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. 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.
Footnotes
This work was supported by the National Natural Science Foundation of China [Grant 90813009].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- VDA
- vascular disrupting agent
- ZD6126
- N-acetylcochinol-O-phosphate
- DMXAA
- 5,6-dimethylxantheonone-4-acetic acid
- TNF
- tumor necrosis factor
- MAPK
- mitogen-activated protein kinase
- ERK
- extracellular signal-regulated kinase
- JNK
- c-Jun N-terminal kinase
- MAPKAPK
- mitogen-activated protein kinase-activated protein kinase
- IL
- interleukin
- HUVEC
- human umbilical vein endothelial cell
- PD0325901
- N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide
- SB202190
- 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole
- SP600125
- 1,9-pyrazoloanthrone
- MLC
- myosin light chain
- PBS
- phosphate-buffered saline
- ELISA
- enzyme-linked immunosorbent assay
- PAGE
- polyacrylamide gel electrophoresis
- siRNA
- small interfering RNA.
- Received January 6, 2012.
- Accepted March 12, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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