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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1558-1565
RED CELLS
Epolones induce erythropoietin expression via hypoxia-inducible
factor-1 activation
Roger M. Wanner,
Patrick Spielmann,
Deborah M. Stroka,
Gieri Camenisch,
Isabelle Camenisch,
Annette Scheid,
David R. Houck,
Christian Bauer,
Max Gassmann, and
Roland H. Wenger
From the Institute of Physiology, University of
Zürich-Irchel, Zürich, Switzerland; and OSI
Pharmaceuticals, MYCOsearch, Durham, NC.
Induction of erythropoietin (Epo) expression under hypoxic
conditions is mediated by the heterodimeric hypoxia-inducible factor (HIF)-1. Following binding to the 3' hypoxia-response element (HRE) of
the Epo gene, HIF-1 markedly enhances Epo transcription. To facilitate
the search for HIF-1 (ant)agonists, a hypoxia-reporter cell line
(termed HRCHO5) was constructed containing a stably integrated
luciferase gene under the control of triplicated heterologous HREs.
Among various agents tested, we identified a class of substances called
epolones, which induced HRE-dependent reporter gene activity in HRCHO5
cells. Epolones are fungal products known to induce Epo expression in
hepatoma cells. We found that epolones (optimal concentration 4-8 µmol/L) potently induce HIF-1 protein accumulation and nuclear
translocation as well as HIF-1 DNA binding and reporter gene
transactivation. Interestingly, the activity of a compound related to
the fungal epolones, ciclopirox olamine (CPX), was blocked after
addition of ferrous iron. This suggests that CPX might interfere with
the putative heme oxygen sensor, as has been proposed for the iron
chelator deferoxamine mesylate (DFX). However, about 10-fold higher
concentrations of DFX (50-100 µmol/L) than CPX were required to
maximally induce reporter gene activity in HRCHO5 cells. Moreover,
structural, functional, and spectrophotometric data imply a
chelator:iron stoichiometry of 1:1 for DFX but 3:1 for CPX. Because the
iron concentration in the cell culture medium was determined to be 16 µmol/L, DFX but not CPX function can be explained by complete
chelation of medium iron. These results suggest that the lipophilic
epolones might induce HIF-1 by intracellular iron chelation.
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