CHM-1, a new vascular targeting agent, induces apoptosis of human umbilical vein endothelial cells via p53-mediated death receptor 5 up-regulation
Journal
Journal of Biological Chemistry
Journal Volume
285
Journal Issue
8
Pages
5497-5506
Date Issued
2010
Author(s)
CHIH-YUAN WANG
CHE-MING TENG
Abstract
CHM-1 (2′-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone) has been identified as a potent antitumor agent in human hepatocellular carcinoma; however, its role in tumor angiogenesis is unclear. This study investigated the effects of CHM-1 and the mechanisms by which it exerts its antiangiogenic and vascular disrupting properties. Using a xenograft model antitumor assay, we found that CHM-1 significantly inhibits tumor growth and microvessel formation. Flow cytometry, immunofluorescence microscopy, and cell death enzyme-linked immunosorbent assay kit revealed that CHM-1 inhibits growth of human umbilical vein endothelial cells (HUVEC) by induction of apoptotic cell death in a concentration-dependent manner. CHM-1 also suppresses HUVEC migration and capillary-like tube formation. Wewere able to correlate CHM-1-induced apoptosis in HUVEC with the cleavage of procaspase-3, -7, and -8, as well as with the cleavage of poly(ADP-ribose) polymerase by Western blotting assay. Such sensitization was achieved through up-regulation of death receptor 5 (DR5) but not DR4 or Fas. CHM-1 was also capable of increasing the expression level of p53, and most importantly, the induction of DR5 by CHM-1 was abolished by p53 small interfering RNA. Taken together, the results of this study indicate that CHM-1 exhibits vascular targeting activity associated with the induction of DR5-mediated endothelial cell apoptosis through p53 up-regulation, which suggests its potential as an antivascular and antitumor therapeutic agent. ? 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
SDGs
Other Subjects
Anti-tumor agents; Anti-tumors; Antiangiogenic; Antivascular; Apoptosis; Apoptotic cell death; Concentration-dependent; Death-receptor; Enzyme linked immunosorbent assay; Expression levels; Hepatocellular carcinoma; Human umbilical vein endothelial cells; Immunofluorescence microscopy; Induced apoptosis; Poly polymerase; Procaspase; Quinolones; Small interfering RNA; Therapeutic agents; Tube formation; Tumor angiogenesis; Tumor growth; Up-regulation; Vascular targeting agent; Western blotting; Blood vessel prostheses; Cell death; Drug products; Flow cytometry; RNA; Self assembly; Tumors; Endothelial cells; 2' fluoro 6,7 methylenedioxy 2 phenyl 4 quinolone; angiogenesis inhibitor; caspase; death receptor 5; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; procaspase 3; procaspase 7; procaspase 8; protein p53; unclassified drug; 1,3 dioxolane derivative; 2' fluoro 6,7 methylenedioxy 2 phenyl 4 quinolone; 2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone; antineoplastic agent; caspase; Fas antigen; FAS protein, human; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein p53; quinolone derivative; TP53 protein, human; tumor necrosis factor related apoptosis inducing ligand receptor; animal experiment; animal model; animal tissue; antiangiogenic activity; apoptosis; article; cancer inhibition; colon cancer; concentration response; controlled study; endothelium cell; enzyme degradation; human; human cell; mouse; nonhuman; priority journal; tumor xenograft; umbilical vein; upregulation; animal; biosynthesis; cell motion; cytology; drug effect; drug screening; endothelium cell; male; metabolism; mouse mutant; tumor cell line; umbilical vein; Animals; Antigens, CD95; Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Movement; Dioxoles; Endothelial Cells; Humans; Male; Mice; Mice, SCID; Poly(ADP-ribose) Polymerases; Quinolones; Receptors, TNF-Related Apoptosis-Inducing Ligand; Tumor Suppressor Protein p53; Umbilical Veins; Up-Regulation; Xenograft Model Antitumor Assays
Type
journal article