The Inhibitory Effect of Docetaxel and p38 MAPK Inhibitor on TZT-1027 (Soblidotin)-induced Antivascular Activity

Abstract

Background: TZT-1027 (Soblidotin), a microtubule (MT)-depolymerizing agent, has antivascular activity through the disruption of microtubules in vascular endothelial cells. Our aim was to elucidate the mechanism of TZT-1027-induced antivascular activity by investigating the impact of various inhibitors. Materials and Methods: The inhibitory effects on TZT-1027-induced antivascular activity were evaluated by a tumor perfusion study in mice bearing Colon26 tumors and a vascular permeability study on human umbilical vein endothelial cells monolayer. Western blotting analyses were performed to verify the mechanism of antivascular activity. Results: Pretreatment with docetaxel and SB220025, a p38 mitogen-activated protein kinase (MAPK) inhibitor, significantly suppressed the TZT-1027-induced reduction of tumor perfusion and increase in vascular permeability. Gross findings showed that SB220025 visibly attenuated the TZT-1027-induced widespread hemorrhage in tumors. Western blotting analyses revealed that TZT-1027 induced the phosphorylation of p38 MAPK only slightly compared to hydrogen peroxide, and that docetaxel and SB220025 increased the acetylation of α-tubulin an effect opposite to that of TZT-1027. Conclusion: TZT-1027-induced antivascular activity was abolished by docetaxel through the stabilization of microtubules, and by p38 MAPK inhibitor not only through the regulation of the p38 MAPK pathway, but also through the direct stabilization of microtubules, similar to docetaxel.