k-7174 and Liver-Neoplasms

Erythropoietin (Epo) gene expression is under the control of hypoxia-inducible factor 1 (HIF-1), and is negatively regulated by GATA. Interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha), which increase the binding activity of GATA and inhibit Epo promoter activity, are increased in patients with anemia of chronic disease (ACD). We previously demonstrated the ability of K-7174 (a GATA-specific inhibitor), when injected intraperitoneally, to improve Epo production that had been inhibited by IL-1beta or TNF-alpha treatment. In the present study, we examined the ability of both K-11706, which inhibits GATA and enhances HIF-1 binding activity, and K-13144, which has no effect on GATA or HIF-1 binding activity, to improve Epo production following inhibition by IL-1beta or TNF-alpha in Hep3B cells in vitro and in an in vivo mouse assay. Oral administration of K-11706 reversed the decreases in hemoglobin and serum Epo concentrations, reticulocyte counts, and numbers of erythroid colony-forming units (CFU-Es) induced by IL-1beta or TNF-alpha. These results raise the possibility of using orally administered K-11706 for treating patients with ACD.

Topics: Administration, Oral; Animals; Anisoles; Azepines; Base Sequence; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Nucleus; DNA Primers; DNA-Binding Proteins; Erythropoietin; GATA2 Transcription Factor; GATA3 Transcription Factor; Hemoglobins; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-1; Liver Neoplasms; Mice; Mice, Inbred ICR; Nuclear Proteins; Promoter Regions, Genetic; Trans-Activators; Transcription Factors; Transfection; Tumor Necrosis Factor-alpha