DDA suppresses angiogenesis and tumor growth of colorectal cancer in vivo through decreasing VEGFR2 signaling
Journal
Oncotarget
Journal Volume
7
Journal Issue
39
Pages
63124-63137
Date Issued
2016
Author(s)
Abstract
As angiogenesis is required for tumor growth and metastasis, suppressing angiogenesis is a promising strategy in limiting tumor progression. Vascular endothelial growth factor (VEGF)-A, a critical pro-angiogenic factor, has thus become an attractive target for therapeutic interventions in cancer. In this study, we explored the underlying mechanisms of a novel anthraquinone derivative DDA in suppressing angiogenesis. DDA inhibited VEGF-A-induced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs). DDA also reduced VEGF-A-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization in vivo. VEGF-A-induced VEGFR1, VEGFR2, FAK, Akt, ERK1/2 or STAT3 phosphorylation was reduced in the presence of DDA. In addition, NRP-1 siRNA reduced VEGF-A's enhancing effects in VEGFR2, FAK and Akt phosphorylation and cell proliferation in HUVECs. DDA disrupted VEGF-A-induced complex formation between NRP-1 and VEGFR2. Furthermore, systemic administration of DDA was shown to suppress tumor angiogenesis and growth in in vivo mouse xenograft models. Taken together, we demonstrated in this study that DDA exhibits anti-angiogenic properties through suppressing VEGF-A signaling. These observations also suggest that DDA might be a potential drug candidate for developing anti-angiogenic agent in the field of cancer and angiogenesis-related diseases.
Subjects
Angiogenesis; Anthraquinone; Endothelial cells; VEGFR
SDGs
Other Subjects
1,5 dihydroxy 4,8 dinitroanthraquinone; anthraquinone derivative; focal adhesion kinase; messenger RNA; mitogen activated protein kinase 1; mitogen activated protein kinase 3; neuropilin 1; protein kinase B; small interfering RNA; STAT3 protein; unclassified drug; vasculotropin A; vasculotropin receptor 1; vasculotropin receptor 2; anthraquinone derivative; KDR protein, human; neuropilin 1; vasculotropin A; vasculotropin receptor 1; vasculotropin receptor 2; VEGFA protein, human; animal experiment; animal model; animal tissue; antiangiogenic activity; antineoplastic activity; antiproliferative activity; aortic ring (slice); Article; blood vessel parameters; breast cancer; cell stimulation; cellular parameters; colorectal cancer; complex formation; concentration response; controlled study; drug dose comparison; drug efficacy; drug mechanism; drug safety; ex vivo study; fibroblast culture; HCT116 cell line; HepG2 cell line; HS68 cell line; human; human cell; in vivo study; male; MDA MB 231 cell line; microvessel sprouting; migration inhibition; mouse; neovascularization (pathology); nonhuman; PC3 cell line; prostate cancer cell line; protein analysis; protein phosphorylation; rat; signal transduction; treatment duration; tube formation; tumor xenograft; umbilical vein endothelial cell; animal; Bagg albino mouse; cancer transplantation; cell motion; cell proliferation; cell survival; colorectal tumor; endothelium cell; genetics; HCT 116 cell line; metabolism; metastasis; neovascularization (pathology); nude mouse; SCID mouse; tumor invasion; Animals; Anthraquinones; Cell Movement; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Endothelial Cells; HCT116 Cells; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; Neuropilin-1; RNA, Small Interfering; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2
Type
journal article