Inhibition of HIF-1 alpha using a novel Iron facilitator LS5-81 and its anti-cancer activity in hepatocellular carcinoma

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Targeting HIF-1a has been of therapeutic interest. In normoxic conditions, HIF-1a is hydroxylated by prolylhydroxylases (PHDs), which require iron for its activity. The tumor suppressor protein VHL binds to the hydroxylated HIF-1a, which is then degraded by proteasomes. We focused on the degradation machinery of HIF-1a mediated by PHDs. In this study, we aimed to inhibit the expression of HIF-1a protein and growth of hepatocellular carcinoma (HCC) using the iron-facilitating activity of LS5-81. In the human HCC cell lines, a combination of LS5-81 and iron inhibited HIF-1a protein expression. A mutated HIF-1a protein, which has proline residues that were replaced with alanine and transfected into HEK293 cells, was not affected by the combination of LS5-81 and iron. Furthermore, LS5-81 inhibited tumor growth of mouse HCC models. These results indicate that LS5-81 inhibits HIF-1a expression through prolyl-hydroxylation of HIF-1a and might have a therapeutic effect in the treatment of HCC.