Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor(194 visite) Costa B, Bendinelli S, Gabelloni P, Da Pozzo E, Daniele S, Scatena F, Vanacore R, Campiglia P, Bertamino A, Gomez-Monterrey I, Sorriento D, Del Giudice C, Iaccarino G, Novellino E, Martini C
Parole chiave: 6-(4-Chlorobenzyl)-1h-Spiro(imidazo(1, 5-C)thiazole-3, 3′-Indoline)-2′, 7(6h, 7ah)-Trione, Antineoplastic Agent, Indole Derivative, Mdm2 Protein, Human, Molecular Library, Protein Binding, Protein Mdm2, Protein P53, Spiro Compound, Agonists, Animal, Antagonists And Inhibitors, Apoptosis, Bagg Albino Mouse, Brain Neoplasms, Cell Proliferation, Drug Effects, Drug Screening, Female, Gene Expression Regulation, Genetics, Glioblastoma, Metabolism, Nude Mouse, Pathology, Pharmacology, Signal Transduction, Tumor Volume, Inhibitory Concentration 50, Inbred Balb C, Proto-Oncogene Proteins C-Mdm2, Small Molecule Libraries, Tumor Burden, Tumor Suppressor Protein P53, Xenograft Model Antitumor Assays,
*** IBB - CNR *** Department of Pharmacy, University of Pisa, Pisa, Italy
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.
Petraglia F, Singh AA, Carafa V, Nebbioso A, Conte M, Scisciola L, Valente S, Baldi A, Mandoli A, Petrizzi VB, Ingenito C, De Falco S, Cicatiello V, Apicella I, Janssen-megens EM, Kim B, Yi G, Logie C, Heath S, Ruvo M, Wierenga ATJ, Flicek P, Yaspo ML, Della Valle V, Bernard O, Tomassi S, Novellino E, Feoli A, Sbardella G, Gut I, Vellenga E, Stunnenberg HG, Mai A, Martens JHA, Altucci L * Combined HAT/EZH2 modulation leads to cancer-selective cell death(120 visite) Oncotarget (ISSN: 1949-2553electronic, 1949-2553linking), 2018 May 22; 9(39): 25630-25646. Impact Factor:5.008 DettagliEsporta in BibTeXEsporta in EndNote
119 Records (109 escludendo Abstract e Conferenze). Impact factor totale: 475.495 (437.944 escludendo Abstract e Conferenze). Impact factor a 5 anni totale: 508.703 (464.313 escludendo Abstract e Conferenze).