吴茱萸碱通过内质网应激介导的凋亡途径抑制非小细胞肺癌的进展。
Evodiamine suppresses the progression of non-small cell lung carcinoma via endoplasmic reticulum stress-mediated apoptosis pathway and .
机构信息
First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
74770National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
出版信息
Int J Immunopathol Pharmacol. 2022 Jan-Dec;36:3946320221086079. doi: 10.1177/03946320221086079.
BACKGROUND
Evodiamine (EVO) is one of the major components isolated from (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.
背景
吴茱萸碱（EVO）是从吴茱萸（Juss.）中分离得到的主要成分之一。最近的研究表明，EVO 具有抗癌作用。然而，EVO 影响癌症的药理机制仍知之甚少。
目的
本研究旨在探讨吴茱萸碱（EVO）对人非小细胞肺癌（NSCLC）的抗癌作用，特别是研究 EVO 是否通过调节内质网应激（ERS）介导的细胞凋亡途径发挥作用。
材料和方法
采用腹腔注射低剂量（5mg/kg）和高剂量（10mg/kg）EVO 处理 Lewis 肺癌（LLC）荷瘤小鼠模型 14d，评估 EVO 对肿瘤生长、凋亡和 ERS 的影响。此外，在体外用 EVO 处理 NSCLC A549 和 LLC 细胞，研究 EVO 对细胞增殖、凋亡和 ERS 的影响。最后，用内质网应激抑制剂 4-苯丁酸（4-PBA）验证 EVO 是否通过调节 ERS 诱导 NSCLC 细胞凋亡。
结果
EVO 处理显著抑制 LLC 荷瘤小鼠肿瘤生长。H&E 染色表明，EVO 处理减少了肿瘤细胞数量和核浆比。免疫组化显示，EVO 处理显著降低了 Ki-67 的表达。TUNEL 染色显示，EVO 诱导肿瘤细胞凋亡。同样，EVO 处理上调了肿瘤中与细胞凋亡相关的基因和蛋白表达，并增加了 ERS 途径的激活。此外，EVO 抑制了 A549 和 LLC 细胞的增殖并增加了细胞凋亡率。EVO 还增加了体外与 ERS 介导的细胞凋亡途径相关的基因和蛋白的表达水平。用 4-PBA 处理可消除 EVO 对凋亡的影响。
结论
本研究表明，EVO 通过调节 ERS 介导的细胞凋亡途径抑制 NSCLC 的进展。
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