imd-0354 and Leukemia-Lymphoma--Adult-T-Cell

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.

Topics: Adult; Animals; Apoptosis; Benzamides; Blotting, Western; Case-Control Studies; Caspases; Cell Cycle; Cell Proliferation; Cells, Cultured; Enzyme Inhibitors; Flow Cytometry; Humans; I-kappa B Kinase; Leukemia-Lymphoma, Adult T-Cell; Leukocytes, Mononuclear; Luciferases; Mice; Mice, Inbred NOD; Mice, SCID; NF-kappa B