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Abstract
The tumor microenvironment is characterized by a poor circulation which results in the 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 analogs) in the human breast cancer cell line MDAMB231, cultured under hypoxia (2% O2 ≉ 14 mmHg) or normoxia (20% O2 ≉ 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 analogs. 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 tumors, including breast cancer, characterized by the presence of hypoxia, angiogenesis and metabolic derangements.
Keywords: Angiogenesis, Anticancer drugs, Breast cancer, Carbonic anhydrase, Cell proliferation, Epigenetic regulation, Gene expression, Hypoxia, Histone, deacetylase, inhibitors, Glucose transporter, Hypoxia-inducible factor (HIF)-1alpha, Histone deacetylase inhibitors, Metabolism, Transcription factors, Tumor microenvironment, Vascular endothelial growth factor
Anti-Cancer Agents in Medicinal Chemistry
Title:Downregulation of Hypoxia-related Responses by Novel Antitumor Histone Deacetylase Inhibitors in MDAMB231 Breast Cancer Cells
Volume: 12 Issue: 4
Author(s): Antonella Naldini, Irene Filippi, Elena Cini, Manuela Rodriquez, Fabio Carraro and Maurizio Taddei
Affiliation:
Keywords: Angiogenesis, Anticancer drugs, Breast cancer, Carbonic anhydrase, Cell proliferation, Epigenetic regulation, Gene expression, Hypoxia, Histone, deacetylase, inhibitors, Glucose transporter, Hypoxia-inducible factor (HIF)-1alpha, Histone deacetylase inhibitors, Metabolism, Transcription factors, Tumor microenvironment, Vascular endothelial growth factor
Abstract: The tumor microenvironment is characterized by a poor circulation which results in the 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 analogs) in the human breast cancer cell line MDAMB231, cultured under hypoxia (2% O2 ≉ 14 mmHg) or normoxia (20% O2 ≉ 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 analogs. 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 tumors, including breast cancer, characterized by the presence of hypoxia, angiogenesis and metabolic derangements.
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Cite this article as:
Naldini Antonella, Filippi Irene, Cini Elena, Rodriquez Manuela, Carraro Fabio and Taddei Maurizio, Downregulation of Hypoxia-related Responses by Novel Antitumor Histone Deacetylase Inhibitors in MDAMB231 Breast Cancer Cells , Anti-Cancer Agents in Medicinal Chemistry 2012; 12 (4) . https://dx.doi.org/10.2174/187152012800228706
DOI https://dx.doi.org/10.2174/187152012800228706 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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