Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease.
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.
Division of Hematology, Institute of Clinical Medicine, Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Yoko
Y
Nakano
Shigehiko
S
Imagawa
Ken
K
Matsumoto
Christian
C
Stockmann
Naoshi
N
Obara
Norio
N
Suzuki
Takeshi
T
Doi
Tatsuhiko
T
Kodama
Satoru
S
Takahashi
Toshiro
T
Nagasawa
Masayuki
M
Yamamoto
D000284:Administration, Oral; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D004921:Erythropoietin / Q000235:genetics*; D050989:GATA2 Transcription Factor; D050990:GATA3 Transcription Factor; D006454:Hemoglobins / Q000037:antagonists & inhibitors / Q000187:drug effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007375:Interleukin-1 / Q000494:pharmacology; D008113:Liver Neoplasms; D051379:Mice; D008813:Mice, Inbred ICR; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000840:Anisoles; D001381:Azepines; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C494712:Gata2 protein, mouse; C494748:Gata3 protein, mouse; C497442:HIF1A protein, human; D006454:Hemoglobins; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007375:Interleukin-1; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; C410337:K 7174