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ID 118740
Title Alternative
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
Author
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
Keywords
ATL
HTLV-1
IRF4
NF-κB
TAK1
Content Type
Thesis or Dissertation
Description
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.
Journal Title
eJHaem
ISSN
26886146
Publisher
British Society for Haematology|John Wiley & Sons
Volume
4
Issue
3
Start Page
667
End Page
678
Published Date
2023-07-27
Remark
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。
Rights
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.
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3759号
Diploma Number
甲医第1584号
Granted Date
2023-10-26
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Oral Sciences
Pharmaceutical Sciences
Medical Sciences