ID | 118740 |
タイトル別表記 | 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
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著者 |
Oda, Asuka
Tokushima University
Inoue, Yusuke
Tokushima University
Maeda, Yusaku
Tokushima University
Maruhashi, Tomoko
Tokushima University
Takahashi, Mamiko
Tokushima University
Nakamura, Masafumi
Tokushima Prefecture Naruto Hospital
Hasegawa, Hiroo
Nagasaki University
Fujiwara, Hiroshi
Mie University
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キーワード | ATL
HTLV-1
IRF4
NF-κB
TAK1
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資料タイプ |
学位論文
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抄録 | 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.
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掲載誌名 |
eJHaem
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ISSN | 26886146
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出版者 | British Society for Haematology|John Wiley & Sons
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巻 | 4
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号 | 3
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開始ページ | 667
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終了ページ | 678
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発行日 | 2023-07-27
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備考 | 内容要旨・審査要旨・論文本文の公開
本論文は,著者Masahiro Ouraの学位論文として提出され,学位審査・授与の対象となっている。 |
権利情報 | 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.
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出版社版DOI | |
出版社版URL | |
フルテキストファイル | |
言語 |
eng
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著者版フラグ |
博士論文全文を含む
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文科省報告番号 | 甲第3759号
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学位記番号 | 甲医第1584号
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学位授与年月日 | 2023-10-26
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学位名 |
博士(医学)
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学位授与機関 |
徳島大学
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部局 |
病院
歯学系
薬学系
医学系
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