title: An IκB kinase 2 inhibitor IMD-0354 suppresses the survival of adult T-cell leukemia cells.
abstract: Adult T-cell leukemia (ATL) is a fatal T-cell malignancy associated with human T-cell leukemia virus type I infection. The aberrant expression of nuclear factor-κB (NF-κB) is considered to contribute to the malignant phenotype and chemo-resistance of ATL cells. Because of the poor prognosis of ATL, the development of new therapeutic strategies is direly needed. In the present study, we show that an IκB kinase 2 (IKK2) inhibitor, IMD-0354, efficiently inhibits the survival of CD4(+) CD25(+) primary ATL cells and prevents the growth of or induces apoptosis of patient-derived ATL cell lines. Assays of transcription with integrated forms of reporter genes revealed that IMD-0354 suppresses NF-κB-dependent transcriptional activity. Moreover, the daily administration of IMD-0354 prevents the growth of tumors in mice inoculated with ATL cells. Our results suggest that targeting IKK2 with a small molecule inhibitor, such as IMD-0354, is an attractive strategy for the treatment of ATL.
authors.affiliation: Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Uota
authors.forename: Md
authors.initials: M
authors.lastname: Zahidunnabi Dewan
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Saitoh
authors.forename: Susumu
authors.initials: S
authors.lastname: Muto
authors.forename: Akiko
authors.initials: A
authors.lastname: Itai
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaoka
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D016328:NF-kappa B; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D008156:Luciferases; D051550:I-kappa B Kinase; D020169:Caspases