αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

• Published in: International journal of cancer 2002-04, Vol.98 (5), p.690-697
• Main Authors: Taga, Takashi, Suzuki, Atsushi, Gonzalez‐Gomez, Ignacio, Gilles, Floyd H., Stins, Monique, Shimada, Hiroyuki, Barsky, Lora, Weinberg, Kenneth I., Laug, Walter E.
• Format: Article
• Language: English
• Subjects: Animals; anti‐angiogenesis; apoptosis; Apoptosis - drug effects; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; brain tumor; Cell Adhesion - drug effects; Cell Division - drug effects; Collagen - metabolism; Flow Cytometry; Fluorescent Antibody Technique; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Immunoenzyme Techniques; In Situ Nick-End Labeling; Integrins - antagonists & inhibitors; Integrins - metabolism; Medulloblastoma - metabolism; Medulloblastoma - pathology; Mice; Mice, Nude; Peptides, Cyclic - pharmacology; Receptors, Vitronectin - antagonists & inhibitors; Receptors, Vitronectin - metabolism; Snake Venoms; Tenascin - metabolism; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism; Tumor Cells, Cultured - pathology; Vitronectin - metabolism; xenograft; αv‐integrins
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.10265

Orthotopic brain tumor growth is inhibited in athymic mice by the daily systemic administration of the αv‐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 αv‐integrin interaction with the matrix proteins vitronectin and tenascin. Here we show that EMD 121974 also induces apoptosis in the αv‐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 αv‐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 αv‐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. © 2002 Wiley‐Liss, Inc.