In-Vitro and Ex-Vivo Investigations of the Microtubule Binding Drug Targetin on Angiogenesis.
In-Vitro and Ex-Vivo Investigations of the Microtubule Binding Drug Targetin on Angiogenesis.
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DOI：
10.14205/2309-3021.2013.01.01.6
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Kamnasaran D
中科院分区：
文献类型：
--
作者：
Ajeawung NF;Mononen L;Thorn A;Pin AL;Joshi HC;Huot J;Kamnasaran D
干扰或抑制新形成的血管网络的干预是减缓血管生成依赖性疾病进展的迫切需要。在癌症中，这与缺氧诱导因子-1α在缺氧激活后产生血管内皮生长因子密切相关。鉴于微管在细胞中发挥的多种作用及其参与低氧诱导因子-1α转录的过程，微管动力学的调节成为抑制肿瘤对血管生成的依赖的一种合理途径。Targetin是一种新的诺华素类化合物，它干扰微管的动力学，并抑制许多类型癌症的细胞系的生长。利用体外和体外血管生成模型，我们发现了Targetin的血管破坏和抗血管生成的特性。在有无血管内皮生长因子和碱性成纤维细胞生长因子的情况下，Targetin通过切断细胞-细胞连接，抑制内皮细胞的增殖和代谢活动来破坏人内皮细胞预先组装的毛细血管样网络。此外，我们还发现，Targetin显著抑制血管生成前刺激的大鼠主动脉外植体的新生血管网络的形成，即血管生成因子或碱性成纤维细胞生长因子。结论：塔格汀是一种具有潜在临床应用前景的抗血管生成药物，可用于包括癌症在内的多种疾病的治疗。
Intervention aimed at disrupting or inhibiting newly formed vascular network is highly desired to attenuate the progression of angiogenesis-dependent diseases. In cancer, this is tightly associated with the generation of VEGF by hypoxia inducible factor-1α following its activation by hypoxia. In light of the multiple cellular roles played by microtubules and their involvement in the processing of the hypoxia inducible factor-1α transcript, modulation of microtubule dynamics is emerging as a logical approach to suppress tumor reliance on angiogenesis. Targetin is a novel noscapinoid that interferes with microtubule dynamicity and inhibits the growth of cell lines from many types of cancers. Utilizing in-vitro and ex-vivo angiogenic models, we discovered the vascular disrupting and anti-angiogenic properties of Targetin. Targetin disrupted pre-assembled capillary-like networks of human endothelial cells by severing cell-cell junctions, inhibiting endothelial cell proliferation and metabolic activity in the presence and absence of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Furthermore, we show that Targetin significantly inhibits the formation of neovasculature network sprouting from rat aortic explants stimulated with proangiogenic stimuli, namely VEGF or bFGF. We conclude that Targetin is a potential clinically promising anti-angiogenic agent for the treatment of many diseases including cancers.