title: p38 mitogen-activated protein kinase is required for the antitumor activity of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid.
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.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai 201203, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.forename: Haitian
authors.initials: H
authors.lastname: Quan
authors.forename: Yongping
authors.initials: Y
authors.lastname: Xu
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Youhong
authors.initials: Y
authors.lastname: Hu
authors.forename: Liguang
authors.initials: L
authors.lastname: Lou
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology; D034622:RNA Interference; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C066668:vadimezan; D048051:p38 Mitogen-Activated Protein Kinases