title: New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53.
abstract: BACKGROUND
  p53 is a transcription factor with tumour suppressor properties, which is able to induce mitochondrial apoptosis independently of its transcriptional activity. We recently synthesised two new compounds (ISA27 and SM13), which block p53-MDM2 interaction and induce apoptosis in p53 wild-type (WT) tumour cells. The aim of this study was to verify the effectiveness of these compounds in tumours carrying a mutated form of p53 gene with no transcriptional activity.
  
  
  METHODS
  In vitro we evaluated the effectiveness of our compounds in cancer cell lines carrying WT, mutated and null p53 gene. In vivo study was performed in Balb/c nude mice and the mitochondrial-dependent apoptotic signalling was evaluated by western blot.
  
  
  RESULTS
  Both ISA27 and SM13 reduced cell proliferation and induced apoptosis in vitro in cells carrying either p53 WT or mutated gene, suggesting that its effect is independent from p53 transcriptional activity. On the contrary, SM13 had no effect in a p53 null cell line. In vivo, ISA27 and SM13 induced cancer cell death in a dose-dependent manner through the activation of the mitochondrial-dependent death signalling in p53-mutated cells. In vivo, SM13 reduced tumour growth.
  
  
  CONCLUSIONS
  Our study proposes SM13 as anticancer compound to use for the treatment of p53-dependent tumours, even in the absence of p53 transcriptional activity.
authors.affiliation: 1] Department of Advanced Biomedical Sciences, 'Federico II' University of Naples, Naples 80131, Italy [2] Institute of Biostructure and Bioimaging (IBB) of the Italian National Research Council (CNR), Naples 80145, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Sorriento
authors.affiliation: Department of Advanced Biomedical Sciences, 'Federico II' University of Naples, Naples 80131, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Del Giudice
authors.affiliation: Department of Pharmaceutical Science, Division of BioMedicine, University of Salerno, Salerno 84084, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bertamino
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Salerno 84081, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ciccarelli
authors.affiliation: Department of Pharmaceutical and Toxicological Chemistry, 'Federico II' University of Naples, Naples 80131, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Gomez-Monterrey
authors.affiliation: Department of Pharmaceutical Science, Division of BioMedicine, University of Salerno, Salerno 84084, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Campiglia
authors.affiliation: Department of Pharmaceutical and Toxicological Chemistry, 'Federico II' University of Naples, Naples 80131, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Translational Medicine, 'Federico II' University of Naples, Naples 80131, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Illario
authors.affiliation: Department of Advanced Biomedical Sciences, 'Federico II' University of Naples, Naples 80131, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Trimarco
authors.affiliation: Department of Translational Medicine, 'Federico II' University of Naples, Naples 80131, Italy.
authors.forename: N
authors.initials: N
authors.lastname: De Luca
authors.affiliation: 1] Department of Medicine and Surgery, University of Salerno, Salerno 84081, Italy [2] IRCCS Multimedica, Milano 20138, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Iaccarino
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / 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; D007211:Indoles; D054852:Small Molecule Libraries; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2