The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor.
Increased neovasculature and resistance to chemotherapy are hallmarks of aggressive cancer; therefore, the development of approaches to simultaneously inhibit these two processes is highly desirable. Previous findings from our laboratory have demonstrated that cathepsin L plays a key role in the development of drug resistance in cancer, and that its inhibition reversed this phenomenon. The goal of the present study was to determine whether targeting cathepsin L would inhibit angiogenesis. For this, the effects of a specific cathepsin L inhibitor, Napsul-Ile-Trp-CHO (NSITC), were tested in vitro on endothelial cell proliferation and interaction with the extracellular matrix, and also in vivo, by measuring its effect on angiogenesis in the chick chorioallantoic membrane (CAM) and mouse matrigel models. The results indicated that NSITC readily inhibits the proliferation of endothelial cells by inducing cell cycle arrest at the G(0)/G(1) phase, and suppresses cell adhesion to different substrates. Investigation of the underlying mechanism(s) indicated that NSITC was able to reduce expression of the adhesion molecule alphaVbeta3 integrin, inhibit cathepsin L-mediated degradation of the extracellular matrix, and disrupt secretion of the pro-angiogenic factors fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). NSITC demonstrated potent efficacy in inhibiting growth factor- and tumor mediated-angiogenesis in the CAM and mouse matrigel models of angiogenesis. The anti-angiogenic effects of NSITC resulted in inhibition of tumor growth in the CAM and in nude mouse xenograft models. Together, these findings provide evidence that cathepsin L plays an important role in angiogenesis and suggest that NSITC represents a potential drug for the treatment of aggressive cancer.
Rebbaa
Abdelhadi
A
The Pharmaceutical Research Institute at Albany, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
Chu
Fei
F
Sudha
Thangirala
T
Gallati
Christine
C
Dier
Usawadee
U
Dyskin
Evgeny
E
Yalcin
Murat
M
Bianchini
Christine
C
Shaker
Olfat
O
Mousa
Shaker A
SA
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D056668:Cathepsin L / Q000037:antagonists & inhibitors*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D004151:Dipeptides / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D004151:Dipeptides; C546623:Napsul-Ile-Trp-CHO; D011480:Protease Inhibitors; C534281:CTSL protein, human; D056668:Cathepsin L