Therapeutic efficacy of the resorcylic acid lactone LL‐Z1640‐2 for adult T‐cell leukaemia/lymphoma

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  • Masahiro Oura
    Department of Hematology Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Takeshi Harada
    Department of Hematology Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Asuka Oda
    Department of Hematology Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Jumpei Teramachi
    Department of Oral Function and Anatomy Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan
  • Atsushi Nakayama
    Graduate School of Science Osaka Metropolitan University Osaka Japan
  • Ryohei Sumitani
    Department of Hematology Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Yusuke Inoue
    Department of Hematology Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Yusaku Maeda
    Department of Hematology Tokushima University Hospital Tokushima Japan
  • Kimiko Sogabe
    Department of Hematology Tokushima University Hospital Tokushima Japan
  • Tomoko Maruhashi
    Department of Hematology Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Mamiko Takahashi
    Department of Hematology Tokushima University Hospital Tokushima Japan
  • Shiro Fujii
    Department of Hematology Tokushima University Hospital Tokushima Japan
  • Shingen Nakamura
    Department of Community Medicine and Medical Science Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Hirokazu Miki
    Division of Transfusion Medicine and Cell Therapy Tokushima University Hospital Tokushima Japan
  • Masafumi Nakamura
    Department of Internal Medicine Tokushima Prefecture Naruto Hospital Tokushima Japan
  • Tomoyo Hara
    Department of Hematology Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Hiroki Yamagami
    Department of Hematology Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Kiyoe Kurahashi
    Department of Community Medicine for Respirology Hematology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Itsuro Endo
    Department of Bioregulatory Sciences Tokushima University Graduate School of Biomedical Sciences Tokushima Japan
  • Hiroo Hasegawa
    Department of Laboratory Medicine Nagasaki University Hospital Nagasaki Japan
  • Hiroshi Fujiwara
    Department of Personalized Cancer Immunotherapy Mie University Graduate School of Medicine Mie Japan
  • Masahiro Abe
    Department of Hematology Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan

Description

<jats:title>Abstract</jats:title><jats:p>Adult T‐cell leukaemia/lymphoma (ATL) remains incurable. The NF‐κB and interferon regulatory factor 4 (IRF4) signalling pathways are among the critical survival pathways for the progression of ATL. TGF‐β‐activated kinase 1 (TAK1), an IκB kinase‐activating kinase, triggers the activation of NF‐κB. The resorcylic acid lactone LL‐Z1640‐2 is a potent irreversible inhibitor of TAK1/extracellular signal‐regulated kinase 2 (ERK2). We herein examined the therapeutic efficacy of LL‐Z1640‐2 against ATL. LL‐Z1640‐2 effectively suppressed the in vivo growth of ATL cells. It induced in vitro apoptosis and inhibited the nuclear translocation of p65/RelA in ATL cells. The knockdown of <jats:italic>IRF4</jats:italic> strongly induced ATL cell death while downregulating MYC. LL‐Z1640‐2 as well as the NF‐κB inhibitor BAY11‐7082 decreased the expression of IRF4 and MYC at the protein and mRNA levels, indicating the suppression of the NF‐κB‐IRF4‐MYC axis. The treatment with LL‐Z1640‐2 also mitigated the phosphorylation of p38 MAPK along with the expression of CC chemokine receptor 4. Furthermore, the inhibition of STAT3/5 potentiated the cytotoxic activity of LL‐Z1640‐2 against IL‐2‐responsive ATL cells in the presence of IL‐2. Therefore, LL‐Z1640‐2 appears to be an effective treatment for ATL. Further studies are needed to develop more potent compounds that retain the active motifs of LL‐Z1640‐2.</jats:p>

Journal

  • eJHaem

    eJHaem 4 (3), 667-678, 2023-07-27

    Wiley

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