Sesquiterpene lactones have been shown to be promising leads for anticancer drug development.
Brevilin A (BLN-A), a
sesquiterpene lactone compound of Centipeda minima has been shown to exhibit anticancer effects against various
cancer cells. However, the anticancer mechanism and cellular targets of BLN-A remain elusive. Here in this study, BLN-A inhibits proliferation and induces cell morphological changes in A549 and NCI-H1650
non-small cell lung cancer cells in a dose-dependent manner. Moreover, BLN-A increased ROS generation and bax/bcl-2 ratio while decreased intracellular
glutathione (GSH), and mitochondrial membrane potential which resulted in induction of apoptosis as evident by
annexin-V/FITC staining,
caspase-3 activation and PARP cleavage. Supplementation of cells with NAC (ROS Scavenger) effectively protected the cells from BLN-A-induced apoptosis. Finally, BLN-A inhibited constitutive as well as IL-6- and
EGF-induced STAT3 activation at Tyr705. Using molecular docking and SPR analyses, we found that BLN-A directly binds with STAT3 and thereby inhibits its activation. Knocking down of STAT3 by stable transfection with
shRNA suppressed growth and augmented cytotoxicity of BLN-A, indicating the key role of STAT3 in BLN-A-mediated apoptosis. Cumulative findings suggest that BLN-A is a promising lead structure for developing it into a potent STAT3 inhibitor and therapeutic agent against NSCLC as well.