title: A natural small molecule harmine inhibits angiogenesis and suppresses tumour growth through activation of p53 in endothelial cells.
abstract: Activation of p53 effectively inhibits tumor angiogenesis that is necessary for tumor growth and metastasis. Reactivation of the p53 by small molecules has emerged as a promising new strategy for cancer therapy. Several classes of small-molecules that activate the p53 pathway have been discovered using various approaches. Here, we identified harmine (β-carboline alkaloid) as a novel activator of p53 signaling involved in inhibition of angiogenesis and tumor growth. Harmine induced p53 phosphorylation and disrupted the p53-MDM2 interaction. Harmine also prevented p53 degradation in the presence of cycloheximide and activated nuclear accumulation of p53 followed by increasing its transcriptional activity in endothelial cells. Moreover, harmine not only induced endothelial cell cycle arrest and apoptosis, but also suppressed endothelial cell migration and tube formation as well as induction of neovascularity in a mouse corneal micropocket assay. Finally, harmine inhibited tumor growth by reducing tumor angiogenesis, as demonstrated by a xenograft tumor model. Our results suggested a novel mechanism and bioactivity of harmine, which inhibited tumor growth by activating the p53 signaling pathway and blocking angiogenesis in endothelial cells.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Dai
authors.forename: Yihua
authors.initials: Y
authors.lastname: Chen
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Song
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Dong
authors.initials: D
authors.lastname: Zhai
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Dong
authors.forename: Li
authors.initials: L
authors.lastname: Lai
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Dali
authors.initials: D
authors.lastname: Li
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Pang
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D020552:Comet Assay; D005455:Fluorescent Antibody Technique; D006213:Hallucinogens / Q000494:pharmacology; D006247:Harmine / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D006213:Hallucinogens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006247:Harmine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2