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.