Fludarabine induces apoptosis of human T-cell leukemia virus type 1-infected T cells via inhibition of the nuclear factor-κB signal pathway

Abstract

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease in which the human T-cell lymphotropic virus type I (HTLV-I) has been recognized as the etiologic agent. Fludarabine is a purine analog that has demonstrated significant activity in B-cell malignancies, including chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma. This study explored the effects of fludarabine on HTLV-1-infected T cells (MT-1, -2, -4 and HUT102). Fludarabine induced growth arrest and apoptosis of these cells, as measured by 3-(4,5-dimethylithiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, cell cycle analysis and annexin V staining. Moreover, exposure of HTLV-1-infected T cells to fludarabine decreased the levels of X-inhibitor of apoptosis protein in conjunction with inhibition of nuclear factor κB (NF-κB)DNA-binding activity, as measured by Western blot analysis and electrophoretic mobility shift and reporter gene assays, respectively. Further studies found that fludarabine accumulated NF-κB and inhibitory subunit of NF-κB in cytosole in conjunction with downregulation of NF-κB in nucleus, suggesting that fludarabine blocked nuclear translocation of NF-κB. Taken together, fludarabine may be useful for treatment of individuals with ATL and other types of cancer in which NF-κB plays a role.