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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.

SUBMITTER: Hu WH

PROVIDER: S-EPMC6966653 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Hu Wei-Hui WH Chan Gallant Kar-Lun GK Duan Ran R Wang Huai-You HY Kong Xiang-Peng XP Dong Tina Ting-Xia TT Tsim Karl Wah-Keung KW

Cancers 20191120 12

Ginkgetin, a biflavone from <i>Ginkgo biloba</i> 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 gi ...[more]

PMID: 31757048

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Project description:BackgroundGrb2-associated binder 2 (Gab2) is a scaffolding protein that serves as a critical signaling amplifier downstream of tyrosine kinase receptors. Our previous study has shown that Gab2 induces epithelial-to-mesenchymal transition (EMT) and promotes metastasis in colorectal cancer (CRC). However, the role of Gab2 in CRC growth and angiogenesis remains unclear.MethodsThe expression of vascular endothelial growth factor (VEGF) in different colorectal tissues was detected by immunohistochemistry and qRT-PCR to evaluate its correlation with Gab2. Lentiviral vectors bearing Gab2 gene and its small interfering RNAs were constructed and transfected into CRC cell lines. The effects of Gab2 on the cell proliferation in vitro and tumorigenesis in vivo, were examined via CCK‑8 assay, colony formation assay as well as tumorigenicity assay respectively. Moreover, to assess its potential role in tumor growth and angiogenesis, the expression of Ki67, CD34 and vascular endothelial growth factor receptor-2 (VEGFR2) were detected by immunohistochemistry in CRC cells tumors. Finally, we evaluated the impact of Gab2 on the expression of c-Myc and VEGF, and the probable effect of mechanistic targeted extracellular signal-regulated kinase (ERK) pathway in suppressing tumor growth and angiogenesis.ResultsUp-regulation of Gab2 expression was found to be positively correlated with VEGF in CRC tissues. Exogenous expression of Gab2 obviously promoted, whereas silencing of Gab2 inhibited, proliferation and clone formation of human CRC cells in vitro. Of note, Gab2 enhanced tumorigenesis and tumor growth in mouse xenografts with high Ki67 expression, and led to an increased vessel density with strong CD34 and VEGFR2 activity. In addition, elevated Gab2 expression obviously up-regulated the expression of VEGF, and stimulated the activation of its downstream genes, ERK1/2 and c-Myc in CRC cells. Instead, down-regulated Gab2 expression significantly reduced the levels of VEGF, and inhibited the transduction of ERK/c-Myc pathway. Finally, we revealed that mechanistic target of mitogen-activated protein kinase (MEK) could attenuate Gab2-induced tumor growth and angiogenesis via altering VEGF and c-Myc levels.ConclusionsThe results from our study suggest that Gab2 promotes intestinal tumor growth and angiogenesis through upregulation of VEGF expression mediated by the MEK/ERK/c-Myc pathway.

Dataset Information

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

Publications

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

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