Interference with endothelial cell function by JG-03-14, an agent that binds to the colchicine site on microtubules.
Interference with endothelial cell function by JG-03-14, an agent that binds to the colchicine site on microtubules.
复制标题
DOI：
10.1016/j.bcp.2009.06.093
复制
发表时间：
2009-11-01
影响因子：
5.8
通讯作者：
Schwartz, Edward L.
中科院分区：
文献类型：
--
作者：
Dalyot-Herman, Nava;Delgado-Lopez, Fernando;Gewirtz, David A.;Gupton, John T.;Schwartz, Edward L.
JG-03-14是一种具有微管解聚和抗增殖活性的新型四取代吡咯，在体外测试其对内皮细胞（EC）功能的影响。JG-03-14是细胞外基质上EC血管样管形成的有效抑制剂（IC 50为40 nM），并分别引起已建立血管的退化、潜在的抗血管生成和血管破坏活性。这些作用不是由于抑制EC增殖或诱导凋亡的JG-03-14。虽然在微管解聚和血管破坏药物combretastatin-A4（CoA 4）中观察到了类似的效果，但相对于其细胞毒性作用，JG-03-14对管形成的选择性作用比CoA 4更强。探讨了JG-03-14抗血管作用的分子机制。与也具有抗血管作用的紫杉烷相反，JG-03-14不破坏粘着斑形成或阻断VEGF诱导的粘着斑激酶磷酸化。然而，它确实抑制VEGF诱导的VE-钙粘蛋白磷酸化，并减少β-连环蛋白与VE-钙粘蛋白的结合。在低浓度下，它引起细胞收缩、细胞间间隙和异常伸长的粘附连接，在高浓度下引起显著但可逆的质膜起泡。这些结果表明，JG-03-14可能通过破坏相邻内皮细胞的相互作用来影响血管形态发生，这可能是对VE-钙粘蛋白、β-连环蛋白和/或肌动蛋白的影响的结果。他们还提供了这类化合物的抗血管活性的第一份报告。
JG-03-14, a novel tetrasubstituted pyrrole with microtubule-depolymerizing and anti-proliferative activities, was tested for its effect on endothelial cell (EC) functions in vitro. JG-03-14 was a potent inhibitor of EC vessel-like tube formation on extracellular matrix (IC50 of 40 nM) and caused the involution of established vessels, potential anti-angiogenic and vascular-disrupting activities, respectively. These actions were not due to the inhibition of EC proliferation or to the induction of apoptosis by JG-03-14. While similar effects were observed with the microtubule-depolymerizing and vascular-disrupting drug combretastatin-A4 (CoA4), JG-03-14 had a more selective effect on tube formation, relative to its cytotoxic actions, than did CoA4. Potential molecular mechanisms for JG-03-14’s anti-vascular actions were explored. In contrast to the taxanes, which also have anti-vascular actions, JG-03-14 did not disrupt focal adhesion formation or block VEGF-induced phosphorylation of focal adhesion kinase. It did, however, inhibit VEGF-induced phosphorylation of VE-cadherin and reduce the association of β-catenin with VE-cadherin. It caused cell retraction, intercellular gaps, and abnormally elongated adherens junctions at low concentrations, and prominent, but reversible, plasma membrane blebbing at higher concentrations. These results suggest that JG-03-14 may affect vascular morphogenesis by disrupting the interaction of adjacent endothelial cells, possibly as a consequence of effects on VE-cadherin, β-catenin, and/or actin. They also provide the first report of anti-vascular activity for this class of compounds.
登录
查看更多内容
DOI：
10.1083/jcb.200802081
发表时间：
2008-06-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fackler OT;Grosse R
通讯作者：
Grosse R
影响因子：
6.4
作者：
Grant, DS;Williams, TL;Dicker, AP
通讯作者：
Dicker, AP
影响因子：
3.4
作者：
Mooberry, Susan L.
通讯作者：
Mooberry, Susan L.
影响因子：
5.8
作者：
Arthur, Christopher R.;Gupton, John T.;Gewirtz, David A.
通讯作者：
Gewirtz, David A.
影响因子：
3.6
作者：
Lu, HY;Murtagh, J;Schwartz, EL
通讯作者：
Schwartz, EL