title: Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor.
abstract: Cancer development and chemo-resistance are often due to impaired functioning of the p53 tumor suppressor through genetic mutation or sequestration by other proteins. In glioblastoma multiforme (GBM), p53 availability is frequently reduced because it binds to the Murine Double Minute-2 (MDM2) oncoprotein, which accumulates at high concentrations in tumor cells. The use of MDM2 inhibitors that interfere with the binding of p53 and MDM2 has become a valid approach to inhibit cell growth in a number of cancers; however little is known about the efficacy of these inhibitors in GBM. We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis. In immunoincompetent BALB/c nude mice bearing a human GBM xenograft, the administration of ISA27 in vivo activated p53, inhibited cell proliferation and induced apoptosis in tumor tissue. Significantly, ISA27 was non-toxic in an in vitro normal human cell model and an in vivo mouse model. ISA27 administration in combination with temozolomide (TMZ) produced a synergistic inhibitory effect on GBM cell viability in vitro, suggesting the possibility of lowering the dose of TMZ used in the treatment of GBM. In conclusion, our data show that ISA27 releases the powerful antitumor capacities of p53 in GBM cells. The use of this MDM2 inhibitor could become a novel therapy for the treatment of GBM patients.
authors: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors: Barbara
authors: B
authors: Costa
authors: Sara
authors: S
authors: Bendinelli
authors: Pamela
authors: P
authors: Gabelloni
authors: Eleonora
authors: E
authors: Da Pozzo
authors: Simona
authors: S
authors: Daniele
authors: Fabrizio
authors: F
authors: Scatena
authors: Renato
authors: R
authors: Vanacore
authors: Pietro
authors: P
authors: Campiglia
authors: Alessia
authors: A
authors: Bertamino
authors: Isabel
authors: I
authors: Gomez-Monterrey
authors: Daniela
authors: D
authors: Sorriento
authors: Carmine
authors: C
authors: Del Giudice
authors: Guido
authors: G
authors: Iaccarino
authors: Ettore
authors: E
authors: Novellino
authors: Claudia
authors: C
authors: Martini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C000594641:6-(4-chlorobenzyl)-1H-spiro(imidazo(1,5-c)thiazole-3,3'-indoline)-2',5,7(6H,7aH)-trione; D000970:Antineoplastic Agents; D007211:Indoles; D054852:Small Molecule Libraries; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
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