The marine-derived oligosaccharide sulfate (MdOS), a novel multiple tyrosine kinase inhibitor, combats tumor angiogenesis both in vitro and in vivo.
The marine-derived oligosaccharide sulfate (MdOS), a novel multiple tyrosine kinase inhibitor, combats tumor angiogenesis both in vitro and in vivo.
复制标题
DOI：
10.1371/journal.pone.0003774
复制
发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Ding, Jian
中科院分区：
文献类型：
--
作者：
Ma, Jingui;Xin, Xianliang;Meng, Linghua;Tong, Linjiang;Lin, Liping;Geng, Meiyu;Ding, Jian
尽管多靶点蛋白酪氨酸激酶（PTK）抑制剂在癌症治疗中取得了成功，但似乎不太可能避免显著的副作用和耐药性问题。本研究的目的是鉴定新型多靶向PTK抑制剂。酶联免疫吸附试验（ELISA）测定激酶活性。采用硫酸罗丹明（SRB）法检测其对人微血管内皮细胞（HMEC）增殖的抑制作用。通过蛋白质印迹分析探测激酶及其下游分子的磷酸化。利用表面等离子体共振（SPR）技术和分子模拟技术研究了MdOS与PTKs的结合模式。结合试管形成法、大鼠主动脉环法和鸡胚绒毛尿囊膜法观察其体内外抗血管生成作用。结果表明，MdOS，一种新的海洋来源的寡糖硫酸酯，表现出广谱的PTK抑制作用。在酶水平上，MdOS抑制HER 2、EGFR、VEGFR、PDGFR、c-Kit、FGFR 1和c-Src，对FGFR 2几乎没有影响。在细胞环境中，MdOS抑制PTKs的磷酸化，例如HER 2、EGFR和VEGFR 2以及Erk 1/2和AKT的下游分子。进一步的研究表明，MdOS通过直接结合入口残基而不是ATP结合口袋的残基来发挥ATP竞争性抑制剂的作用。此外，MdOS抑制HMEC的增殖和管形成，阻止大鼠主动脉环的微血管生长和阻碍鸡胚尿囊膜的新生血管。总之，本文提供的结果表明，MdOS以PTK依赖性方式表现出抗血管生成活性，并使其成为进一步评价PTK相关癌症治疗的有前途的药物。
Despite the emerging success of multi-targeted protein tyrosine kinase (PTK) inhibitors in cancer therapy, significant side effects and resistance concerns seems to be avoided unlikely. The aim of the present study was to identify novel multi-targeting PTK inhibitors. The kinase enzymatic activities were measured by enzyme-linked immunosorbent assay (ELISA). The antiproliferative activities in human microvascular endothelial cells (HMECs) were evaluated by sulforhodamine (SRB) assay. The phosphorylation of kinases and their downstream molecules was probed by western blot analysis. The binding mode between MdOS and PTKs was profiled by surface plasmon resonance (SPR) approach and molecular simulation. Tube formation assay, rat aortic ring method and chicken chorioallantoic membrane assay were combined to illustrate the in vitro and in vivo anti-angiogenic effects. Results indicated that MdOS, a novel marine-derived oligosaccharide sulfate, exhibited a broad-spectrum PTK inhibitory action. At an enzymatic level, MdOS inhibited HER2, EGFR, VEGFR, PDGFR, c-Kit, FGFR1 and c-Src, with little impact on FGFR2. In cellular settings, MdOS inhibited phosphorylation of PTKs, exemplified by HER2, EGFR and VEGFR2, and downstream molecules of Erk1/2 and AKT. Further studies demonstrated that MdOS acted as an ATP-competitive inhibitor via directly binding to the residues of entrance rather than those of the ATP-binding pocket. Furthermore, MdOS inhibited proliferation and tube formation of HMECs, arrested microvessel outgrowth of rat aortic rings and hindered the neovascularization of chick allantoic membrane. Taken together, results presented here indicated that MdOS exhibited anti-angiogenic activity in a PTK-dependent manner and make it a promising agent for further evaluation in PTK-associated cancer therapy.
登录
查看更多内容
DOI：
10.1016/j.bbagen.2004.04.015
发表时间：
2004-08-04
影响因子：
3
作者：
Guo, XN;Zhong, L;Ding, J
通讯作者：
Ding, J
影响因子：
7.3
作者：
Lin, Li-Gen;Xie, Hua;Ye, Yang
通讯作者：
Ye, Yang
影响因子：
3.6
作者：
Miao, BC;Li, J;Geng, MY
通讯作者：
Geng, MY
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B
影响因子：
2.1
作者：
GASTEIGER, J;MARSILI, M
通讯作者：
MARSILI, M