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A novel HSP90 inhibitor, 17-DMAG, induces Tax down-regulation and its oral administration to ATL-model mice intervenes against the infiltration property of the ATL-like lymphocytes and provides extended survival period

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Retrovirology201411 (Suppl 1) :P44

  • Published:


  • Survival Period
  • HSP90 Inhibitor
  • Client Protein
  • Transformed Cell Line
  • Proper Interaction

In the peripheral blood leukocytes (PBL) infected with human T-cell leukemia virus type-1 (HTLV-1), which causes HTLV-1 associated diseases including adult T-cell leukemia (ATL), HTLV-1 associated myelopathy (HAM) and HTLV-1 uveitis (HU), NF-κB-mediated anti-apoptotic signals or inflammatory signals are constitutively activated primarily by the HTLV-1 encoded oncoprotein Tax.

Tax interacts with the I-κB kinase regulatory subunit, NEMO, to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, Hsp90, and its co-chaperone Cdc37. The antibiotic geldanamycin (GA) inhibits Hsp90’s ATP binding for its proper interaction with client proteins. Administration of a novel water soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG) to Tax-expressing ATL transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines while this treatment has no apparent effects on normal PBLs. 17-DMAG also down-regulated Tax-mediated intracellular signals including activation of NF-κB, AP-1 or HTLV1-LTR in Tax-transfected HEK293 cells.

Oral administration of 17-DMAG to ATL-model mice xenografted with lymphomatous transgenic Lck-Tax cells or HTLV-1 producing tumor cells dramatically attenuated the aggressive infiltration into multiple organs, viral replication and improved survival periods. These observations identified 17-DMAG as a promising candidate for prevention of ATL progression.

Authors’ Affiliations

Department of Infectious Diseases, Oita University, Faculty of Medicine, Japan
Department of Pathology, National Institute of Infectious Diseases, Japan
Department of Microbiology, Kansai Medical University, Japan
Department of Hematology, Ibaragi Pref. Central Hospital, Japan
Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
Department of Immunology, Graduate School of Medicine University of Ryukyus, Japan
Department of Molecular Pathobiology, Hokkaido University Research Center Zoonosis Control, Japan
Department of Medicine and Microbiology, Centre Research Infectious Disease, Conway Institute Biomolecular Biomedical Research University, Coll. Dublin, Ireland
Department of Biotechnology, Maebashi Institute Technology, Japan
Laboratory and Molecular Microbiology, National Institutes of Health, USA
Department of Hematology, Oita University, Faculty of Medicine, Japan
Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Japan


© Ikebe et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.