New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53 (565 views)
Br J Cancer (ISSN: 0007-0920, 0007-0920print, 0007-0920linking), 2015 Jan 6; 112(1): 77-85.
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Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 5.569, 5-year impact factor: 5.617
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-84920640925&partnerID=40&md5=e76558c49a187d405b2fdb057054e85c
Keywords: Apoptosis, Mdm2, 5 Bromo 3, (cyclohexane Carbonyl) 1 Methyl 2 Oxospiro[indoline 3, Thiazolidine], 6 (4chlorobenzyl) 1h Spiro[imidazo[1, 5 C]thiazole 3, Indolin] 2, 7(6h, 7ah)trione, Antineoplastic Agent, Caspase 3, Protein Bax, Protein P53, Unclassified Drug, 6-(4-Chlorobenzyl)-1h-Spiro(imidazo(1, 5-C)thiazole-3, -Indoline)-2, 7ah)-Trione, Indole Derivative, Mdm2 Protein, Human, Molecular Library, Protein Mdm2, Spiro Compound, Tp53 Protein, Animal Experiment, Animal Model, Animal Tissue, Antineoplastic Activity, Article, Cancer Inhibition, Cell Proliferation, Controlled Study, Drug Efficacy, Drug Megadose, In Vitro Study, In Vivo Study, Low Drug Dose, Mitochondrion, Mouse, Nonhuman, Western Blotting, Antagonists And Inhibitors, Bagg Albino Mouse, Cell Growth, Drug Effects, Drug Screening, Genetics, Mcf 7 Cell Line, Metabolism, Nude Mouse, Pathology, Pharmacology, Cell Growth Processes, Mcf-7 Cells, Inbred Balb C, Proto-Oncogene Proteins C-Mdm2, Small Molecule Libraries, Tumor Suppressor Protein P53, Xenograft Model Antitumor Assays, Drug Therapy,
Affiliations:
*** IBB - CNR ***
Department of Advanced Biomedical Sciences, 'Federico II' University of Naples, Naples, Italy
Institute of Biostructure and Bioimaging (IBB), Italian National Research Council (CNR), Naples, Italy
Department of Pharmaceutical Science, Division of BioMedicine, University of Salerno, Salerno, Italy
Department of Medicine and Surgery, University of Salerno, Salerno, Italy
Department of Translational Medicine, 'Federico II' University of Naples, Naples, Italy
IRCCS Multimedica, Milano, Italy
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., Department of Advanced Biomedical Sciences, 'Federico II' University of Naples, Naples 80131, Italy., Department of Pharmaceutical Science, Division of BioMedicine, University of Salerno, Salerno 84084, Italy., Department of Medicine and Surgery, University of Salerno, Salerno 84081, Italy., Department of Pharmaceutical and Toxicological Chemistry, 'Federico II' University of Naples, Naples 80131, Italy., Department of Translational Medicine, 'Federico II' University of Naples, Naples 80131, Italy., 1] Department of Medicine and Surgery, University of Salerno, Salerno 84081, Italy [2] IRCCS Multimedica, Milano 20138, Italy.,
References:
Not available.
Br J Cancer (ISSN: 0007-0920, 0007-0920print, 0007-0920linking), 2015 Jan 6; 112(1): 77-85.
Export to BibTeX Export to EndNote
Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 5.569, 5-year impact factor: 5.617
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-84920640925&partnerID=40&md5=e76558c49a187d405b2fdb057054e85c
Keywords: Apoptosis, Mdm2, 5 Bromo 3, (cyclohexane Carbonyl) 1 Methyl 2 Oxospiro[indoline 3, Thiazolidine], 6 (4chlorobenzyl) 1h Spiro[imidazo[1, 5 C]thiazole 3, Indolin] 2, 7(6h, 7ah)trione, Antineoplastic Agent, Caspase 3, Protein Bax, Protein P53, Unclassified Drug, 6-(4-Chlorobenzyl)-1h-Spiro(imidazo(1, 5-C)thiazole-3, -Indoline)-2, 7ah)-Trione, Indole Derivative, Mdm2 Protein, Human, Molecular Library, Protein Mdm2, Spiro Compound, Tp53 Protein, Animal Experiment, Animal Model, Animal Tissue, Antineoplastic Activity, Article, Cancer Inhibition, Cell Proliferation, Controlled Study, Drug Efficacy, Drug Megadose, In Vitro Study, In Vivo Study, Low Drug Dose, Mitochondrion, Mouse, Nonhuman, Western Blotting, Antagonists And Inhibitors, Bagg Albino Mouse, Cell Growth, Drug Effects, Drug Screening, Genetics, Mcf 7 Cell Line, Metabolism, Nude Mouse, Pathology, Pharmacology, Cell Growth Processes, Mcf-7 Cells, Inbred Balb C, Proto-Oncogene Proteins C-Mdm2, Small Molecule Libraries, Tumor Suppressor Protein P53, Xenograft Model Antitumor Assays, Drug Therapy,
Affiliations:
*** IBB - CNR ***
Department of Advanced Biomedical Sciences, 'Federico II' University of Naples, Naples, Italy
Institute of Biostructure and Bioimaging (IBB), Italian National Research Council (CNR), Naples, Italy
Department of Pharmaceutical Science, Division of BioMedicine, University of Salerno, Salerno, Italy
Department of Medicine and Surgery, University of Salerno, Salerno, Italy
Department of Translational Medicine, 'Federico II' University of Naples, Naples, Italy
IRCCS Multimedica, Milano, Italy
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., Department of Advanced Biomedical Sciences, 'Federico II' University of Naples, Naples 80131, Italy., Department of Pharmaceutical Science, Division of BioMedicine, University of Salerno, Salerno 84084, Italy., Department of Medicine and Surgery, University of Salerno, Salerno 84081, Italy., Department of Pharmaceutical and Toxicological Chemistry, 'Federico II' University of Naples, Naples 80131, Italy., Department of Translational Medicine, 'Federico II' University of Naples, Naples 80131, Italy., 1] Department of Medicine and Surgery, University of Salerno, Salerno 84081, Italy [2] IRCCS Multimedica, Milano 20138, Italy.,
References:
Not available.
New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53
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. © 2015 Cancer Research UK.
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. © 2015 Cancer Research UK.
New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53
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