New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53 (376 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:
Arima, Y., Nitta, M., Kuninaka, S., Zhang, D., Fujiwara, T., Taya, Y., Nakao, M., Saya, H., Transcriptional blockade induces p53-dependent apoptosis associated with translocation of p53 to mitochondria (2005) J Biol Chem, 280 (19), pp. 19166-1917
Bertamino, A., Soprano, M., Musella, S., Rusciano, M.R., Sala, M., Vernieri, E., Di Sarno, V., Gomez-Monterrey, I., Synthesis, in vitro, and in cell studies of a new series of [Indoline-3,2'-thiazolidine]-based p53 modulators (2013) J Med Chem, 56, pp. 5407-5421
Blagosklonny, M.V., Giannakakou, P., Wojtowicz, M., Romanova, L.Y., Ain, K.B., Bates, S.E., Fojo, T., Effects of p53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells (1998) J Clin Endocrinol Metab, 83 (7), pp. 2516-2522
Bourdon, J.C., Fernandes, K., Murray-Zmijewski, F., Liu, G., Diot, A., Xirodimas, D.P., Saville, M.K., Lane, D.P., P53 isoforms can regulate p53 transcriptional activity (2005) Genes Dev, 19 (18), pp. 2122-2137
Brown, C.J., Lain, S., Verma, C.S., Fersht, A.R., Lane, D.P., Awakening guardian angels: Drugging the p53 pathway (2009) Nat Rev Cancer, 9 (12), pp. 862-873
Chen, J., Wu, X., Lin, J., Levine, A.J., Mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein (1996) Mol Cell Biol, 16 (5), pp. 2445-2452
Ciccarelli, M., Sorriento, D., Cipolletta, E., Santulli, G., Fusco, A., Zhou, R.H., Eckhart, A.D., Iaccarino, G., Impaired neoangiogenesis in beta(2)-adrenoceptor gene-deficient mice: Restoration by intravascular human beta(2)-adrenoceptor gene transfer and role of NFkappaB and CREB transcription factors (2011) Br J Pharmacol, 162 (3), pp. 712-721
Cittadini, A., Monti, M.G., Castiello, M.C., D'Arco, E., Galasso, G., Sorriento, D., Saldamarco, L., Sacca, L., Insulin-like growth factor-1 protects from vascular stenosis and accelerates re-endothelialization in a rat model of carotid artery injury (2009) J Thromb Haemost, 7 (11), pp. 1920-1928
Costa, B., Bendinelli, S., Gabelloni, P., Da Pozzo, E., Daniele, S., Scatena, F., Vanacore, R., Martini, C., Human glioblastoma multiforme: P53 reactivation by a novel MDM2 inhibitor (2013) PloS One, 8 (8), p. e72281
Finlay, C.A., The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth (1993) Mol Cell Biol, 13 (1), pp. 301-306
Geyer, R.K., Yu, Z.K., Maki, C.G., The MDM2 RING-finger domain is required to promote p53 nuclear export (2000) Nat Cell Biol, 2 (9), pp. 569-573
Green, D.R., Kroemer, G., Cytoplasmic functions of the tumour suppressor p53 (2009) Nature, 458 (7242), pp. 1127-1130
Ha, J.H., Shin, J.S., Yoon, M.K., Lee, M.S., He, F., Bae, K.H., Yoon, H.S., Chi, S.W., Dual-site interactions of p53 protein transactivation domain with anti-apoptotic Bcl-2 family proteins reveal a highly convergent mechanism of divergent p53 pathways (2013) J Biol Chem, 288 (10), pp. 7387-7398
Harms, K., Nozell, S., Chen, X., The common and distinct target genes of the p53 family transcription factors (2004) Cell Mol Life Sci, 61 (7-8), pp. 822-842
Harms, K.L., Chen, X., The C terminus of p53 family proteins is a cell fate determinant (2005) Mol Cell Biol, 25 (5), pp. 2014-2030
Haupt, Y., Maya, R., Kazaz, A., Oren, M., Mdm2 promotes the rapid degradation of p53 (1997) Nature, 387 (6630), pp. 296-299
Iaccarino, G., Izzo, R., Trimarco, V., Cipolletta, E., Lanni, F., Sorriento, D., Iovino, G.L., Trimarco, B., Beta2-adrenergic receptor polymorphisms and treatment-induced regression of left ventricular hypertrophy in hypertension (2006) Clin Pharmacol Ther, 80 (6), pp. 633-645
Kakudo, Y., Shibata, H., Otsuka, K., Kato, S., Ishioka, C., Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s (2005) Cancer Res, 65 (6), pp. 2108-2114
Kim, S.S., Chae, H.S., Bach, J.H., Lee, M.W., Kim, K.Y., Lee, W.B., Jung, Y.M., Suh, Y.H., P53 mediates ceramide-induced apoptosis in SKN-SH cells (2002) Oncogene, 21 (13), pp. 2020-2028
Kroemer, G., Galluzzi, L., Brenner, C., Mitochondrial membrane permeabilization in cell death (2007) Physiol Rev, 87 (1), pp. 99-163
Levine, A.J., P53, the cellular gatekeeper for growth and division (1997) Cell, 88 (3), pp. 323-331
Malaguarnera, R., Vella, V., Vigneri, R., Frasca, F., P53 family proteins in thyroid cancer (2007) Endocr Relat Cancer, 14 (1), pp. 43-60
Mihara, M., Erster, S., Zaika, A., Petrenko, O., Chittenden, T., Pancoska, P., Moll, U.M., P53 has a direct apoptogenic role at the mitochondria (2003) Mol Cell, 11 (3), pp. 577-590
Moll, U.M., Petrenko, O., The MDM2-p53 interaction (2003) Mol Cancer Res, 1 (14), pp. 1001-1008
Momand, J., Zambetti, G.P., Olson, D.C., George, D., Levine, A.J., The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation (1992) Cell, 69 (7), pp. 1237-1245
Namba, H., Hara, T., Tukazaki, T., Migita, K., Ishikawa, N., Ito, K., Nagataki, S., Yamashita, S., Radiation-induced G1 arrest is selectively mediated by the p53-WAF1/Cip1 pathway in human thyroid cells (1995) Cancer Res, 55 (10), pp. 2075-2080
Phelps, M., Darley, M., Primrose, J.N., Blaydes, J.P., P53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells (2003) Cancer Res, 63 (10), pp. 2616-2623
Riley, T., Sontag, E., Chen, P., Levine, A., Transcriptional control of human p53-regulated genes (2008) Nat Rev Mol Cell Biol, 9 (5), pp. 402-412
Santulli, G., Basilicata, M.F., De Simone, M., Del Giudice, C., Anastasio, A., Sorriento, D., Saviano, M., Iaccarino, G., Evaluation of the anti-angiogenic properties of the new selective alphaVbeta3 integrin antagonist RGDechiHCit (2011) J Transl Med, 9, p. 7
Santulli, G., Cipolletta, E., Sorriento, D., Del Giudice, C., Anastasio, A., Monaco, S., Maione, A.S., Iaccarino, G., CaMK4 gene deletion induces hypertension (2012) J Am Heart Assoc, 1 (4), p. e001081
Shangary, S., Wang, S., Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: A novel approach for cancer therapy (2009) Annu Rev Pharmacol Toxicol, 49, pp. 223-241
Sorriento, D., Campanile, A., Santulli, G., Leggiero, E., Pastore, L., Trimarco, B., Iaccarino, G., A new synthetic protein, TAT-RH, inhibits tumor growth through the regulation of NFkappaB activity (2009) Mol Cancer, 8, p. 97
Sorriento, D., Ciccarelli, M., Santulli, G., Campanile, A., Altobelli, G.G., Cimini, V., Galasso, G., Iaccarino, G., The G-protein-coupled receptor kinase 5 inhibits NFkappaB transcriptional activity by inducing nuclear accumulation of IkappaB alpha (2008) Proc Natl Acad Sci USA, 105 (46), pp. 17818-17823
Sorriento, D., Santulli, G., Del Giudice, C., Anastasio, A., Trimarco, B., Iaccarino, G., Endothelial cells are able to synthesize and release catecholamines both in vitro and in vivo (2012) Hypertension, 60 (1), pp. 129-136
Speidel, D., Transcription-independent p53 apoptosis: An alternative route to death (2010) Trends Cell Biol, 20 (1), pp. 14-24
Vousden, K.H., Lu, X., Live or let die: The cell's response to p53 (2002) Nat Rev Cancer, 2 (8), pp. 594-604
Wolf, D., Rotter, V., Major deletions in the gene encoding the p53 tumor antigen cause lack of p53 expression in HL-60 cells (1985) Proc Natl Acad Sci USA, 82 (3), pp. 790-794
Wu, L., Levine, A.J., Differential regulation of the p21/WAF-1 and mdm2 genes after high-dose UV irradiation: P53-dependent and p53-independent regulation of the mdm2 gene (1997) Mol Med, 3 (7), pp. 441-451
Zhao, Y., Chaiswing, L., Velez, J.M., Batinic-Haberle, I., Colburn, N.H., Oberley St, T.D., Clair, D.K., P53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense proteinmanganese superoxide dismutase (2005) Cancer Res, 65 (9), pp. 3745-3750
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:
Arima, Y., Nitta, M., Kuninaka, S., Zhang, D., Fujiwara, T., Taya, Y., Nakao, M., Saya, H., Transcriptional blockade induces p53-dependent apoptosis associated with translocation of p53 to mitochondria (2005) J Biol Chem, 280 (19), pp. 19166-1917
Bertamino, A., Soprano, M., Musella, S., Rusciano, M.R., Sala, M., Vernieri, E., Di Sarno, V., Gomez-Monterrey, I., Synthesis, in vitro, and in cell studies of a new series of [Indoline-3,2'-thiazolidine]-based p53 modulators (2013) J Med Chem, 56, pp. 5407-5421
Blagosklonny, M.V., Giannakakou, P., Wojtowicz, M., Romanova, L.Y., Ain, K.B., Bates, S.E., Fojo, T., Effects of p53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells (1998) J Clin Endocrinol Metab, 83 (7), pp. 2516-2522
Bourdon, J.C., Fernandes, K., Murray-Zmijewski, F., Liu, G., Diot, A., Xirodimas, D.P., Saville, M.K., Lane, D.P., P53 isoforms can regulate p53 transcriptional activity (2005) Genes Dev, 19 (18), pp. 2122-2137
Brown, C.J., Lain, S., Verma, C.S., Fersht, A.R., Lane, D.P., Awakening guardian angels: Drugging the p53 pathway (2009) Nat Rev Cancer, 9 (12), pp. 862-873
Chen, J., Wu, X., Lin, J., Levine, A.J., Mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein (1996) Mol Cell Biol, 16 (5), pp. 2445-2452
Ciccarelli, M., Sorriento, D., Cipolletta, E., Santulli, G., Fusco, A., Zhou, R.H., Eckhart, A.D., Iaccarino, G., Impaired neoangiogenesis in beta(2)-adrenoceptor gene-deficient mice: Restoration by intravascular human beta(2)-adrenoceptor gene transfer and role of NFkappaB and CREB transcription factors (2011) Br J Pharmacol, 162 (3), pp. 712-721
Cittadini, A., Monti, M.G., Castiello, M.C., D'Arco, E., Galasso, G., Sorriento, D., Saldamarco, L., Sacca, L., Insulin-like growth factor-1 protects from vascular stenosis and accelerates re-endothelialization in a rat model of carotid artery injury (2009) J Thromb Haemost, 7 (11), pp. 1920-1928
Costa, B., Bendinelli, S., Gabelloni, P., Da Pozzo, E., Daniele, S., Scatena, F., Vanacore, R., Martini, C., Human glioblastoma multiforme: P53 reactivation by a novel MDM2 inhibitor (2013) PloS One, 8 (8), p. e72281
Finlay, C.A., The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth (1993) Mol Cell Biol, 13 (1), pp. 301-306
Geyer, R.K., Yu, Z.K., Maki, C.G., The MDM2 RING-finger domain is required to promote p53 nuclear export (2000) Nat Cell Biol, 2 (9), pp. 569-573
Green, D.R., Kroemer, G., Cytoplasmic functions of the tumour suppressor p53 (2009) Nature, 458 (7242), pp. 1127-1130
Ha, J.H., Shin, J.S., Yoon, M.K., Lee, M.S., He, F., Bae, K.H., Yoon, H.S., Chi, S.W., Dual-site interactions of p53 protein transactivation domain with anti-apoptotic Bcl-2 family proteins reveal a highly convergent mechanism of divergent p53 pathways (2013) J Biol Chem, 288 (10), pp. 7387-7398
Harms, K., Nozell, S., Chen, X., The common and distinct target genes of the p53 family transcription factors (2004) Cell Mol Life Sci, 61 (7-8), pp. 822-842
Harms, K.L., Chen, X., The C terminus of p53 family proteins is a cell fate determinant (2005) Mol Cell Biol, 25 (5), pp. 2014-2030
Haupt, Y., Maya, R., Kazaz, A., Oren, M., Mdm2 promotes the rapid degradation of p53 (1997) Nature, 387 (6630), pp. 296-299
Iaccarino, G., Izzo, R., Trimarco, V., Cipolletta, E., Lanni, F., Sorriento, D., Iovino, G.L., Trimarco, B., Beta2-adrenergic receptor polymorphisms and treatment-induced regression of left ventricular hypertrophy in hypertension (2006) Clin Pharmacol Ther, 80 (6), pp. 633-645
Kakudo, Y., Shibata, H., Otsuka, K., Kato, S., Ishioka, C., Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s (2005) Cancer Res, 65 (6), pp. 2108-2114
Kim, S.S., Chae, H.S., Bach, J.H., Lee, M.W., Kim, K.Y., Lee, W.B., Jung, Y.M., Suh, Y.H., P53 mediates ceramide-induced apoptosis in SKN-SH cells (2002) Oncogene, 21 (13), pp. 2020-2028
Kroemer, G., Galluzzi, L., Brenner, C., Mitochondrial membrane permeabilization in cell death (2007) Physiol Rev, 87 (1), pp. 99-163
Levine, A.J., P53, the cellular gatekeeper for growth and division (1997) Cell, 88 (3), pp. 323-331
Malaguarnera, R., Vella, V., Vigneri, R., Frasca, F., P53 family proteins in thyroid cancer (2007) Endocr Relat Cancer, 14 (1), pp. 43-60
Mihara, M., Erster, S., Zaika, A., Petrenko, O., Chittenden, T., Pancoska, P., Moll, U.M., P53 has a direct apoptogenic role at the mitochondria (2003) Mol Cell, 11 (3), pp. 577-590
Moll, U.M., Petrenko, O., The MDM2-p53 interaction (2003) Mol Cancer Res, 1 (14), pp. 1001-1008
Momand, J., Zambetti, G.P., Olson, D.C., George, D., Levine, A.J., The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation (1992) Cell, 69 (7), pp. 1237-1245
Namba, H., Hara, T., Tukazaki, T., Migita, K., Ishikawa, N., Ito, K., Nagataki, S., Yamashita, S., Radiation-induced G1 arrest is selectively mediated by the p53-WAF1/Cip1 pathway in human thyroid cells (1995) Cancer Res, 55 (10), pp. 2075-2080
Phelps, M., Darley, M., Primrose, J.N., Blaydes, J.P., P53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells (2003) Cancer Res, 63 (10), pp. 2616-2623
Riley, T., Sontag, E., Chen, P., Levine, A., Transcriptional control of human p53-regulated genes (2008) Nat Rev Mol Cell Biol, 9 (5), pp. 402-412
Santulli, G., Basilicata, M.F., De Simone, M., Del Giudice, C., Anastasio, A., Sorriento, D., Saviano, M., Iaccarino, G., Evaluation of the anti-angiogenic properties of the new selective alphaVbeta3 integrin antagonist RGDechiHCit (2011) J Transl Med, 9, p. 7
Santulli, G., Cipolletta, E., Sorriento, D., Del Giudice, C., Anastasio, A., Monaco, S., Maione, A.S., Iaccarino, G., CaMK4 gene deletion induces hypertension (2012) J Am Heart Assoc, 1 (4), p. e001081
Shangary, S., Wang, S., Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: A novel approach for cancer therapy (2009) Annu Rev Pharmacol Toxicol, 49, pp. 223-241
Sorriento, D., Campanile, A., Santulli, G., Leggiero, E., Pastore, L., Trimarco, B., Iaccarino, G., A new synthetic protein, TAT-RH, inhibits tumor growth through the regulation of NFkappaB activity (2009) Mol Cancer, 8, p. 97
Sorriento, D., Ciccarelli, M., Santulli, G., Campanile, A., Altobelli, G.G., Cimini, V., Galasso, G., Iaccarino, G., The G-protein-coupled receptor kinase 5 inhibits NFkappaB transcriptional activity by inducing nuclear accumulation of IkappaB alpha (2008) Proc Natl Acad Sci USA, 105 (46), pp. 17818-17823
Sorriento, D., Santulli, G., Del Giudice, C., Anastasio, A., Trimarco, B., Iaccarino, G., Endothelial cells are able to synthesize and release catecholamines both in vitro and in vivo (2012) Hypertension, 60 (1), pp. 129-136
Speidel, D., Transcription-independent p53 apoptosis: An alternative route to death (2010) Trends Cell Biol, 20 (1), pp. 14-24
Vousden, K.H., Lu, X., Live or let die: The cell's response to p53 (2002) Nat Rev Cancer, 2 (8), pp. 594-604
Wolf, D., Rotter, V., Major deletions in the gene encoding the p53 tumor antigen cause lack of p53 expression in HL-60 cells (1985) Proc Natl Acad Sci USA, 82 (3), pp. 790-794
Wu, L., Levine, A.J., Differential regulation of the p21/WAF-1 and mdm2 genes after high-dose UV irradiation: P53-dependent and p53-independent regulation of the mdm2 gene (1997) Mol Med, 3 (7), pp. 441-451
Zhao, Y., Chaiswing, L., Velez, J.M., Batinic-Haberle, I., Colburn, N.H., Oberley St, T.D., Clair, D.K., P53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense proteinmanganese superoxide dismutase (2005) Cancer Res, 65 (9), pp. 3745-3750
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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