An IκB kinase 2 inhibitor IMD‐0354 suppresses the survival of adult T‐cell leukemia cells

• Published in: Cancer science Vol. 103; no. 1; pp. 100 - 106
• Main Authors: Uota, Shin, Zahidunnabi Dewan, Md, Saitoh, Yasunori, Muto, Susumu, Itai, Akiko, Utsunomiya, Atae, Watanabe, Toshiki, Yamamoto, Naoki, Yamaoka, Shoji
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2012; John Wiley & Sons, Inc
• Subjects: Adult; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Benzamides - pharmacology; Blotting, Western; Cancer; Case-Control Studies; Caspases - metabolism; CD25 antigen; CD4 antigen; Cell Cycle - drug effects; Cell Proliferation - drug effects; Cell survival; Cells, Cultured; Cytokines; Diabetes; Enzyme inhibitors; Enzyme Inhibitors - pharmacology; Flow Cytometry; Human T-lymphotropic virus 1; Humans; I Kappa B kinase; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - metabolism; IKK2 protein; Infection; Kinases; Leukemia; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - metabolism; Leukemia-Lymphoma, Adult T-Cell - pathology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Luciferases - metabolism; Lymphocytes T; Malignancy; Mice; Mice, Inbred NOD; Mice, SCID; NF- Kappa B protein; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Original; Patients; Phenotypes; Prognosis; Review boards; Transcription; Tumors; United States > US; Japan
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2011.02110.x

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. (Cancer Sci 2012; 103: 100–106)