A derivative of aminopeptidase inhibitor (BE15) has a dual inhibitory effect of invasion and motility on tumor and endothelial cells.
Bestatin is an inhibitor of aminopeptidase N (APN)/CD13 and aminopeptidase B. In our previous report, bestatin inhibited the tumor cell invasion and the angiogenesis induced by the inoculation of B16-BL6 melanoma cells into mice and capillary formation on human umbilical vein endothelial cells (HUVECs) in vitro. The results show that the enzymatic activity of APN is deeply involved in tumor invasion and angiogenesis. We investigated the effect of three bestatin derivatives on A375 human melanoma cells and in vitro. All the derivatives inhibited the activity of APN, but BE15 was most effective and controlled the migration of A375 cells and HUVECs and capillary formation of HUVECs. Furthermore, the bestatin derivatives had an inhibitory effect not only on aminopeptidase activity but also on cell motility. Compared with bestatin and the other derivatives, BE15 had a marked inhibitory effect on the formation of capillary structure by HUVECs in vitro. These results suggest that new anti-metastatic and anti-angiogenic agents, which have a dual inhibitory effect on the degradation of the extra cellular matrix and cell motility, may be developed from bestatin.
Saitoh
Yurika
Y
Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Sugitani, Japan.
Koizumi
Keiichi
K
Minami
Takayuki
T
Sekine
Keiko
K
Sakurai
Hiroaki
H
Saiki
Ikuo
I
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002196:Capillaries / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D005109:Extracellular Matrix / Q000187:drug effects; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; C510396:BE15 compound; D011480:Protease Inhibitors; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex