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

• Material Type: 博士論文
• Title: Therapeutic efficacy of the resorcylic acid lactone LL-Z1640-2 for adult T-cell leukaemia/lymphoma
• Author/Editor: Oura, Masahiro; Harada, Takeshi; Oda, Asuka; Teramachi, Jumpei; Nakayama, Atsushi; Sumitani, Ryohei; Inoue, Yusuke; Maeda, Yusaku; Sogabe, Kimiko; Maruhashi, Tomoko; Takahashi, Mamiko; Fujii, Shiro; Nakamura, Shingen; Miki, Hirokazu; Nakamura, Masafumi; Hara, Tomoyo; Yamagami, Hiroki; Kurahashi, Kiyoe; Endo, Itsuro; Hasegawa, Hiroo; Fujiwara, Hiroshi; Abe, Masahiro
• Author Heading: Oura, Masahiro; Harada, Takeshi; Oda, Asuka; Teramachi, Jumpei; Nakayama, Atsushi; Sumitani, Ryohei; Inoue, Yusuke; Maeda, Yusaku; Sogabe, Kimiko; Maruhashi, Tomoko; Takahashi, Mamiko; Fujii, Shiro; Nakamura, Shingen; Miki, Hirokazu; Nakamura, Masafumi; Hara, Tomoyo; Yamagami, Hiroki; Kurahashi, Kiyoe; Endo, Itsuro; Hasegawa, Hiroo; Fujiwara, Hiroshi; Abe, Masahiro
• Publication, Distribution, etc.: British Society for Haematology|John Wiley & Sons
• Publication Date: 2023-07-27
• Publication Date (W3CDTF): 2023-07-27
• Alternative Title: レゾルシル酸ラクトンLL-Z1640-2の成人T細胞白血病/リンパ腫に対する治療効果
• Periodical title: eJHaem
• No. or year of volume/issue: 4 3
• Volume: 4
• Issue: 3
• Pages: 667-678
• ISSN (Periodical Title): ISSN : 2688-6146
• Degree grantor/type: 徳島大学
• Date Granted: 2023-10-26
• Dissertation Number: 甲第3759号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: ATL; HTLV-1; IRF4; NF-κB; TAK1
• Target Audience: 一般
• Note (General): 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 IRF4 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.
• Access Restrictions: インターネット公開
• Rights (production): This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
• Related Material (DOI): 10.1002/jha2.758
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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http://repo.lib.tokushima-u.ac.jp/files/public/11/118740/20231115111111986326/k3759_abstract.pdf fulltext

http://repo.lib.tokushima-u.ac.jp/files/public/11/118740/2023111511111295873/k3759_review.pdf fulltext

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