Deacetylmycoepoxydiene is an agonist of Rac1, and simultaneously induces autophagy and apoptosis.

Lung cancer is the second most common cause of cancer-related death in the world. Most cases of lung cancer are not curable, especially non-small cell lung cancer (NSCLC). Thus, novel treatment targets for this malignant disease are urgently needed. Here, we demonstrate the feasibility of Rac1 in treating p53-null human NSCLC H1299 as a novel drug target. Deacetylmycoepoxydiene (DA-MED), a cytotoxic natural polyketide, functions as a Rac1 agonist in p53-null NSCLC H1299 cells. DA-MED treatment drives Rac1 activation and promotes robust production of reactive oxygen species, activating mitochondrial permeability transition and the intrinsic apoptotic pathway. Knockdown of Rac1 decreases ROS production in DA-MED-treated cells, resulting in a concomitant decrease in DA-MED-induced apoptosis. DA-MED-activated Rac1 induces autophagy by inhibiting mammalian target of rapamycin, leading to anti-apoptotic and anti-metastatic effects. Therefore, this study provides novel insight into the complex cytotoxic and pro-survival mechanisms associated with a potent Rac1 agonist and suggests that further development of more potent Rac1 agonists could be an effective strategy for future non-small cell lung cancer treatments.