Apigenin Inhibits Expression of Vascular Endothelial Growth Factor and Angiogenesis in Human Lung Cancer Cells: Implication of Chemoprevention of Lung Cancer

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Abstract
Apigenin is a natural dietary flavonoid. It has recently been shown to have anticancer effects on prostate and ovarian cancer cells. However, the molecular basis of the effect of apigenin on cancer cells remains to be elucidated. In this study, we found that apigenin inhibited A549 lung cancer cell proliferation and vascular endothelial growth factor (VEGF) transcriptional activation in a dose-dependent manner. In an attempt to understand the mechanism of apigenin-inhibited VEGF expression, we found that apigenin inhibited VEGF transcriptional activation through the hypoxia-inducible factor 1 (HIF-1) binding site and specifically decreased HIF-1α but not HIF-1β subunit expression in the cells. In our efforts to understand the signaling pathway that mediates VEGF transcriptional activation, we found that apigenin inhibited AKT and p70S6K1 activation. When testing the effect of apigenin in vivo, we found that apigenin significantly inhibited tumor growth in nude mice. Apigenin inhibited HIF-1α and VEGF expression in the tumor tissues, suggesting an inhibitory effect of apigenin on angiogenesis. To confirm this, we showed that apigenin inhibited angiogenesis in nude mice using the Matrigel assay. HIF-1α and VEGF are well known inducers of angiogenesis. Our data suggested that apigenin may inhibit human lung cancer angiogenesis by inhibiting HIF-1α and VEGF expression, thus providing a novel explanation for the anticancer action of apigenin.