Document Detail


Histone deacetylase inhibitor AR-42 differentially affects cell-cycle transit in meningeal and meningioma cells, potently inhibiting NF2-deficient meningioma growth.
MedLine Citation:
PMID:  23151902     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Meningiomas constitute about 34% of primary intracranial tumors and are associated with increased mortality in patients with neurofibromatosis type 2 (NF2). To evaluate potential medical therapies for these tumors, we have established a quantifiable orthotopic model for NF2-deficient meningiomas. We showed that telomerase-immortalized Ben-Men-1 benign meningioma cells harbored a single nucleotide deletion in NF2 exon 7 and did not express the NF2 protein, merlin. We also showed that AR-42, a pan-histone deacetylase inhibitor, inhibited proliferation of both Ben-Men-1 and normal meningeal cells by increasing expression of p16(INK4A), p21(CIP1/WAF1), and p27(KIP1). In addition, AR-42 increased proapoptotic Bim expression and decreased anti-apoptotic Bcl(XL) levels. However, AR-42 predominantly arrested Ben-Men-1 cells at G(2)-M whereas it induced cell-cycle arrest at G(1) in meningeal cells. Consistently, AR-42 substantially decreased the levels of cyclin D1, E, and A, and proliferating cell nuclear antigen in meningeal cells while significantly reducing the expression of cyclin B, important for progression through G(2), in Ben-Men-1 cells. In addition, AR-42 decreased Aurora A and B expression. To compare the in vivo efficacies of AR-42 and AR-12, a PDK1 inhibitor, we generated and used luciferase-expressing Ben-Men-1-LucB cells to establish intracranial xenografts that grew over time. While AR-12 treatment moderately slowed tumor growth, AR-42 caused regression of Ben-Men-1-LucB tumors. Importantly, AR-42-treated tumors showed minimal regrowth when xenograft-bearing mice were switched to normal diet. Together, these results suggest that AR-42 is a potential therapy for meningiomas. The differential effect of AR-42 on cell-cycle progression of normal meningeal and meningioma cells may have implications for why AR-42 is well-tolerated while it potently inhibits tumor growth.
Authors:
Sarah S Burns; Elena M Akhmametyeva; Janet L Oblinger; Matthew L Bush; Jie Huang; Volker Senner; Ching-Shih Chen; Abraham Jacob; D Bradley Welling; Long-Sheng Chang
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-11-14
Journal Detail:
Title:  Cancer research     Volume:  73     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-18     Completed Date:  2013-03-26     Revised Date:  2014-01-23    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  792-803     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Cycle / genetics
Cell Line, Tumor
Cell Proliferation / drug effects
Genes, Neurofibromatosis 2*
Histone Deacetylase Inhibitors / pharmacology*
Humans
Meningeal Neoplasms / genetics*,  pathology
Meninges / drug effects*
Meningioma / genetics*,  pathology
Mice
Mice, SCID
Phenylbutyrates / pharmacology*
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
DC005985/DC/NIDCD NIH HHS; R01 DC005985/DC/NIDCD NIH HHS
Chemical
Reg. No./Substance:
0/Histone Deacetylase Inhibitors; 0/OSU-HDAC42 compound; 0/Phenylbutyrates
Comments/Corrections

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