Evodiamine suppresses the progression of non-small cell lung carcinoma via endoplasmic reticulum stress-mediated apoptosis pathway in vivo and in vitro

Yuting Li; Yuming Wang; Xiaoqun Wang; Lulu Jin; Lu Yang; Jinli Zhu; Hongwu Wang; Fang Zheng; Huantian Cui; Xiaojiang Li; Yingjie Jia

doi:10.1177/03946320221086079

Evodiamine suppresses the progression of non-small cell lung carcinoma via endoplasmic reticulum stress-mediated apoptosis pathway in vivo and in vitro

Int J Immunopathol Pharmacol. 2022 Jan-Dec:36:3946320221086079. doi: 10.1177/03946320221086079.

Authors

Yuting Li^{1

2

3}, Yuming Wang¹, Xiaoqun Wang^{2

3}, Lulu Jin¹, Lu Yang¹, Jinli Zhu^{2

3}, Hongwu Wang¹, Fang Zheng¹, Huantian Cui⁴, Xiaojiang Li^{2

3}, Yingjie Jia^{2

3}

Affiliations

¹ First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
² 74770National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
³ Tianjin University of Traditional Chinese Medicine, Tianjin, China.
⁴ Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, 12589Shandong University, Qingdao, China.

Abstract

Background: Evodiamine (EVO) is one of the major components isolated from Evodia rutaecarpa (Juss.). Recent studies have shown that EVO has an anti-cancer effect. However, the pharmacological mechanism by which EVO impacts cancer is still poorly understood.

Objectives: This study focused on asking the anti-cancer effect of EVO in human non-small cell lung carcinoma (NSCLC), and in particular to investigate whether EVO acts via modulating the endoplasmic reticulum stress (ERS)-mediated apoptosis pathway.

Materials and methods: A Lewis lung carcinoma (LLC) tumor-bearing mouse model was treated with low-dose EVO (5 mg/kg) and high-dose EVO (10 mg/kg) intraperitoneally for 14 d. The effects of EVO on tumor growth, apoptosis, and ERS were assessed. In addition, NSCLC A549 and LLC cells were treated with EVO in vitro. The effects of EVO on cell proliferation, apoptosis, and ERS were investigated. Finally, 4-phenylbutyric acid (4-PBA), an ERS inhibitor, was used to validate whether EVO induced apoptosis of NSCLC cells by modulating ERS.

Results: EVO treatment significantly inhibited tumor growth in LLC tumor-bearing mice. H&E staining indicated that EVO treatment reduced the number of tumor cells and the nucleo-plasmic ratio. Immunostaining showed that EVO treatment significantly decreased the expression of Ki-67. TUNEL staining revealed that EVO induced apoptosis in the tumor. Likewise, EVO treatment up-regulated the expression of apoptosis-related genes and proteins and increased activation of the ERS pathway in the tumor. Additionally, EVO inhibited cell proliferation and increased cell apoptotic rates in A549 and LLC cells. EVO also increased the expression levels of genes and proteins associated with ERS-mediated apoptosis pathway in vitro. The effects of EVO on apoptosis were abolished by 4-PBA treatment.

Conclusions: Our study demonstrated that EVO suppresses the progression of NSCLC by modulating the ERS-mediated apoptosis pathway.

Keywords: A549 cells; Evodiamine; apoptosis; endoplasmic reticulum stress; lewis lung carcinoma cells; non-small cell lung carcinoma.

MeSH terms

Animals
Apoptosis
Carcinoma, Non-Small-Cell Lung* / metabolism
Cell Line, Tumor
Endoplasmic Reticulum Stress
Lung Neoplasms* / metabolism
Mice
Quinazolines

Substances

Quinazolines
evodiamine