N-/C-terminal deleted mutant of human endostatin efficiently acts as an anti-angiogenic and anti-tumorigenic agent.
Non-collagenous (NC-1) fragments at the C-terminus of basement membrane collagen IV, XV and XIII have been implicated as negative regulators of angiogenesis. Endostatin is an endogenous carboxyl-terminal fragment of collagen XVIII/NC-1, suppressing endothelial cell proliferation, migration in vitro and tumor growth in mouse models. Endostatin can bind zinc through N- and C-terminal residues. Here we demonstrate that N-/C-terminal deleted derivative of human endostatin, H5, effectively inhibited the proliferation of human umbilical vein endothelial cells (HUVECs). Also, tube formation in vitro was comparably inhibited either by H5 or endostatin. The anti-angiogenic and anti-tumorigenic activities of H5 and endostatin were confirmed by an in vivo assay using chick chorioallantoic membrane (CAM) and mouse models, respectively. Treatment of 30 ng of H5 inhibited the capillary formation in CAM by 50%. In addition, H5 exhibited more potent anti-tumor activity than wild-type endostatin in in vivo mouse metastasis assay. These results indicate that the N-/C-terminal deletion mutant would be a strong candidate of anti-cancer agent against spontaneous tumor development and growth.
Cho
Heeyeong
H
Department of Molecular Biology, Pusan National University, Pusan 609-735, Korea.
Kim
Woo Jean
WJ
Lee
You Mie
YM
Kim
Young-Mi
YM
Kwon
Young-Guen
YG
Park
Yong Suk
YS
Choi
Eu-Yul
EY
Kim
Kyu-Won
KW
D000482:Allantois / Q000098:blood supply; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D043169:Endostatins / Q000235:genetics / Q000494:pharmacology*; D017353:Gene Deletion; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000517:prevention & control / Q000556:secondary
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D043169:Endostatins; D011994:Recombinant Proteins