title: DDA suppresses angiogenesis and tumor growth of colorectal cancer in vivo through decreasing VEGFR2 signaling.
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.
authors: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Shiu-Wen
authors: SW
authors: Huang
authors: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
authors: Jin-Cherng
authors: JC
authors: Lien
authors: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
authors: Sheng-Chu
authors: SC
authors: Kuo
authors: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Tur-Fu
authors: TF
authors: Huang
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D039942:Neuropilin-1 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: C000626797:1,5-dihydroxy-4,8-dinitro anthraquinone; D000880:Anthraquinones; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; C000588866:KDR protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: VEGFR; angiogenesis; anthraquinone; endothelial cells