Bay 11-7082 inhibits transcription factor NF-kappa B and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells

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Abstract
Human T-cell leukemia virus type I (HTLV-I) is the causative agent of an aggressive form of leukemia designated adult T-cell leukemia (ATL). We have previously demonstrated that all T-cell lines infected with HTLV-I and primary leukemic cells from ATL patients display constitutively high activity of transcription factor NF-κB. In this study we showed that Bay 11-7082, an inhibitor of NF-κB, induced apoptosis of HTLV-I–infected T-cell lines but only negligible apoptosis of HTLV-I–negative T cells. Bay 11-7082 rapidly and efficiently reduced the DNA binding of NF-κB in HTLV-I–infected T-cell lines and down-regulated the expression of the antiapoptotic gene, Bcl-xL, regulated by NF-κB, whereas it had little effect on the DNA binding of another transcription factor, AP-1. Although the viral protein Tax is an activator of NF-κB, Bay 11-7082–induced apoptosis of HTLV-I–infected cells was not associated with reduced expression of Tax. Furthermore, Bay 11-7082– induced apoptosis of primary ATL cells was more prominent than that of normal peripheral blood mononuclear cells, and apoptosis of these cells was also associated with down-regulation of NF-κB activity. Our results indicate that NF-κB plays a crucial role in the pathogenesis and survival of HTLV-I–infected leukemic cells and that it is a suitable target for the prevention and treatment of ATL.

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