosis, were not ameliorated by inhibitors of necroptosis, autophagy, or pan caspase inhibitors in Hep3B cells. Our study showed that cynaropicrin-induced cytotoxicity was accompanied by mitochondrial dysfunction and endoplasmic reticulum stress along with increased cellular calcium ion levels. These effects were significantly mitigated by endoplasmic reticulum stress inhibitor or protein synthesis inhibitor. Moreover, cynaropicrin treatment in Hep3B cells increased reactive oxygen species generation and downregulated apoptosis-linked gene 2-interacting protein X (Alix), a protein that inhibits paraptosis. The addition of the reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) neutralized cynaropicrin-induced changes in Alix expression and endoplasmic reticulum stress marker proteins counteracting endoplasmic reticulum stress and mitochondrial impairment. This demonstrates a close relationship between endoplasmic reticulum stress and reactive oxygen species generation. Additionally, cynaropicrin activated p38 mitogen activated protein kinase and a selective p38 mitogen activated protein kinase blocker alleviated the biological phenomena induced by cynaropicrin. NAC pretreatment showed the best reversal of cynaropicrin induced vacuolation and cellular inactivity. Our findings suggest that cynaropicrin induced oxidative stress in Hep3B cells contributes to paraptotic events including endoplasmic reticulum stress and mitochondrial damage.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education (RS-2023-00270936, RS-2022-NR070862 and RS-2024-00336900).

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