Sesquiterpene lactones from Elephantopus scaber exhibit cytotoxic effects on glioma cells by targeting GSTP1.

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.