The microtubule binding drug laulimalide inhibits vascular endothelial growth factor-induced human endothelial cell migration and is synergistic when combined with docetaxel taxotere)
The microtubule binding drug laulimalide inhibits vascular endothelial growth factor-induced human endothelial cell migration and is synergistic when combined with docetaxel taxotere)
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DOI：
10.1124/mol.105.019075
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发表时间：
2006-04-01
影响因子：
3.6
通讯作者：
Schwartz, EL
中科院分区：
文献类型：
--
作者：
Lu, HY;Murtagh, J;Schwartz, EL
劳利马利德是一种来自海洋海绵的天然产物，是一种微管稳定剂，它与微管蛋白结合的位置与紫杉醇的位置不同。在本研究中，我们发现劳利马利抑制人脐静脉内皮细胞(HUVEC)小管的形成和血管内皮生长因子(VEGF)诱导的HUVEC迁移，这是血管生成过程的关键组成部分。它们发生的浓度比抑制HUVEC增殖的浓度低得多。当劳利马利特和多西紫杉醇(紫杉醇)合用时，它们协同抑制细胞的迁移和小管形成，但它们对细胞增殖的联合作用是拮抗的。探讨了劳利马利抑制血管内皮生长因子诱导的内皮细胞迁移的可能机制(S)。与多西紫杉醇相似，劳利马利对血管内皮细胞生长因子受体Flk-1/KDR(VEGFR-2)酪氨酸磷酸化无影响。低浓度的劳利马利基本上阻止了随后的VEGFR-2下游事件，多西紫杉醇也是如此，包括粘着斑激酶(FAK)的Tyr(397)和Tyr(407)残基的磷酸化，VEGFR-2与FAK和Hsp90的关联，以及Paxlin的Tyr(31)磷酸化。洛利马利特抑制整合素的激活，但与多西紫杉醇相比，它对VEGF诱导的VEGFR-2与α(5)β(1)整合素结合的抑制作用较弱。与多西紫杉醇相比，劳利马利德更有效地降低了磷酸化的帕西林的组成水平(即在没有血管内皮生长因子的情况下)，并更有效地抑制了RhoA与α(5)β(1)整合素的联系。综上所述，尽管多西紫杉醇和劳利马利都抑制了介导血管内皮生长因子诱导的细胞迁移的整合素相关信号通路，但它们在信号级联反应中的作用似乎并不相同。这些互补作用可能解释了它们对HUVEC的协同作用。
Laulimalide, a natural product from marine sponges, is a microtubule-stabilizing agent that binds to tubulin at a site distinct from that of the taxoids. In the present study, we found that laulimalide inhibited human umbilical vein endothelial cell (HUVEC) tubule formation and vascular endothelial growth factor (VEGF)-induced HUVEC migration, key components of the angiogenic process. These occurred at concentrations substantially lower than that which inhibited HUVEC proliferation. When combined, laulimalide and docetaxel (Taxotere) synergistically inhibited migration and tubule formation, but their combined effect on proliferation was antagonistic. Possible mechanism(s) by which laulimalide inhibited VEGF-induced HUVEC migration were explored. Similar to docetaxel, laulimalide had no effect on the VEGF-induced tyrosine phosphorylation of the VEGF receptor Flk-1/KDR (VEGFR-2). Low concentrations of laulimalide substantially blocked subsequent VEGFR-2 downstream events, as did docetaxel, including the phosphorylation of the Tyr(397) and Tyr(407) residues of focal adhesion kinase (FAK), the association of VEGFR-2 with FAK and Hsp90, and the Tyr(31) phosphorylation of paxillin. Laulimalide inhibited integrin activation; however, compared with docetaxel, it had a weaker inhibitory effect on the VEGF-induced association of VEGFR-2 with the alpha(5)beta(1) integrin. Compared with docetaxel, laulimalide more potently caused a reduction in the constitutive levels (i.e., in the absence of VEGF) of phosphorylated paxillin and more potently inhibited the association of RhoA with the alpha(5)beta(1) integrin. In conclusion, although both docetaxel and laulimalide inhibited integrin-associated signaling pathways that mediated VEGF-induced cell migration, their actions on the signaling cascade seemed not to be identical. These complementary actions could account for their synergistic effects on HUVEC.