Differential Effect of Grape Seed Extract against Human Non-Small-Cell Lung Cancer Cells: the role of Reactive Oxygen Species and Apoptosis Induction

摘要

Present study examines grape seed extract (GSE) efficacy against a series of Non-small-cell lung cancer (NSCLC) cell lines which differ in their Kras and p53 status to establish GSE potential as a cytotoxic agent against a wide-range of lung cancer cells. GSE suppressed growth and induced apoptotic death in NSCLC cells irrespective of their k-Ras status, with more sensitivity towards H460 and H322 (wt k-Ras) than A549 and H1299 cells (mutated k-Ras). Mechanistic studies in A549 and H460 cells, selected, based on comparative efficacy of GSE at higher and lower doses, respectively, showed that apoptotic death involves cytochrome c release associated caspases 9 and 3 activation, and PARP cleavage, strong phosphorylation of ERK1/2 and JNK1/2, down regulation of cell survival proteins, and up regulated pro-apoptotic Bak expression. Importantly, GSE treatment caused a strong superoxide radical-associated oxidative stress, significantly decreased intracellular reduced glutathione levels, suggesting, for the first-time, the involvement of GSE-caused oxidative stress in its apoptotic inducing activity in these cells. Since GSE is a widely-consumed dietary agent with no known untoward effects, our results support future studies to establish GSE efficacy and usefulness against NSCLC control.