CHM-1, a new vascular targeting agent, induces apoptosis of human umbilical vein endothelial cells via p53-mediated death receptor 5 up-regulation.
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. We were 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.
Tsai
An-Chi
AC
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Pan
Shiow-Lin
SL
Sun
Hui-Lung
HL
Wang
Chih-Ya
CY
Peng
Chieh-Yu
CY
Wang
Shih-Wei
SW
Chang
Ya-Ling
YL
Kuo
Sheng-Chu
SC
Lee
Kuo-Hsiung
KH
Teng
Che-Ming
CM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism
C525063:2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone; D000970:Antineoplastic Agents; D004149:Dioxoles; C491901:FAS protein, human; D015363:Quinolones; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases