Tetraarsenic oxide, a novel orally administrable angiogenesis inhibitor.
Arsenic compounds have been used to treat angiogenic diseases such as cancer, psoriasis, and rheumatoid arthritis in traditional oriental medicine. In recent years, arsenic trioxide (As2O3, diarsenic oxide) has been successfully used to treat acute promyelocytic leukemia. We investigated the antiangiogenic properties of tetraarsenic oxide (As4O6), another trivalent arsenic compound. In in vitro studies, tetraarsenic oxide inhibited the proliferation (IC50 = 99.7 nM), migration into the denuded area (IC50 = 27.4 nM), and invasion through a layer of Matrigel (IC50 = 73.5 nM) of basic fibroblast growth factor (bFGF)-stimulated bovine capillary endothelial (BCE) cells in a dose-dependent manner. Tetraarsenic oxide also inhibited the tube formation of human umbilical vein endothelial cells. Tetraarsenic oxide induced cell cycle arrest of bFGF-stimulated BCE cells in the G2/M phase and inhibited the secretion of matrix metalloproteinase-2 from BCE cells. Orally administered tetraarsenic oxide (50 mg/kg/day) inhibited bFGF-induced new-vessel formation in a rat corneal micropocket assay, and reduced by about 54% the number of experimental pulmonary metastatic nodules in mice implanted with B16F10 melanoma cells. Thus, we provide evidence that tetraarsenic oxide has effective antiangiogenic activities.
Laboratory of Cell Biology, Korea Cancer Center Hospital, Seoul 139-706, Korea.
Myung Jin
MJ
Park
In Chul
IC
Park
Ill Ju
IJ
Bae
Kang Moon
KM
Seo
Seung Hoon
SH
Lee
Seok Il
SI
Hong
Choong Ki
CK
Eun
Wei
W
Zhang
Chang Hun
CH
Rhee
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001149:Arsenates / Q000008:administration & dosage / Q000494:pharmacology*; D002196:Capillaries; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D001149:Arsenates; C009277:sodium arsenate