학술논문
Therapeutic efficacy of the resorcylic acid lactone LL‐Z1640‐2 for adult T‐cell leukaemia/lymphoma
Document Type
article
Author
Masahiro Oura; Takeshi Harada; Asuka Oda; Jumpei Teramachi; Atsushi Nakayama; Ryohei Sumitani; Yusuke Inoue; Yusaku Maeda; Kimiko Sogabe; Tomoko Maruhashi; Mamiko Takahashi; Shiro Fujii; Shingen Nakamura; Hirokazu Miki; Masafumi Nakamura; Tomoyo Hara; Hiroki Yamagami; Kiyoe Kurahashi; Itsuro Endo; Hiroo Hasegawa; Hiroshi Fujiwara; Masahiro Abe
Source
eJHaem, Vol 4, Iss 3, Pp 667-678 (2023)
Subject
Language
English
ISSN
2688-6146
Abstract
Abstract 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.