Grape seed proanthocyanidins inhibit cigarette smoke condensate-induced lung cancer cell migration through inhibition of NADPH oxidase and reduction in the binding of p22(phox) and p47(phox) proteins.

Cigarette smoking is the major cause of lung cancer. It is therefore important to develop effective strategies that target molecular abnormalities induced by cigarette smoke condensate (CSC). Cigarette smoking increases oxidative stress particularly via activation of NADPH oxidase (NOX), a key source of superoxide anion production. Here, we report that grape seed proanthocyanidins (GSPs) exert an inhibitory effect on the CSC-induced migration of non-small cell lung cancer (NSCLC) cells (A549, H460, and H1299). Using an in vitro invasion assay, we found that treatment of NSCLC cells with CSC increased NSCLC cell migration by enhancing NOX mediated-oxidative stress. Treatment of NSCLC cells with GSPs inhibited the CSC-induced cell migration through reduction in oxidative stress levels and a reduction in the epithelial-to-mesenchymal transition. To identify the molecular targets of GSPs, we examined the effects of GSPs on CSC-induced alterations in the levels of key NOX components, namely p22(phox) and p47(phox) proteins, using A549 cells. We also determined the effect of GSPs on CSC-induced interaction/binding between these proteins, which is a key event in NOX activation. We found that treatment of A549 cells with GSPs not only inhibited the CSC-induced increase in the expression levels of p22(phox) and p47(phox) , but also reduced the binding of p22(phox) to p47(phox) proteins. This new insight into the anti-lung cancer cell migration activity of GSPs could serve as a basis for development of improved chemopreventive or therapeutic strategies for lung cancer.