Mistry Sucharita J, Bank Alexander, Atweh George F
Division of Hematology-Oncology, Department of Medicine, Box 1079, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Mol Cancer Res. 2007 Aug;5(8):773-82. doi: 10.1158/1541-7786.MCR-06-0290. Epub 2007 Aug 1.
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 replication-deficient 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.
Stathmin是真核细胞中微管细胞骨架和有丝分裂纺锤体的关键调节因子之一。它在多种人类癌症中高表达，可能成为癌症治疗的一个有吸引力的靶点。我们之前已经表明，抑制Stathmin会导致恶性表型的消除。微管干扰药物紫杉醇具有抗肿瘤和抗血管生成特性。我们还表明，紫杉醇和抑制Stathmin的抗肿瘤活性具有协同作用。我们推测，紫杉醇和抑制Stathmin可能也具有协同抗血管生成活性。一种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被用于靶向Stathmin mRNA。单独将内皮细胞暴露于抗Stathmin腺病毒会导致增殖、迁移以及分化为毛细血管样结构的剂量依赖性抑制。将转导后的内皮细胞暴露于极低浓度的紫杉醇会显著增强这种抑制作用，这导致内皮细胞的增殖、迁移和分化几乎完全丧失。相比之下，仅将未转导的内皮细胞暴露于紫杉醇会导致增殖、迁移和分化受到适度抑制。我们的详细分析表明，抑制Stathmin和暴露于紫杉醇的联合抗血管生成作用具有协同性。我们的研究还表明，这种协同相互作用的机制可能是通过微管的稳定来介导的。因此，这种新的联合疗法可能提供一种有吸引力的治疗策略，它将协同抗肿瘤活性与协同抗血管生成活性结合在一起。
