Anti-invasive effect of contortrostatin, a snake venom disintegrin, and TNF-alpha on malignant glioma cells.
BACKGROUND
The snake venom disintegrin contortrostatin has been shown to bind to integrins alpha IIb beta 3, alpha v beta 3, alpha v beta 5, and alpha 5 beta 1 and to exert an anti-tumor activity in vitro and in vivo. The cytokine TNF-alpha has been demonstrated to have anti-invasive properties in vitro.


METHODS
The human glioblastoma cell line T98G was treated with controtrostatin or colloidal gold-TNF-alpha (CG-TNF-alpha) alone, or in combination. Vitronectin- and fibronectin-dependent adhesion of untreated and treated glioma cells was studied and compared. Invasion through a reconstituted basement membrane (Matrigel) was also examined.


RESULTS
Although both contortrostatin and CG-TNF-alpha inhibited invasion of T98G cells through Matrigel, the mechanism of inhibition appears to be different. Contortrostatin significantly decreased cell adhesion to vitronectin and fibronectin; CG-TNF-alpha did not. Contortrostatin binds to T98G integrins in an RGD-dependent manner, whereas protein kinase C (PKC) appears to be involved in CG-TNF-alpha actions, leading to inhibition of cell invasion. The efficiency of contortrostatin in inhibiting cell invasion was enhanced by combination with CG-TNF-alpha.


CONCLUSIONS
The combined use of contortrostatin and CG-TNF-alpha may have potential for malignant glioma therapy by effectively inhibiting glioma cell invasion.
Schmitmeier
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S
Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, 1200 N. State St #5046, Los Angeles, CA 90033, USA.
Markland
F S
FS
Chen
T C
TC
D002273:Carcinogens / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D003094:Collagen; D019483:Disintegrins / Q000378:metabolism / Q000494:pharmacology*; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D005353:Fibronectins / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017979:Gold Colloid / Q000494:pharmacology; D006801:Humans; D007797:Laminin; D009361:Neoplasm Invasiveness; D011493:Protein Kinase C / Q000378:metabolism; D011509:Proteoglycans; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*; D019096:Vitronectin / Q000378:metabolism
D002273:Carcinogens; D019483:Disintegrins; D004338:Drug Combinations; D005353:Fibronectins; D017979:Gold Colloid; D007797:Laminin; D011509:Proteoglycans; D014409:Tumor Necrosis Factor-alpha; D019096:Vitronectin; C403494:contortrostatin; C059485:matrigel; D003094:Collagen; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate