Synergistic Antiangiogenic Effects of Stathmin Inhibition and Taxol Exposure

Abstract

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. (Mol Cancer Res 2007;5(8):773 -82)

p27Kip1 expression inhibits glioblastoma growth, invasion, and tumor-induced neoangiogenesis

“…Thus, it is not surprising that interfering with stathmin activity can result in the alteration of several aspects of the cell physiology. Accordingly, Atweh et al recently confirmed a prominent role for stathmin in the control of HUVEC motility (43), thus independently confirming our finding.…”

Stathmin expression in glioma-derived microvascular endothelial cells: A novel therapeutic target

“…A recent study by Mistry et al shows that application of anti-stathmin ribozyme to human umbilical vascular microvasular endothelial cells results in inhibition of angio genesis (25). In this study, we confirmed that the level of stathmin expression in GDMEC was significantly higher than NDMEC.…”

Identification of c-myc-dependent proteins in the medulloblastoma cell line D425Med

“…It diminishes the action of microtubule destabilising agents, such as vinca alkaloids and taxanes (Hait and Yang 2006) and its down-regulation reverses susceptibility to these drugs as shown in breast cancer cells (Alli et al 2007a). Its inhibition was reported to contribute synergistically to taxol-induced antiproliferative and migratory effects of endothelial cells, suggesting a possible therapeutic anti-angiogenic potential of anti-stathmin agents (Mistry et al 2007).…”