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.