title: Cilengitide targets pediatric glioma and neuroblastoma cells through cell detachment and anoikis induction.
abstract: The prognosis of children with high-grade glioma or high-risk neuroblastoma remains poor. Cilengitide is a selective antagonist of αvβ3 and αvβ5 integrins, which are involved in tumor growth and development of metastasis. We have evaluated the effects of cilengitide on pediatric glioma and neuroblastoma cell lines for the first time. Expression levels of αvβ3 and αvβ5 were determined by flow cytometry in three neuroblastoma and five pediatric glioma cell lines compared with adult U87-MG before and after irradiation. Cell detachment, cytotoxicity, and cell growth under nonadhesive conditions were measured using the MTS assay. Cell death and apoptosis were assessed by annexin-V/propidium iodide staining. The varying αvβ3 and αvβ5 expression levels were unrelated to tumor grade. Irrespective of the αvβ5 expression level, the pediatric cells expressing αvβ3 were dose dependently sensitive to cilengitide. UW479 cells expressed only αvβ5 integrin and were not sensitive to cilengitide, suggesting that cilengitide's action largely depends on αvβ3 inhibition. Cell detachment resulted in a higher cytotoxicity in pediatric glioma compared with U87-MG cells, which seem able to grow despite the significant cilengitide-induced cell detachment. Growth kinetics on polyHEMA showed that only pediatric glioma cells were sensitive to anoikis and so died after cilengitide-induced detachment. Furthermore, irradiation of glioma cells increased αvβ3 expression slightly but not cilengitide sensitivity. Cilengitide's action on glioma and neuroblastoma cells appears to be dependent on αvβ3 expression and sensitivity to anoikis. Cilengitide is able to target pediatric glioma and neuroblastoma cells in vitro directly and efficiently. Tumor context could validate these promising observations.
authors.affiliation: Pediatric Oncology Unit, Centre Oscar Lambret, Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Leblond
authors.forename: Amélie
authors.initials: A
authors.lastname: Dewitte
authors.forename: Florence
authors.initials: F
authors.lastname: Le Tinier
authors.forename: Christine
authors.initials: C
authors.lastname: Bal-Mahieu
authors.forename: Marc
authors.initials: M
authors.lastname: Baroncini
authors.forename: Thierry
authors.initials: T
authors.lastname: Sarrazin
authors.forename: Eric
authors.initials: E
authors.lastname: Lartigau
authors.forename: Amélie
authors.initials: A
authors.lastname: Lansiaux
authors.forename: Samuel
authors.initials: S
authors.lastname: Meignan
mesh_terms: D000367:Age Factors; D023102:Anoikis / Q000187:drug effects* / Q000528:radiation effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects* / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D060787:Neoplasm Grading; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D018714:Radiotherapy, Adjuvant; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D012910:Snake Venoms / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D019030:Receptors, Vitronectin; D012910:Snake Venoms; C064660:integrin alphaVbeta5; C422910:Cilengitide