Qiong Wu, Haitian Quan, Yongping Xu, Yun Li, Youhong Hu, Liguang Lou
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai 201203, China.
The Journal of pharmacology and experimental therapeutics 2012 Jun5,6-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. Here, we demonstrate that p38 MAPK is critically involved in DMXAA-induced cytoskeleton reorganization in endothelial cells and tumor necrosis factor-α (TNF-α) production in macrophages, both of which were essential for DMXAA-induced vascular disruption. Inhibition of p38 mitogen-activated protein kinase (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. These results indicate that p38 MAPK plays a critical role in DMXAA-induced endothelial cell cytoskeleton reorganization and TNF-α production, thus regulating DMXAA-induced antitumor activity.
Qiong Wu, Haitian Quan, Yongping Xu, Yun Li, Youhong Hu, Liguang Lou. p38 mitogen-activated protein kinase is required for the antitumor activity of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. The Journal of pharmacology and experimental therapeutics. 2012 Jun;341(3):709-17
PMID: 22414857
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