Abstract 930: p38 MAPK is required for the antitumor activity of the vascular disrupting agent DMXAA

Abstract

Abstract 5, 6-Dimethylxanthenone-4-acetic acid (DMXAA), a potent vascular disrupting agent, selectively destroys established tumor vasculature, causing a rapid collapse in blood flow that ultimately leads to inhibition of tumor growth. In this study, we explored the role of p38 MAPK in the antitumor activity of DMXAA. It was found that p38 MAPK was critically involved in DMXAA-induced cytoskeleton reorganization in endothelial cells and TNF-α production in macrophages, both of which were essential for DMXAA-induced vascular disruption. Inhibition of p38 MAPK significantly attenuated DMXAA-induced actin cytoskeleton reorganization in human umbilical vein endothelial cells and TNF-α production in macrophages. In vivo, p38 MAPK inhibition attenuated the immediate reduction in tumor blood flow induced by DMXAA treatment (<30 min) by inhibiting actin cytoskeleton reorganization in tumor vascular endothelial cells, and blunted the long-lasting (>4 h) DMXAA-induced shutdown of the tumor vasculature by inhibiting intratumoral TNF-α production. Our results indicate that p38 MAPK is required for DMXAA-induced endothelial cell cytoskeleton reorganization and TNF-α production, and thus regulates DMXAA-induced antitumor activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 930. doi:1538-7445.AM2012-930