The inhibitory effect of docetaxel and p38 MAPK inhibitor on TZT-1027 (Soblidotin)-induced antivascular activity.
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.


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 alpha-tubulin an effect opposite to that of TZT-1027.


CONCLUSIONS
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.
Watanabe
Junichi
J
ASKA Pharmaceutical Co. Ltd., Research and Development Division, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan. watanabe-j@aska-pharma.co.jp
Natsume
Tsugitaka
T
Kobayashi
Motohiro
M
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy; D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy; D000077143:Docetaxel; D004347:Drug Interactions; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007093:Imidazoles; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C110631:SB 220025; D043823:Taxoids; D000077143:Docetaxel; C105791:soblidotin; D048051:p38 Mitogen-Activated Protein Kinases