New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53

D. Sorriento, C. Del Giudice, A. Bertamino, M. Ciccarelli, I. Gomez-Monterrey, P. Campiglia, E. Novellino, M. Illario, B. Trimarco, N. De Luca, G. Iaccarino

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)77-85
Number of pages9
JournalBritish Journal of Cancer
Volume112
Issue number1
DOIs
Publication statusPublished - Jan 6 2015

Fingerprint

Growth
Neoplasms
p53 Genes
Apoptosis
Cell Line
Null Lymphocytes
Nude Mice
Cell Death
Transcription Factors
Western Blotting
Cell Proliferation
Genes
In Vitro Techniques

Keywords

  • apoptosis
  • MDM2
  • p53

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Sorriento, D., Del Giudice, C., Bertamino, A., Ciccarelli, M., Gomez-Monterrey, I., Campiglia, P., ... Iaccarino, G. (2015). New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53. British Journal of Cancer, 112(1), 77-85. https://doi.org/10.1038/bjc.2014.577

New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53. / Sorriento, D.; Del Giudice, C.; Bertamino, A.; Ciccarelli, M.; Gomez-Monterrey, I.; Campiglia, P.; Novellino, E.; Illario, M.; Trimarco, B.; De Luca, N.; Iaccarino, G.

In: British Journal of Cancer, Vol. 112, No. 1, 06.01.2015, p. 77-85.

Research output: Contribution to journalArticle

Sorriento, D, Del Giudice, C, Bertamino, A, Ciccarelli, M, Gomez-Monterrey, I, Campiglia, P, Novellino, E, Illario, M, Trimarco, B, De Luca, N & Iaccarino, G 2015, 'New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53', British Journal of Cancer, vol. 112, no. 1, pp. 77-85. https://doi.org/10.1038/bjc.2014.577
Sorriento D, Del Giudice C, Bertamino A, Ciccarelli M, Gomez-Monterrey I, Campiglia P et al. New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53. British Journal of Cancer. 2015 Jan 6;112(1):77-85. https://doi.org/10.1038/bjc.2014.577
Sorriento, D. ; Del Giudice, C. ; Bertamino, A. ; Ciccarelli, M. ; Gomez-Monterrey, I. ; Campiglia, P. ; Novellino, E. ; Illario, M. ; Trimarco, B. ; De Luca, N. ; Iaccarino, G. / New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53. In: British Journal of Cancer. 2015 ; Vol. 112, No. 1. pp. 77-85.
@article{489f627abff8421e8800d7c1331c4cf3,
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.",
keywords = "apoptosis, MDM2, p53",
author = "D. Sorriento and {Del Giudice}, C. and A. Bertamino and M. Ciccarelli and I. Gomez-Monterrey and P. Campiglia and E. Novellino and M. Illario and B. Trimarco and {De Luca}, N. and G. Iaccarino",
year = "2015",
month = "1",
day = "6",
doi = "10.1038/bjc.2014.577",
language = "English",
volume = "112",
pages = "77--85",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53

AU - Sorriento, D.

AU - Del Giudice, C.

AU - Bertamino, A.

AU - Ciccarelli, M.

AU - Gomez-Monterrey, I.

AU - Campiglia, P.

AU - Novellino, E.

AU - Illario, M.

AU - Trimarco, B.

AU - De Luca, N.

AU - Iaccarino, G.

PY - 2015/1/6

Y1 - 2015/1/6

N2 - 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.

AB - 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.

KW - apoptosis

KW - MDM2

KW - p53

UR - http://www.scopus.com/inward/record.url?scp=84920640925&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920640925&partnerID=8YFLogxK

U2 - 10.1038/bjc.2014.577

DO - 10.1038/bjc.2014.577

M3 - Article

C2 - 25422906

AN - SCOPUS:84920640925

VL - 112

SP - 77

EP - 85

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 1

ER -