Human malignant glioma therapy using anti-alpha(v)beta3 integrin agents.
Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults and is invariably fatal. We have investigated the effect of cyclo-(Arg-Gly-Asp-D-Phe-Val) (cRGDfV) peptide on survival of human malignant glioma cells in vitro and in vivo. Immunofluorescent analyses revealed the presence of alpha(v)beta3 integrin on U-87MG and U-373MG cells, but minimal expression on U-251MG cells. Treatment of U-87MG and U-373MG cells in vitro with cRGDfV (20 microg/ml), but not the linear peptide, resulted in the appearance of rounded and loosely attached cells with subsequent cell death. By comparison, neither this cyclic peptide nor its linear homolog had any significant effect on growth and morphology of U-251MG cells. The death of cRGDfV-treated (20 microg/ml) glioma cells was blocked by pretreatment (10 microM) of cells with DEVD-FMK and LEHD-FMK, inhibitors of caspase-3 and caspase-9, respectively. Moreover, when glioma cells grown as spheroids were treated with cRGDfV (50 microg/ml), spheroid formation was markedly reduced. Further, treatment of intracranial U-87MG tumors in scid mice with cyclic peptide significantly (p < 0.001) prolonged their survival. These results indicated (i) that cRGDfV induced apoptosis of human glioma cells by binding alpha(v)beta3 integrin expressed on their cell surfaces and (ii) that cRGDfV may be an effective and non-toxic direct anti-tumor therapy for alpha(v)beta3-expressing GBMs.
Chatterjee
S
S
JCR Biopharmaceuticals, Inc., San Diego, CA 92121, USA. schat@jcrbio.com
Matsumura
A
A
Schradermeier
J
J
Gillespie
G Y
GY
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3; D053453:Caspase 9; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D015552:Injections, Intralesional; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects; D014407:Tumor Cells, Cultured
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; C092113:cyclo(arginyl-glycyl-aspartyl-phenylalanyl-valyl); C047981:arginyl-glycyl-aspartic acid; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9