Fludarabine induces apoptosis of human T-cell leukemia virus type 1-infected T cells via inhibition of the nuclear factor-kappaB signal pathway.
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 kappaB (NF-kappaB)/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-kappaB and inhibitory subunit of NF-kappaB in cytosole in conjunction with downregulation of NF-kappaB in nucleus, suggesting that fludarabine blocked nuclear translocation of NF-kappaB. Taken together, fludarabine may be useful for treatment of individuals with ATL and other types of cancer in which NF-kappaB plays a role.
Nishioka
C
C
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
Ikezoe
T
T
Yang
J
J
Koeffler
H P
HP
Taguchi
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000821:virology*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D016328:NF-kappa B; D014740:Vidarabine; C024352:fludarabine