Synergistic Antiangiogenic effects of stathmin inhibition and taxol exposure
Synergistic Antiangiogenic effects of stathmin inhibition and taxol exposure
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DOI：
10.1158/1541-7786.mcr-06-0290
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发表时间：
2007-08-01
影响因子：
5.2
通讯作者：
Atweh, George F.
中科院分区：
文献类型：
--
作者：
Mistry, Sucharita J.;Bank, Alexander;Atweh, George F.
Stathmin是真核细胞中微管骨架和纺锤体的关键调节因子之一。它在多种人类癌症中以高水平表达，并可能为癌症治疗提供有吸引力的靶点。我们先前已经表明，stathmin抑制导致恶性表型的废除。微管干扰药物紫杉醇具有抗肿瘤和抗血管生成的特性。我们还发现，紫杉醇和stathmin抑制剂的抗肿瘤活性是协同的。我们假设紫杉醇和stathmin抑制也可能具有协同抗血管生成活性。共表达绿色荧光蛋白和抗stathmin核酶的复制缺陷型双顺反子腺病毒载体用于靶向stathmin mRNA。内皮细胞单独暴露于抗stathmin腺病毒导致增殖、迁移和分化为毛细血管样结构的剂量依赖性抑制。这种抑制作用显着增强的转导内皮细胞暴露于非常低浓度的紫杉醇，这导致几乎完全丧失的增殖，迁移和分化的内皮细胞。与此相反，暴露于非转导的内皮细胞紫杉醇单独导致适度抑制增殖，迁移和分化。我们的详细分析表明，stathmin抑制和紫杉醇暴露的组合的抗血管生成作用是协同的。我们的研究还表明，这种协同作用的机制可能是通过稳定微管介导的。因此，这种新的组合可以提供一种有吸引力的治疗策略，其将协同抗肿瘤活性与协同抗血管生成活性相结合。
Stathmin is one of the key regulators of the microtubule cytoskeleton and the mitotic spindle in eukaryotic cells. It is expressed at high levels in a wide variety of human cancers and may provide an attractive target for cancer therapy. We had previously shown that stathmin inhibition results in the abrogation of the malignant phenotype. The microtubule-interfering drug, taxol, has both antitumorigenic and antiangiogenic properties. We had also shown that the antitumor activities of taxol and stathmin inhibition are synergistic. We hypothesized that taxol and stathmin inhibition may also have synergistic antiangiogenic activities. A replicationdeficient bicistronic adenoviral vector that coexpresses green fluorescent protein and an anti-stathmin ribozyme was used to target stathmin mRNA. Exposure of endothelial cells to anti-stathmin adenovirus alone resulted in a dose-dependent inhibition of proliferation, migration, and differentiation into capillary-like structures. This inhibition was markedly enhanced by exposure of transduced endothelial cells to very low concentrations of taxol, which resulted in a virtually complete loss of proliferation, migration, and differentiation of endothelial cells. In contrast, exposure of nontransduced endothelial cells to taxol alone resulted in a modest inhibition of proliferation, migration, and differentiation. Our detailed analysis showed that the antiangiogenic effects of the combination of stathmin inhibition and taxol exposure are synergistic. Our studies also showed that the mechanism of this synergistic interaction is likely to be mediated through the stabilization of microtubules. Thus, this novel combination may provide an attractive therapeutic strategy that combines a synergistic antitumor activity with a synergistic antiangiogenic activity.