Abstract
Ginkgetin, a biflavone from Ginkgo biloba leaf, and resveratrol, a polyphenol found in grape and wine, are two phytochemicals being identified for its binding to vascular endothelial growth factor (VEGF): the binding, therefore, resulted in the alteration of the physiological roles of VEGF-mediated angiogenesis. The bindings of ginkgetin and resveratrol were proposed on different sites of VEGF, but both of them suppressed the angiogenic properties of VEGF. The suppressive activities of ginkgetin and resveratrol in VEGF-mediated angiogenesis were supported by several lines of evidence including (i) inhibiting the formation of sub-intestinal vessel in zebrafish embryos and microvascular sprouting in rat aortic ring; and (ii) suppressing the phosphorylations of VEGFR2, Akt, eNOS, and Erk as well as expressions of matrix metalloproteinases (MMPs), MMP-2, and MMP-9 in human umbilical vein endothelial cells (HUVECs). Here, we showed the synergy of ginkgetin and resveratrol in suppressing the VEGF-induced endothelial cell proliferation, migration, invasion, and tube formation. The synergy of ginkgetin and resveratrol was further illustrated in HT-29 colon cancer xenograft nude mice. Ginkgetin and resveratrol, when applied together, exerted a synergistic anti-tumor effect of 5-fluorouracil with decreasing microvessel density of tumors. In parallel, the combination of ginkgetin and resveratrol synergistically relieved the 5-fluorouracil-induced inflammatory response by suppressing expressions of COX-2 and inflammatory cytokines. Thus, the anti-angiogenic roles of ginkgetin and/or resveratrol could provide effective therapeutic strategy in cancer, similar to that of Avastin, in suppressing the VEGF-mediated angiogenesis during cancer development.
Highlights
Angiogenesis is formation of neovessels from pre-existing vessels, and has been proven to play significant roles in both normal and pathological conditions, in cancer development [1]
The results showed that the combined ginkgetin–resveratrol treatment significantly reduced the levels of Tumor Necrosis Factor (TNF)-α and IL-6 cytokines in 5-FU-treated tumor tissues, which were consistent with the expression of COX-2 protein (Figure 8B)
Resveratrol, a natural compound commonly found in grapes, peanuts, pines as well as in many Chinese medicinal herbs was compound commonly found in grapes, peanuts, pines as well as in many Chinese medicinal herbs demonstrated to exert inhibitory effects on inflammation [34], bladder cancer [35], colon cancer [36], was demonstrated to exert inhibitory effects on inflammation [34], bladder cancer [35], colon cancer and primary gastric cancer [37]
Summary
Angiogenesis is formation of neovessels from pre-existing vessels, and has been proven to play significant roles in both normal and pathological conditions, in cancer development [1]. This process involves complex interactions among endothelial cells, angiogenic factors, and extracellular matrix components [2]. There are different angiogenesis-related growth factors in regulating the synchronization of complex events of angiogenesis. Among these activators, compelling evidence has suggested that vascular endothelial growth factor (VEGF) is the most potent angiogenic stimulator [3,4]. There are five members in the Cancers 2019, 11, 1828; doi:10.3390/cancers11121828 www.mdpi.com/journal/cancers
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