Inhibition of human vascular endothelial cell migration and capillary-like tube formation by the microtubule-stabilizing agent peloruside A.

Abstract

Peloruside A is a microtubule-stabilizing agent that is currently under investigation as a potential anticancer agent. Peloruside A binds to a site on β-tubulin that is distinct to that of the taxanes (paclitaxel and docetaxel) and the epothilones. An attractive clinical quality of microtubule-stabilizing agents is their ability to target multiple mechanisms of tumour growth. In addition to inducing tumour cell apoptosis by arresting cells in mitosis, microtubule-stabilizing agents also inhibit angiogenesis, a process needed by tumor cells for growth and metastasis. In this study, the effects of peloruside A on endothelial cell processes important for angiogenesis were assessed in comparison to docetaxel. Both peloruside A and docetaxel potently inhibited the proliferation of human umbilical vein endothelial cells, with IC50 values of 1.4 and 1.7 nM, respectively. Peloruside also potently blocked endothelial cell migration during wound closure and the three-dimensional organization of the endothelial cells into capillary-like tubes. In the wound scratch assay, peloruside A inhibited wound recovery with an IC50 of 6.3 nM after 18 h. Docetaxel was approximately 3-fold more potent than peloruside A. The number of capillary-like tubes that formed after 16 h culture in Matrigel™ was also inhibited in a dose-dependent manner with an IC50 of 4.5 nM. Docetaxel was about 2-fold more potent than peloruside A in preventing tube formation. This inhibition of endothelial cell function occurred at relatively non-cytotoxic concentrations over the 16-18 h incubations for both stabilizing agents, suggesting that anti-angiogenic effects are likely to occur before therapeutically relevant doses begin to inhibit tumor growth or adverse side effects develop.