Inhibition of in vitro angiogenesis by 2-methoxy- and 2-ethyl-estrogen sulfamates.
Sulfamoylation of 2-methoxyestrone (2-MeOE1) was shown previously to enhance its potency as an anti-proliferative agent against breast cancer cells. We have examined the ability of a series of 2-methoxyestradiol (2-MeOE2) and 2-ethylestradiol (2-EtE2) sulfamates to inhibit angiogenesis in vitro. 2-MeOE2 bis-sulfamate and 2-EtE2 sulfamate were potent inhibitors of human umbilical vein endothelial cell (HUVEC) proliferation with IC(50) values of 0.05 microM and 0.01 microM, respectively. A novel co-culture system, in which endothelial cells were cultured in a matrix of human dermal fibroblasts, was also used to assess the anti-angiogenic potential of these drugs. In this system endothelial cells proliferate and migrate through the culture matrix to form tubule structures. Whereas 2-MeOE2 (1.0 microM) caused a small reduction in tubule formation, both 2-MeOE2 bis-sulfamate (0.1 microM) and 2-EtE2 sulfamate (0.1 microM) almost completely abolished tubule formation. 2-MeOE2 bis-sulfamate and 2-EtE2 sulfamate both induced BCL-2 phosphorylation, p53 protein expression and apoptosis in HUVECs. Microarray analysis of a limited number of genes known to be involved in the angiogenic process did not show any gross changes in cells treated with the 2-substituted estrogens. The sulfamoylated derivatives of 2-MeOE2 and 2-EtE2 are potent inhibitors of in vitro angiogenesis and both compounds should have therapeutic potential.
Newman
Simon P
SP
Endocrinology and Metabolic Medicine and Sterix Ltd, Faculty of Medicine, Imperial College, St. Mary's Hospital, London, United Kingdom.
Leese
Mathew P
MP
Purohit
Atul
A
James
David R C
DR
Rennie
Catherine E
CE
Potter
Barry V L
BV
Reed
Michael J
MJ
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012867:Skin / Q000166:cytology; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C483692:2-ethylestradiol sulfamate; C483691:2-methoxyestradiol sulfamate; D020533:Angiogenesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013451:Sulfonic Acids; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; C005741:sulfamic acid