Synergy of Ginkgetin and Resveratrol in Suppressing VEGF-Induced Angiogenesis: A Therapy in Treating Colorectal Cancer

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.

Resveratrol and Its Nanoformulation Attenuate Growth and the Angiogenesis of Xenograft and Orthotopic Colon Cancer Models

“…Here, RSV significantly reduced the Hb percentages of tumor mass, indicating the anti-angiogenetic effect of RSV against implanted COLO205-luc. Similar results were reported by Hu et al [25], who found a significant anti-angiogenetic effect of RSV alone or in combination with ginkgetin, a biflavone from Ginkgo biloba leaf, through the downregulation of vascular endothelial growth factor (VEGF)-mediated angiogenesis. Moreover, RSV induced apoptosis of in vivo implanted breast cancer cells (MDA-MB-231) through a significant reduction in extracellular levels of VEGF [26].…”

Ocular lamellar crystalline gels for sustained release and enhanced permeation of resveratrol against corneal neovascularization

“…The expression levels of VEGF in the control group were higher compared to the healthy group ( Figure 8(F,G) ), indicating that corneal alkali burns increased VEGF expression, which thereby induced CNV. Resveratrol is a highly effective anti-VEGF agent against CNV (Hu et al., 2019 ). Ocular drug delivery has been a challenge due to physiological eye obstacles such as blinking and the production of tears.…”

Resveratrol and Tumor Microenvironment: Mechanistic Basis and Therapeutic Targets

“…This investigation also covers the down-regulation of the products of the following genes, COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA [ 93 ]. This recent study also emphasized and defined the pharmacological significance of the activity of resveratrol and ginkgetin in angiogenesis, in cancer cells and its related signaling mechanisms [ 94 ]. It was found out that combining resveratrol and ginkgetin can be efficient as an angiogenesis inhibitor and has the potential characteristics of a drug for cancer treatment and drug development.…”

“…This combination was found to suppress VEGF through a succeeding steps interfering with the VEGF-related signaling transduction. These activities of resveratrol and ginkgetin in comparison with other anti-angiogenesis agents, can be studied further for the treatment and prophylaxis of different types of angiogenesis-related illnesses and can be a novel angiogenesis inhibitors [ 94 ].…”