Document Detail


The combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer.
MedLine Citation:
PMID:  23042302     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Novel drugs and drug combinations are needed for the chemoprevention and treatment of cancer. We show that the histone deacetylase inhibitor vorinostat [suberoylanilide hydroxamic acid (SAHA)] and the methyl ester or ethyl amide derivatives of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me and CDDO-Ea, respectively) cooperated to inhibit the de novo synthesis of nitric oxide in RAW 264.7 macrophage-like cells and in primary mouse peritoneal macrophages. Additionally, SAHA enhanced the ability of synthetic triterpenoids to delay formation of estrogen receptor-negative mammary tumors in MMTV-polyoma middle T (PyMT) mice. CDDO-Me (50 mg/kg diet) and SAHA (250 mg/kg diet) each significantly delayed the initial development of tumors by 4 (P < 0.001) and 2 (P < 0.05) weeks, respectively, compared with the control group in the time required to reach 50% tumor incidence. CDDO-Ea (400 mg/kg diet), as a single agent, did not delay tumor development. The combination of either triterpenoid with SAHA was significantly more potent than the individual drugs for delaying tumor development, with a 7 week (P < 0.001) delay before 50% tumor incidence was reached. SAHA, alone and in combination with CDDO-Me, also significantly (P < 0.05) inhibited the infiltration of tumor-associated macrophages into the mammary glands of PyMT mice and levels of the chemokine macrophage colony-stimulating factor in primary PyMT tumor cells. In addition, SAHA and the synthetic triterpenoids cooperated to suppress secreted levels of the pro-angiogenic factor matrix metalloproteinase-9. Similar results were observed in mouse models of pancreatic and lung cancer. At concentrations that were anti-inflammatory, SAHA had no effect on histone acetylation. These studies suggest that both SAHA and triterpenoids effectively delay tumorigenesis, thereby demonstrating a promising, novel drug combination for chemoprevention.
Authors:
Kim Tran; Renee Risingsong; Darlene B Royce; Charlotte R Williams; Michael B Sporn; Patricia A Pioli; Lalji K Gediya; Vincent C Njar; Karen T Liby
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-06
Journal Detail:
Title:  Carcinogenesis     Volume:  34     ISSN:  1460-2180     ISO Abbreviation:  Carcinogenesis     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-02-25     Revised Date:  2014-04-07    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  199-210     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Proliferation
Disease Models, Animal
Drug Therapy, Combination
Enzyme-Linked Immunosorbent Assay
Histone Deacetylase Inhibitors / administration & dosage,  pharmacology*
Hydroxamic Acids / administration & dosage,  pharmacology*
Mammary Neoplasms, Experimental / prevention & control*
Mice
Triterpenes / administration & dosage,  pharmacology*
Grant Support
ID/Acronym/Agency:
P30 CA023108/CA/NCI NIH HHS; P30 GM103415/GM/NIGMS NIH HHS; R01 CA078814/CA/NCI NIH HHS; R01 CA129379/CA/NCI NIH HHS; R01 CA129379/CA/NCI NIH HHS; R01 CA78814/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/Triterpenes; 149647-78-9/vorinostat
Comments/Corrections

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


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