Bay 11-7082 inhibits transcription factor NF-kappaB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells.
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-kappaB. In this study we showed that Bay 11-7082, an inhibitor of NF-kappaB, 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-kappaB in HTLV-I-infected T-cell lines and down-regulated the expression of the antiapoptotic gene, Bcl-x(L), regulated by NF-kappaB, 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-kappaB, 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-kappaB activity. Our results indicate that NF-kappaB 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.
Mori
Naoki
N
Department of Preventive Medicine and AIDS Research, Institute of Tropical Medicine, Nagasaki University, Japan. n-mori@med.u-ryukyu.ac.jp
Yamada
Yasuaki
Y
Ikeda
Shuichi
S
Yamasaki
Yoshihiro
Y
Tsukasaki
Kunihiro
K
Tanaka
Yuetsu
Y
Tomonaga
Masao
M
Yamamoto
Naoki
N
Fujii
Masahiro
M
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects / Q000302:isolation & purification*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009570:Nitriles; D009930:Organic Chemicals; D013450:Sulfones; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D014407:Tumor Cells, Cultured
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D016328:NF-kappa B; D009570:Nitriles; D009930:Organic Chemicals; D013450:Sulfones