SCP-7, a germacrane-type sesquiterpene lactone derivative, induces ROS-mediated apoptosis in NSCLC cells in vitro and in vivo

Scabertopin (SCP), an abundant germacrane-type sesquiterpene lactone (SLC) isolated from Elephantopus scaber , was selected as a reference compound for modification and evaluation as anticancer agents for non-small cell lung cancer (NSCLC) treatment. All derivatives ( SCP-1 - SCP-13 ) except for SCP-3 showed potential inhibitory effect (IC 50 5.2–9.7 μM) against A549 cells. The most promising compound SCP-7 also showed good cytotoxic activity against another two NSCLC cell lines (H1299 and H460), with IC 50 value of 4.4 and 8.9 μM, respectively. Furthermore, SCP-7 could induce apoptotic cell death that was associated with the increased reactive oxygen species (ROS) generation, the loss of mitochondrial membrane potential, Bcl-2 family proteins modulation, caspases-3 and PARP cleavage. In addition, SCP-7 also inhibited cell growth by increasing Bax expression and reducing the Ki-67 positive cells in vivo , but there were no obvious toxic and side effects on internal organs. Mechanistically, PharmMapper, molecular docking and Western blot analysis revealed that SCP-7 might interact with the epidermal growth factor receptor (EGFR) and inhibit its expression in lung cancer cells. Together, above results suggest further effective application of SCP-7 as a potential anti-tumor agent in the treatment of NSCLC. • 13 germacrane-type sesquiterpene lactone derivatives with anti-NSCLC cells activities were synthesized. • SCP-7 had the most potent inhibitory activity on NSCLC cells. • SCP-7 induced apoptosis and mitochondrial dysfunction in NSCLC cells. • SCP-7 markedly inhibited the cell growth of NSCLC xenograft tumor in vivo.