Suppression of PERK/eIF2α/CHOP pathway enhances oridonin-induced apoptosis by inhibiting autophagy in Small-Cell lung cancer cells.

Autor: Xu L; Department of Cardiology, Hangzhou First People's Hospital, Zhejiang 310006, China; School of Basic Medical Sciences and Forensic Medicine, Hangzhou medical college, Hangzhou, Zhejiang 310053, China; Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, China., Jiang Y; School of Basic Medical Sciences and Forensic Medicine, Hangzhou medical college, Hangzhou, Zhejiang 310053, China., Bi Y; Department of Clinical Laboratorial Examination, Air Force Hangzhou Special Service Recuperation Center Sanatorium Area 3, Hangzhou, Zhejiang 310013, China., Zheng S; School of Basic Medical Sciences and Forensic Medicine, Hangzhou medical college, Hangzhou, Zhejiang 310053, China., Wu Y; Department of Cardiology, Hangzhou First People's Hospital, Zhejiang 310006, China., Wu Y; Department of Cardiology, Hangzhou First People's Hospital, Zhejiang 310006, China., Xu Y; Department of Cardiology, Hangzhou First People's Hospital, Zhejiang 310006, China. Electronic address: xyzhzsyxnk@163.com., Chen J; School of Basic Medical Sciences and Forensic Medicine, Hangzhou medical college, Hangzhou, Zhejiang 310053, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, Hangzhou, Zhejiang 310053, China. Electronic address: chenjian@hmc.edu.cn.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Jun; Vol. 175, pp. 116684. Date of Electronic Publication: 2024 May 06.
DOI: 10.1016/j.biopha.2024.116684
Abstrakt: Chinese herbs have been used to treat small-cell lung cancer (SCLC) due to their low toxicity and significant efficacy. This study focused on oridonin, a natural compound extracted from Rabdosia rubescens, and aimed to investigate its potential antitumor activity on SCLC and to evaluate the synergistic effect of combining oridonin with other small molecules. In this study, oridonin exhibited a dual effect. At lower concentrations, it suppressed the cell viability of SCLC cells (H1688 and H446). At high concentrations, oridonin induced SCLC cell apoptosis, damaged HBE cells in vitro and compromised the function of the liver and heart in vivo. The lower concentration of oridonin induced autophagy by enhancing the expression of p62 and the LC3B-II/LC3B-I ratio. This phenomenon might be associated with the activation of the protein kinase RNA-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α)/growth arrest and DNA damage-inducible gene 153 (CHOP/GAD153) pathway. Therefore, the combined effect of oridonin with GSK2606414 or 3- methyladenine increased apoptosis in SCLC cells and reduced tumor growth. A similar phenomenon was observed after oridonin was combined with p62 or CHOP RNA interference treatment. Simultaneously, the combination of oridonin and GSK2606414 exhibited therapeutic efficacy without manifesting adverse effects. Our findings suggest that oridonin at lower concentrations can induce autophagy by activating the PERK/eIF2α/CHOP signaling pathway. The inhibition of the PERK/eIF2α/CHOP pathway could enhance oridonin therapeutic responses by triggering apoptosis. The novel therapeutic approach of combining oridonin with a PERK inhibitor is promising as a strategy for the treatment of SCLC.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Linhao Xu reports financial support was provided by Medical and Health Science and Technology Program of Zhejiang Province (2022RC227). Yizhou Xu reports financial support was provided by the Construction Fund of Key Medical Disciplines of Hangzhou (OO20200121). Jian Chen reports financial support was provided by the Zhejiang Special Health Funding Program of Hangzhou Medical College (YS2022002)
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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