Anti-tumor angiogenesis effect of aminopeptidase inhibitor bestatin against B16-BL6 melanoma cells orthotopically implanted into syngeneic mice.
We investigated the effect of bestatin, an inhibitor of aminopeptidase N (APN)/CD13 and aminopeptidase B, on the angiogenesis induced by B16-BL6 melanoma cells. Oral administration of bestatin (100-200 mg/kg/day) was found to significantly inhibit the melanoma cell-induced angiogenesis in a mouse dorsal air sac assay. Additionally, anti-APN/CD13 mAb (WM15), which neutralizes the aminopeptidase activity in tumor cells, as well as bestatin inhibited the tube-like formation of human umbilical vein endothelial cells (HUVECs) in vitro. Furthermore, the intraperitoneal administration of bestatin (50-100 mg/kg/day) after the orthotopic implantation of B16-BL6 melanoma cells into mice reduced the number of vessels oriented towards the established primary tumor mass on the dorsal side of mice. These findings suggest that bestatin is an active anti-angiogenic agent that may inhibit tumor angiogenesis in vivo and tube-like formation of endothelial cells in vitro through its inhibition of APN/CD13 activity.
Aozuka
Yasushi
Y
Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Koizumi
Keiichi
K
Saitoh
Yurika
Y
Ueda
Yasuji
Y
Sakurai
Hiroaki
H
Saiki
Ikuo
I
D000818:Animals; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008545:Melanoma / Q000098:blood supply* / Q000473:pathology* / Q000662:veterinary; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D011480:Protease Inhibitors / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000098:blood supply* / Q000473:pathology* / Q000662:veterinary; D014183:Transplantation, Heterologous; D014471:Umbilical Veins / Q000166:cytology
D011480:Protease Inhibitors; D007930:Leucine; C012211:ubenimex