Antiproliferative and antiangiogenic effects of 3-methylcholanthrene, an aryl-hydrocarbon receptor agonist, in human umbilical vascular endothelial cells.
There is increasing interest in the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and polycyclic aromatic hydrocarbons on cardiovascular diseases. Their chemical structures are similar, although polycyclic aromatic hydrocarbons contain no chlorine as does TCDD. The biochemical mechanism of their action is mainly mediated by the aryl hydrocarbon receptor. In addition, oxidative stress also plays a role in the biological and toxic effects of these chemicals. In this study, we used an aryl hydrocarbon receptor agonist, 3-methylcholanthrene (3-MC), to investigate its effect on the proliferation and angiogenesis of human umbilical vascular endothelial cells. 3-MC suppressed DNA synthesis of human umbilical vascular endothelial cells as determined by [(3)H]thymidine incorporation in a concentration-dependent fashion and arrested cells at the G0/G1 phase of the cell cycle. Interestingly, the inhibition of DNA synthesis by 3-MC was eliminated to a greater extent by aryl hydrocarbon receptor antagonists, alpha-NF (0.5 and 1 microM) and resveratrol (5 and 10 microM), than by the antioxidant, N-acetylcysteine (5 and 10 mM). Cell permeability, adhesion, and tube formation in human umbilical vascular endothelial cells exposed to 3-MC decreased in concentration-dependent manners. We also demonstrated that cell adhesion signaling (phosphorylated focal adhesion kinase (FAK)) decreased upon 3-MC treatment, suggesting that cell adhesion inhibited by 3-MC might be due to inhibition of cell adhesion signaling. Additionally, alpha-naphthoflavon (alpha-NF) ameliorated the effects of 3-MC on cell permeability, adhesion and tube formation, indicating the involvement of the aryl hydrocarbon receptor in angiogenesis. The results suggest that the adverse effects of 3-MC are mainly mediated by the aryl hydrocarbon receptor and not via increased oxidative stress.
Juan
Shu-Hui
SH
Graduate Institute of Medical Sciences, Taipei Medical University, Taiwan. juansh@tmu.edu.tw
Lee
Ja-Ling
JL
Ho
Pei-Yin
PY
Lee
Yi-Hsuan
YH
Lee
Wen-Sen
WS
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008748:Methylcholanthrene / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D000077185:Resveratrol; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D006131:Growth Inhibitors; D018336:Receptors, Aryl Hydrocarbon; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D014316:Tritium; D012710:Serum Albumin, Bovine; D008748:Methylcholanthrene; D019363:Cytochrome P-450 CYP1A1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D000077185:Resveratrol; D013936:Thymidine