This study investigates the anticancer effect of dehydrocostuslactone (DHE), a 
medicinal plant-derived sesquiterpene lactone, on human non-small cell lung 
cancer cell lines, A549, NCI-H460 and NCI-H520. Our results show that DHE 
inhibits the proliferation of A549, NCI-H460 and NCI-H520 cells. DHE-induced 
apoptosis in both A549 and NCI-H460 cells. DHE triggered endoplasmic reticulum 
(ER) stress, as indicated by changes in cytosol-calcium levels, PKR-like ER 
kinase (PERK) phosphorylation, inositol requiring protein 1 (IRE1) and 
CHOP/GADD153 upregulation, X-box transcription factor-1 (XBP-1) mRNA splicing, 
and caspase-4 activation. The release of calcium triggered the production of 
ROS, which further enhances calcium overloading and subsequently activates p38, 
JNK and ERK1/2. Both IRE1 miRNA transfection and BAPTA-AM pretreatment inhibit 
DHE-mediated apoptosis, supporting the hypothesis that DHE induces cell death 
through ER stress. Importantly, a novel anticancer agent for the treatment of 
non-small cell lung cancer, and is supported by animal studies which have shown 
a dramatic 50% reduction in tumor size after 28 days of treatment. This study 
demonstrates that DHE may be a novel anticancer agent for the treatment of 
non-small cell lung cancer.