alpha v-Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin.
Orthotopic brain tumor growth is inhibited in athymic mice by the daily systemic administration of the alpha v-integrin antagonist EMD 121974. This compound, a cyclic RGD-penta-peptide, is a potent inhibitor of angiogenesis, which induces apoptosis of growing endothelial cells through inhibition of their alpha v-integrin interaction with the matrix proteins vitronectin and tenascin. Here we show that EMD 121974 also induces apoptosis in the alpha v-integrin-expressing tumor cell lines U87 MG and DAOY by detaching them from vitronectin and tenascin, matrix proteins known to be essential for brain tumor growth and invasion. These matrix proteins are shown to be produced by the brain tumor cells in vitro and in vivo. Furthermore, only tumor cells expressing alpha v-integrins responded to the treatment with EMD 121974, after xenotransplantation into the forebrain of nude mice, supporting the importance of tumor cell-matrix interactions in tumor cell survival in the brain. Thus, the alpha v-antagonist EMD 121974 suppresses brain tumor growth through induction of apoptosis in both brain capillary and brain tumor cells by preventing their interaction with the matrix proteins vitronectin and tenascin. The dual action of this peptide explains its potent growth suppression of orthotopically transplanted brain tumors.
Taga
Takashi
T
Division of Hematology-Oncology, Department of Pediatrics, Childrens Center for Cancer and Blood Diseases, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.
Suzuki
Atsushi
A
Gonzalez-Gomez
Ignacio
I
Gilles
Floyd H
FH
Stins
Monique
M
Shimada
Hiroyuki
H
Barsky
Lora
L
Weinberg
Kenneth I
KI
Laug
Walter E
WE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D010456:Peptides, Cyclic / Q000494:pharmacology*; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012910:Snake Venoms; D019063:Tenascin / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019096:Vitronectin / Q000378:metabolism
D016023:Integrins; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; D012910:Snake Venoms; D019063:Tenascin; D019096:Vitronectin; C064660:integrin alphaVbeta5; C422910:Cilengitide; D003094:Collagen