ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2024; 20(3):1093-1109. doi:10.7150/ijbs.85443 This issue Cite
Research Paper
Promotion of ROS-mediated apoptosis, G2/M arrest, and autophagy by naringenin in non-small cell lung cancer
1. School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan.
2. Department and Institute of Physiology, College of Medicine, National Yang-Ming Chiao Tung University, Taipei 11221, Taiwan.
3. Department of Nursing, Division of Basic Medical Sciences, and Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chiayi 61363, Taiwan.
4. Department of Safety Health and Environmental Engineering, Ming Chi University of Technology, New Taipei City 24301, Taiwan.
5. Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
6. Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi 61363, Taiwan.
7. Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan.
8. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
9. Center for Environmental Toxin and Emerging-Contaminant Research, Cheng Shiu University, Kaohsiung 83347, Taiwan.
10. Super Micro Research and Technology Center, Cheng Shiu University, Kaohsiung 83347, Taiwan.
11. Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
12. School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan.
13. Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan.
14. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan.
15. Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan.
Abstract
Background: As lung cancer is the leading cause of cancer death worldwide, the development of new medicines is a crucial endeavor. Naringenin, a flavanone derivative, possesses anti-cancer and anti-inflammatory properties and has been reported to have cytotoxic effects on various cancer cells. The current study investigated the underlying molecular mechanism by which naringenin induces cell death in lung cancer.
Methods: The expression of apoptosis, cell cycle arrest, and autophagy markers in H1299 and A459 lung cancer cells was evaluated using a terminal deoxynucleotidyl transferase dUTP nick end labeling assay (TUNEL), Western blot, Annexin V/PI stain, PI stain, acridine orange staining, and transmission electron microscopy (TEM). Using fluorescence microscopy, DALGreen was used to observe the degradation of p62, a GFP-LC3 plasmid was used to evaluate puncta formation, and a pcDNA3-GFP-LC3-RFP-LC3ΔG plasmid was used to evaluate autophagy flux. Furthermore, the anti-cancer effect of naringenin was evaluated in a subcutaneous H1299 cell xenograft model.
Results: Naringenin treatment of lung cancer cells (H1299 and A459) reduced cell viability and induced cell cycle arrest. Pretreatment of cells with ROS scavengers (N-acetylcysteine or catalase) suppressed the naringenin-induced cleavage of apoptotic protein and restored cyclin-dependent kinase activity. Naringenin also triggered autophagy by mediating ROS generation, thereby activating AMP-activated protein kinase (AMPK) signaling. ROS inhibition not only inhibited naringenin-induced autophagic puncta formation but also decreased the ratio of microtubule-associated proteins 1A/1B light chain 3 II (LC3II)/LC3I and activity of the AMPK signaling pathway. Furthermore, naringenin suppressed tumor growth and promoted apoptosis in the xenograft mouse model.
Conclusion: This study demonstrated the potent anti-cancer effects of naringenin on lung cancer cells, thereby providing valuable insights for developing small-molecule drugs that can induce cell cycle arrest, apoptosis, and autophagic cell death.
Keywords: human lung cancer, naringenin, apoptosis, ROS, autophagy
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