Document Detail


SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2.
MedLine Citation:
PMID:  20371709     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
SIRT proteins play an important role in the survival and drug resistance of tumor cells, especially during chemotherapy. In this study, we investigated the potency, specificity, and cellular targets of three SIRT inhibitors, Sirtinol, Salermide, and EX527. Cell proliferative and cell cycle analyses showed that Sirtinol and Salermide, but not EX527, were effective in inducing cell death at concentrations of 50 micromol/L or over in MCF-7 cells. Instead, EX527 caused cell cycle arrest at G(1) at comparable concentrations. In vitro SIRT assays using a p53 peptide substrate showed that all three compounds are potent SIRT1/2 inhibitors, with EX527 having the highest inhibitory activity for SIRT1. Computational docking analysis showed that Sirtinol and Salermide have high degrees of selectivity for SIRT1/2, whereas EX527 has high specificity for SIRT1 but not SIRT2. Consistently, Sirtinol and Salermide, but not EX527, treatment resulted in the in vivo acetylation of the SIRT1/2 target p53 and SIRT2 target tubulin in MCF-7 cells, suggesting that EX527 is ineffective in inhibiting SIRT2 and that p53 mediates the cytotoxic function of Sirtinol and Salermide. Studies using breast carcinoma cell lines and p53-deficient mouse fibroblasts confirmed that p53 is essential for the Sirtinol and Salermide-induced apoptosis. Further, we showed using small interfering RNA that silencing both SIRTs, but not SIRT1 and SIRT2 individually, can induce cell death in MCF-7 cells. Together, our results identify the specificity and cellular targets of these novel inhibitors and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death. Mol Cancer Ther; 9(4); 844-55. (c)2010 AACR.
Authors:
Barrie Peck; Chun-Yuan Chen; Ka-Kei Ho; Paolo Di Fruscia; Stephen S Myatt; R Charles Coombes; Matthew J Fuchter; Chwan-Deng Hsiao; Eric W-F Lam
Related Documents :
17692879 - A crystalline compound (bm-anf1) from the indian toad (bufo melanostictus, schneider) s...
10477729 - Atm is upregulated during the mitogenic response in peripheral blood mononuclear cells.
20214619 - Mechanisms of drug-induced mitotic catastrophe in cancer cells.
11668189 - Quantitative and qualitative immunofluorescence studies of neoplastic cells transfected...
8562479 - Transfection of wild-type but not mutant p53 induces early monocytic differentiation in...
9764849 - Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells.
23900689 - Bone formation induced by bmp-2 in human osteosarcoma cells.
10496879 - Mycobacterium avium infection of epithelial cells results in inhibition or delay in the...
20958319 - Surface-exposed calreticulin in the interaction between dying cells and phagocytes.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-04-06
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  9     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-09     Completed Date:  2010-07-07     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  844-55     Citation Subset:  IM    
Affiliation:
Cancer Research-UK Laboratory, Department of Surgery and Cancer, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Acetylation / drug effects
Benzamides / pharmacology*
Carbazoles / pharmacology*
Cell Death / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Screening Assays, Antitumor
G1 Phase / drug effects
Gene Silencing / drug effects
Humans
Lysine / metabolism
Models, Molecular
Naphthols / pharmacology*
Paclitaxel / pharmacology
Phenylpropionates / pharmacology*
Protein Structure, Secondary
Sirtuin 1 / chemistry,  metabolism*
Sirtuin 2 / chemistry,  metabolism*
Tubulin / metabolism
Tumor Suppressor Protein p53 / metabolism*
Grant Support
ID/Acronym/Agency:
//Biotechnology and Biological Sciences Research Council
Chemical
Reg. No./Substance:
0/6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; 0/Benzamides; 0/Carbazoles; 0/N-(3-((2-hydroxynaphthalen-1-ylmethylene)amino)phenyl)-2-phenylpropionamide; 0/Naphthols; 0/Phenylpropionates; 0/Tubulin; 0/Tumor Suppressor Protein p53; 0/sirtinol; 33069-62-4/Paclitaxel; 56-87-1/Lysine; EC 3.5.1.-/SIRT1 protein, human; EC 3.5.1.-/SIRT2 protein, human; EC 3.5.1.-/Sirtuin 1; EC 3.5.1.-/Sirtuin 2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  A molecularly targeted theranostic probe for ovarian cancer.
Next Document:  Bridging the gap between cytotoxic and biologic therapy with metronomic topotecan and pazopanib in o...