Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, China; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province, China; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, China; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province, China; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
Bioorg Chem. 2022 Dec;129:106183. doi: 10.1016/j.bioorg.2022.106183. Epub 2022 Sep 30.
Sesquiterpene lactones possess excellent anti-tumor activity in multiple cancer cell lines, including glioma, the most common type of malignant brain tumor with high mortality. However, the detailed mechanism of this type of constituent, especially the potential target for anti-glioma effect, is still unclear. Here, we collected 52 sesquiterpene lactones from Elephantopus scaber Linn. for network pharmacology analysis. The results demonstrated that the targets of the active components were markedly enriched on the pathways in cancer, which were closely related to cell proliferation regulation. Next, the Gene Expression Omnibus (GEO) and DisGeNET were analyzed by bioinformatics, and 429 glioma-related targets were obtained. Furtherly, 34 common targets of compounds and glioma were revealed, and they were significantly enriched in MAPK signaling pathway. Subsequently, we constructed a common target-compound network, and glutathione S-transferase Pi 1 (GSTP1) had the highest degree value, which explained its significance in the network. Therefore, we speculated that the compounds might exert an anti-glioma effect by targeting GSTP1. To verify the above results, we obtained part of sesquiterpene lactones isolated from E. scaber in our laboratory and evaluated their activities against glioma U87 cells. Among these sesquiterpene lactones (1-27), compounds 1 (elephantopinolide A), 2 (cis-scabertopin) and 3 (elephantopinolide F) exhibited the strongest inhibitory effect, and the IC values were 4.22 ± 0.14 µM, 4.28 ± 0.21 µM and 1.79 ± 0.24 µM, respectively. The results from molecular docking, cellular thermal shift assay (CETSA), as well as RT-PCR and Western blot analysis suggested that the compounds exerted an inhibitory effect by targeting GSTP1. Meanwhile, the compounds also activated JNK/STAT3 signaling pathway. Furthermore, we found that 1, 2 and 3 could suppress cell proliferation and also induce mitochondrial dysfunction as well as oxidative stress, eventually leading to cellular apoptosis. Taken together, this study revealed that sesquiterpene lactones from E. scaber could be a promising therapeutic strategy for the treatment of glioma by targeting GSTP1.
倍半萜内酯在多种癌细胞系中具有优异的抗肿瘤活性，包括神经胶质瘤，这是一种死亡率很高的最常见的恶性脑瘤。然而，这种成分的详细机制，特别是其抗神经胶质瘤作用的潜在靶点，仍不清楚。在这里，我们从 Elephantopus scaber Linn. 中收集了 52 种倍半萜内酯，用于网络药理学分析。结果表明，活性成分的靶点在癌症途径中明显富集，这些途径与细胞增殖调节密切相关。接下来，通过生物信息学分析基因表达综合数据库（GEO）和 DisGeNET，获得了 429 个与神经胶质瘤相关的靶点。进一步，揭示了化合物与神经胶质瘤的 34 个共同靶点，这些靶点在 MAPK 信号通路中显著富集。随后，我们构建了一个共同的靶标-化合物网络，其中谷胱甘肽 S-转移酶 Pi 1（GSTP1）的度数值最高，这解释了其在网络中的重要性。因此，我们推测这些化合物可能通过靶向 GSTP1 发挥抗神经胶质瘤作用。为了验证上述结果，我们从实验室中获得了部分从 E. scaber 中分离得到的倍半萜内酯，并评估了它们对神经胶质瘤 U87 细胞的活性。在这些倍半萜内酯（1-27）中，化合物 1（elephantopinolide A）、2（cis-scabertopin）和 3（elephantopinolide F）表现出最强的抑制作用，IC 值分别为 4.22 ± 0.14 μM、4.28 ± 0.21 μM 和 1.79 ± 0.24 μM。分子对接、细胞热转移分析（CETSA）以及 RT-PCR 和 Western blot 分析的结果表明，这些化合物通过靶向 GSTP1 发挥抑制作用。同时，这些化合物还激活了 JNK/STAT3 信号通路。此外，我们发现 1、2 和 3 可以抑制细胞增殖，并诱导线粒体功能障碍和氧化应激，最终导致细胞凋亡。总之，这项研究揭示了 E. scaber 中的倍半萜内酯可以通过靶向 GSTP1 成为治疗神经胶质瘤的一种有前途的治疗策略。
