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Apoptosis

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.

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Acknowledgements

This work was supported in part by Grant-in-Aid from the Ministry of Education, Culture Sports, Science, and Technology of Japan (to T.I), Public Trust Haraguchi Memorial Cancer Research Fund (to T.I) and Uehara Memorial Foundation (to T.I). HPK is supported by NIH grants as well as the Inger Fund.

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Correspondence to T Ikezoe.

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Nishioka, C., Ikezoe, T., Yang, J. et al. Fludarabine induces apoptosis of human T-cell leukemia virus type 1-infected T cells via inhibition of the nuclear factor-κB signal pathway. Leukemia 21, 1044–1049 (2007). https://doi.org/10.1038/sj.leu.2404622

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