The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions
The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions
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DOI：
10.1016/j.mvr.2008.08.003
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发表时间：
2009-03-01
影响因子：
3.1
通讯作者：
Bartlett, J. Blake
中科院分区：
文献类型：
--
作者：
Lu, Ling;Payvandi, Faribourz;Bartlett, J. Blake
来那度胺（Revlimid（R））被批准用于治疗因低风险或中等风险骨髓增生异常综合征（MDS）伴del 5 q细胞遗传学异常（伴或不伴其他细胞遗传学异常）导致的贫血的输血依赖性患者，并与地塞米松联合治疗至少接受过一种既往治疗的多发性骨髓瘤患者。先前的报告表明，来那度胺是抗血管生成的，这一特性似乎与MDS患者的疗效有关。我们研究了来那度胺对微血管形成的影响，在一种新的体外血管生成试验中，利用人脐动脉环和毛细血管样索形成试验中，使用培养的原代内皮细胞。我们发现来那度胺以剂量依赖性方式持续抑制动脉环的芽形成和内皮细胞的索形成。我们还发现来那度胺对钙粘蛋白5、β-连环蛋白和CD 31之间的关联具有抑制作用，这些粘附连接蛋白的相互作用对于内皮细胞索形成至关重要。此外，来那度胺抑制VEGF诱导的P13 K-Akt通路信号传导，已知其调节粘附连接形成。我们还发现来那度胺对缺氧诱导的内皮细胞索形成和HIF-1 α表达具有强烈的抑制作用，后者是缺氧介导效应的主要介质，也是血管生成和转移的关键驱动因素。在B16-F10小鼠黑色素瘤模型中，来那度胺的体内抗转移活性通过与未治疗小鼠相比黑色素瘤肺集落计数减少>40%得到证实。我们的研究结果表明，对微血管形成的抑制作用，特别是粘附连接形成和抑制缺氧诱导的过程支持这种临床活性药物的潜在抗血管生成和抗转移机制。(c)2008年爱思唯尔公司All rights reserved.
Lenalidomide (Revlimid (R)) is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk Myelodysplastic Syndromes (MDS) associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy. Previous reports suggest that lenalidomide is anti-angiogenic and this property appears to be related to efficacy in patients with MDS. We have investigated the effect of lenalidomide on the formation of microvessels in a novel in vitro angiogenesis assay utilizing human umbilical arterial rings and in a capillary-like cord formation assay using cultured primary endothelial cells. We found that lenalidomide consistently inhibits both sprout formation by arterial rings and cord formation by endothelial cells in a dose-dependent manner. We also found an inhibitory effect of lenalidomide on the associations between cadherin 5, beta-catenin and CD31, adherens junction proteins whose interaction is critical for endothelial cell cord formation. Furthermore, lenalidomide inhibited VEGF-induced P13K-Akt pathway signaling, which is known to regulate adherens junction formation. We also found a strong inhibitory effect of lenalidomide on hypoxia-induced endothelial cell formation of cords and HIF-1 alpha expression, the main mediator of hypoxia-mediated effects and a key driver of angiogenesis and metastasis. Anti-metastatic activity of lenalidomide in vivo was confirmed in the B16-F10 mouse melanoma model by a >40% reduction in melanoma lung colony counts versus untreated mice. Our results suggest that inhibitory effects on microvessel formation, in particular adherens junction formation and inhibition of hypoxia-induced processes support a potential antiangiogenic and anti-metastatic mechanism for this clinically active drug. (c) 2008 Elsevier Inc. All rights reserved.