Shikonin induces tumor apoptosis in glioma cells via endoplasmic reticulum stress, and Bax/Bak mediated mitochondrial outer membrane permeability
Shikonin induces tumor apoptosis in glioma cells via endoplasmic reticulum stress, and Bax/Bak mediated mitochondrial outer membrane permeability
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DOI：
10.1016/j.jep.2020.113059
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发表时间：
2020-12-05
影响因子：
5.4
通讯作者：
Yang, Wanhua
中科院分区：
文献类型：
--
作者：
Ma, Xiaoqin;Yu, Meixiang;Yang, Wanhua
民族药理意义：紫草素是中草药紫草的主要有效成分之一，临床上广泛用于治疗包括病毒感染和炎症在内的多种疾病。其抗肿瘤活性已载入《中草药》。近年来，有关其抗脑胶质瘤作用的研究已有报道。目的：本研究旨在系统揭示和验证紫草素抗脑胶质瘤的药理作用机制。材料与方法：采用网络药理学方法、生存分析和皮尔逊共表达分析等方法揭示和验证紫草素在脑胶质瘤中的药理作用机制。结果：网络药理学结果表明，紫草素通过干扰针对Caspase-3的内质网应激介导的肿瘤细胞凋亡，以及Bax/Bak诱导的线粒体外膜通透性(MOMP)触发肿瘤细胞凋亡而发挥抗胶质瘤作用。生存分析提示CASP3与脑胶质瘤相关(P<；0.05)。Pearson相关分析表明，CASP3可能通过正反馈调节与PERK相互作用。紫草素或联合14G2a以剂量依赖方式诱导少突胶质瘤Hs683细胞凋亡，最高凋亡率分别为33%~37.5%和73%~77%。免疫印迹分析表明，紫草素使Caspase-3活性增加约4.29倍，与14G2a结合时增加9倍。紫草素与14G2a合用后，可使PERK和CHOP蛋白的表达水平分别增加约4.4倍和5.6倍。结论：紫草素诱导胶质瘤细胞凋亡的药理机制可能是紫草素的作用机制之一。
Ethnopharmacological relevance: Shikonin, one of the main active ingredients of Chinese herbal medicine Lithospermum erythrorhizon, has been widely used to treat various disease including virus infection and inflammation in clinical. Its anti-tumor activity has been recorded in "Chinese herbal medicine". Recently, some studies about its anti-glioma effects have been reported. However, little is known about the molecular pharmacological activity of Shikonin in glioma.Aim: This study aimed to systematically uncover and validate the pharmacological mechanism of Shikonin against glioma.Material and methods: Network pharmacology approach, survival analysis, and Pearson co-expression analysis were performed to uncover and test the pharmacological mechanisms of Shikonin in glioma. Apoptosis assay, Caspase-3 activity assay and immunoblot analysis were practiced to validate the mechanisms.Results: Network pharmacology results suggested, anti-glioma effect of Shikonin by interfering endoplasmic reticulum (ER) stress-mediated tumor apoptosis targeting Caspase-3, and Bax/Bak-induced mitochondrial outer membrane permeabilization (MOMP) triggering cancer cell apoptosis. Survival analysis suggested the association of CASP3 with glioma (P < 0.05). Pearson correlation analysis indicated possible interaction of CASP3 with PERK through positive feedback regulation. Shikonin or in combination with 14G2a induced cell apoptosis in oligodendroglioma Hs683 cells in a dose-dependent manner with at a maximum apoptosis rate of 33%-37.5%, and 73%-77% respectively. Immunoblot analysis showed that Shikonin increased Caspase-3 activity to about 4.29 times, and increased 9 times when it combined with 14G2a. Shikonin increased also the expression levels of the proteins PERK and CHOP by about 4.4 and 5.6 folds, respectively, when it combined with 14G2a.Conclusions: This study highlights the pharmacological mechanisms of Shikonin in the induction of tumor apoptosis in glioma cells.