Abstract A53: Antiangiogenic activity of GER, a derivative of sweet leaf tea extract, is mediated by the downregulation of bFGF and VEGF Free

Mounting evidence indicates that angiogenesis is essential for the proliferation and survival of number of malignant diseases, thus inhibition of angiogenesis might be an effective therapeutic strategy. Antiangiogenic agent that targets both bFGF and VEGF (VEGFR) are considered to be effective adjuncts to the treatment of solid tumors or cancer preventive. Chinese sweet leaf tea, a hot water extract of Rubus suavissimus S. Lee (Rosaceae) (RUS) has been reported to have antiangiogenic activities evidenced by its ability to inhibit the angiogenic initiation and growth of human placental vein tissue (Liu et al., Phytother, Res. 20: 806-813, 2006) and experimental corneal neovascularization (Hakan, O.F., et al, Pharmaceu. Biol. 45: 44-47, 2007). We reported that this particular extract has the ability to inhibit the endothelial tubule formation, migration, and VEGF (VEGFR) of the HUVEC cells (Proc. Am. Assoc. Cancer Res, 1432, 2009). Here we investigated the anti-angiogenic activity of GER, a combination of gallic acid, ellagic acid, and rubusoside purified from the RUS and the relevant molecular mechanisms using HUVEC cells. Our preliminary data demonstrated that GER (5 to 25 µg/ml) markedly inhibited migration of HUVEC cells compared to the vehicle control. This inhibitory effect was concentration-dependent. At a similar concentration, the endothelial tubule formation was almost completely inhibited. When HUVEC cells were treated with GER (5 to 20 µg/ml), the expression of both bFGF and VEGF were markedly inhibited even at the lowest starting concentration. These inhibitory effects were also concentration-dependent. To further confirm the involvement of VEGF pathway in GER-induced anti-angiogenic activity, the protein level of tyrosine kinase receptor VEGFR2 (Flk-1/KDR) was examined. Intriguingly, the expression of Flk-1 was significantly suppressed in HUVEC cells treated with GER (40 µg/ml) by 54.1% ± 2.3% in comparison to that of vehicle control. In contrast, VEGFR2 kinase activity and protein levels of VEGFR1 remained unchanged compared to that of the vehicle control. These results suggest that GER derived from the sweet leaf tea extract may be completely responsible for the observed anti-angiogenic effect of the sweet leaf tea reported previously by down-regulating proangiogenic factors bFGF and VEGF. The chemopreventive effect of GER and its parent extract RUS on the development of human pancreatic carcinoma (L3.6pl cells) in mouse orthotopic model is currently under investigation and will be reported. This study was supported by NIH grant 1R21 AT002882-01A2.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A53.