Lung cancer is the leading cause of cancer related deaths in both menand women in the United States and also worldwide. One of every three cancer-related deaths is attributable to lung cancer, and the dismal 5-year survival rate of approximately 14% has shown no improvement over the past 30 years. It thus has a tremendous impact on public health and healthcare expenditures. Therefore, it would be desirable to develop newer and more effective chemopreventive agents and/or strategies that can reduce the risk of lung cancer development. Grape seed proanthocyanidins (GSPs) have been shown to inhibit the growth of tumors in some murine models. As p53 is the most commonly mutated tumor suppressor gene, and lack of functional p53 is associated with an increased risk of cancer development, we examined the effects of GSPs on both p53-positive and p53-deficient non-small cell human lung cancer cells in vitro and in vivo. Treatment of A549, which are p53-positive, and H1299, which are p53-deficient, human lung cancer cells with GSPs resulted in a dose- and time-dependent inhibition of cell proliferation, and increase in apoptotic cell death, although the A549 cells were more sensitive to the GSPs-induced effects than the H1299 cells. The GSPs-induced apoptosis of both the A549 and H1299 lung cancer cells was associated with the disruption of mitochondrial membrane potential, reduction in the levels of anti-apoptotic proteins (Bcl-2, Bcl-xl) and increase in pro-apoptotic protein (Bax), and activation of caspases and PARP proteins. Treatment of the cells with pan-caspase inhibitor (z-VAD-fmk) inhibited GSPs-induced apoptosis. Intriguingly, treatment of the p53-positive A549 cells with pifithrin-α, a specific inhibitor of p53, or transfection with p53 antisense oligodeoxynucleotide resulted in reduction in the GSPs-induced inhibition of cell proliferation and apoptosis. Administration of 50, 100 or 200 mg GSPs/kg body weight of mice by oral gavage significantly inhibited the growth of subcutaneous A549 and H1299 lung tumor xenografts in athymic nude mice and without inducing any apparent toxic effects. The inhibition of tumor growth by GSPs was associated with the induction of apoptotic cell death, inhibition of tumor cell proliferation and activation of caspase-9 and -3 in tumors. The growth inhibitory effects of the GSPs were more pronounced in p53-positive-A549 tumor xenograft than the p53-deficient-H1299 tumor xenograft. Together, these results suggest that grape seed proanthocyanidins are potential agent for the chemoprevention of lung cancer, and therefore warrant further studies.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA