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Downregulation of Hypoxia-related Responses by Novel Antitumor Histone Deacetylase Inhibitors in MDAMB231 Breast Cancer Cells.
MedLine Citation:
PMID:  22043993     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The tumour microenvironment is characterized by a poor circulation which results in selection of neoplastic cells that can grow or survive under hypoxic conditions. The relationship between hypoxia and histone deacetylase (HDAC) inhibitors has been previously established. In this work we evaluated the effects of novel HDAC inhibitors (the natural peptide FR235222 and three tetrapeptide analogues) in the human breast cancer cell line MDAMB231, cultured under hypoxia (2% O(2) ≈ 14 mmHg) or normoxia (20% O(2) ≈ 140 mmHg). First, we found that the novel HDAC inhibitors reduced cell proliferation in MDAMB231 cells at an extent which was similar or even higher than that exerted by the classic HDAC inhibitors trichostatin-A and suberoylanilide hydroxamic acid. More interestingly, the antiproliferative effects of the novel HDAC inhibitors were, in general, significantly higher in hypoxic cells than in normoxic controls. Hypoxic MDAMB231 cells expressed high levels of the hypoxia-inducible factor (HIF)-1α and HIF-1α-related genes, such as vascular endothelial growth factor, Bcl-2/E1B 19 kDa interacting protein-3, glucose transporter-1, carbonic anhydrase IX, as determined by Western blot analysis and qRT-PCR. Finally, we found that HIF-1α and HIF-1α-related genes were significantly downregulated by FR235222 and analogues. In conclusion, the identification of novel effects exerted by the HDAC inhibitors, characterized by a strong efficacy in inhibiting the expression of HIF-1α and its related genes, may have important implications in the pharmacological control of several tumours, including breast cancer, characterized by the presence of hypoxia, angiogenesis and metabolic derangements.
Authors:
Antonella Naldini; Irene Filippi; Elena Cini; Manuela Rodriquez; Fabio Carraro; Maurizio Taddei
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-10-25
Journal Detail:
Title:  Anti-cancer agents in medicinal chemistry     Volume:  -     ISSN:  1875-5992     ISO Abbreviation:  -     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-11-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101265649     Medline TA:  Anticancer Agents Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Physiology, University of Siena, Via Aldo Moro, 53100 SIENA, ITALY. Naldini@Unisi.it.
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