title: Cilengitide modulates attachment and viability of human glioma cells, but not sensitivity to irradiation or temozolomide in vitro.
abstract: Cilengitide is a cyclic peptide antagonist of integrins alphavbeta3 and alphavbeta5 that is currently being evaluated as a novel therapeutic agent for recurrent and newly diagnosed glioblastoma. Its mode of action is thought to be mainly antiangiogenic but may include direct effects on tumor cells, notably on attachment, migration, invasion, and viability. In this study we found that, at clinically relevant concentrations, cilengitide (1-100 microM) induces detachment in some but not all glioma cell lines, while the effect on cell viability is modest. Detachment induced by cilengitide could not be predicted by the level of expression of the cilengitide target molecules, alphavbeta3 and alphavbeta5, at the cell surface. Glioma cell death induced by cilengitide was associated with the generation of caspase activity, but caspase activity was not required for cell death since ectopic expression of cytokine response modifier (crm)-A or coexposure to the broad-spectrum caspase inhibitor zVAD-fmk was not protective. Moreover, forced expression of the antiapoptotic protein marker Bcl-X(L) or altering the p53 status did not modulate cilengitide-induced cell death. No consistent effects of cilengitide on glioma cell migration or invasiveness were observed in vitro. Preliminary clinical results indicate a preferential benefit from cilengitide added to temozolomide-based radiochemotherapy in patients with O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation. Accordingly, we also examined whether the MGMT status determines glioma cell responses to cilengitide alone or in combination with temozolomide. Neither ectopic expression of MGMT in MGMT-negative cells nor silencing the MGMT gene in MGMT-positive cells altered glioma cell responses to cilengitide alone or to cilengitide in combination with temozolomide. These data suggest that the beneficial clinical effects derived from cilengitide in vivo may arise from altered perfusion, which promotes temozolomide delivery to glioma cells.
authors.affiliation: Department of Neurology, University Hospital of Tübingen, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
authors.forename: Gabriele D
authors.initials: GD
authors.lastname: Maurer
authors.forename: Isabel
authors.initials: I
authors.lastname: Tritschler
authors.forename: Barbara
authors.initials: B
authors.lastname: Adams
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Tabatabai
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019175:DNA Methylation; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004359:Drug Therapy, Combination; D020868:Gene Silencing; D005910:Glioma / Q000473:pathology*; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors; D012910:Snake Venoms / Q000494:pharmacology*; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D039302:Integrin alphaVbeta3; D019030:Receptors, Vitronectin; D012910:Snake Venoms; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; C064660:integrin alphaVbeta5; C422910:Cilengitide; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide