title: Combretastatin A-4 efficiently inhibits angiogenesis and induces neuronal apoptosis in zebrafish.
abstract: Cis-stilbene combretastatin A-4 (CA-4) and a large group of its derivant compounds have been shown significant anti-angiogenesis activity. However the side effects even the toxicities of these chemicals were not evaluated adequately. The zebrafish model has become an important vertebrate model for evaluating drug effects. The testing of CA-4 on zebrafish is so far lacking and assessment of CA-4 on this model will provide with new insights of understanding the function of CA-4 on angiogenesis, the toxicities and side effects of CA-4. We discovered that 7-9 ng/ml CA-4 treatments resulted in developmental retardation and morphological malformation, and led to potent angiogenic defects in zebrafish embryos. Next, we demonstrated that intraperitoneal injection of 5, 10 and 20 mg/kg CA-4 obviously inhibited vessel plexus formation in regenerated pectoral fins of adult zebrafish. Interestingly, we proved that CA-4 treatment induced significant cell apoptosis in central nervous system of zebrafish embryos and adults. Furthermore, it was demonstrated that the neuronal apoptosis induced by CA-4 treatment was alleviated in p53 mutants. In addition, notch1a was up-regulated in CA-4 treated embryos, and inhibition of Notch signaling by DAPT partially rescued the apoptosis in zebrafish central nervous system caused by CA-4.
authors.affiliation: Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Yun-Wei
authors.initials: YW
authors.lastname: Shi
authors.affiliation: Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of life science, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Jie
authors.initials: J
authors.lastname: Gong
authors.affiliation: Laboratory Animal Center, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Shun-Xing
authors.initials: SX
authors.lastname: Zhu
authors.affiliation: Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Chai
authors.affiliation: School of medicine, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Jia-Ling
authors.initials: JL
authors.lastname: Qi
authors.affiliation: Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Yin-Yin
authors.initials: YY
authors.lastname: Qin
authors.affiliation: Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: School of medicine, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Zhou
authors.affiliation: School of medicine, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Xiao-Le
authors.initials: XL
authors.lastname: Fan
authors.affiliation: School of medicine, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Chun-Ya
authors.initials: CY
authors.lastname: Ji
authors.affiliation: School of medicine, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.|Department of Pharmacology, University of California, Irvine, CA 92697, USA.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Wang
authors.affiliation: Co-innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D023421:Models, Animal; D009024:Morphogenesis / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D015027:Zebrafish / Q000378:metabolism; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C058728:fosbretabulin