Combretastatin A-4 efficiently inhibits angiogenesis and induces neuronal apoptosis in zebrafish.
Combretastatin A-4 efficiently inhibits angiogenesis and induces neuronal apoptosis in zebrafish.
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Combretastatin A-4 有效抑制斑马鱼血管生成并诱导神经元凋亡
DOI：
10.1038/srep30189
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发表时间：
2016-07-25
影响因子：
4.6
通讯作者：
Liu D
中科院分区：
文献类型：
--
作者：
Shi YW;Yuan W;Wang X;Gong J;Zhu SX;Chai LL;Qi JL;Qin YY;Gao Y;Zhou YL;Fan XL;Ji CY;Wu JY;Wang ZW;Liu D
顺式芪考布他汀A-4（CA-4）及其衍生物具有显著的抗血管生成活性。然而，这些化学品的副作用甚至毒性都没有得到充分的评估。斑马鱼模型已成为评价药物作用的重要脊椎动物模型。CA-4在斑马鱼上的实验研究尚不多见，在此模型上对CA-4的评价将为了解CA-4在血管生成中的作用、CA-4的毒副作用提供新的思路。我们发现，7-9 ng/ml CA-4处理导致发育迟缓和形态畸形，并导致斑马鱼胚胎中强有力的血管生成缺陷。接下来，我们证明了腹腔注射5，10和20 mg/kg CA-4明显抑制成年斑马鱼胸鳍再生血管丛的形成。有趣的是，我们证明CA-4处理诱导斑马鱼胚胎和成体中枢神经系统的细胞凋亡。此外，证明CA-4处理诱导的神经元凋亡在p53突变体中减轻。此外，Notch 1a在CA-4处理的胚胎中上调，并且DAPT抑制Notch信号传导部分地挽救了CA-4引起的斑马鱼中枢神经系统的凋亡。
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.