title: Azidothymidine inhibits NF-kappaB and induces Epstein-Barr virus gene expression in Burkitt lymphoma.
abstract: The antiviral compound azidothymidine (AZT), alone or in combination with other agents, induces apoptosis in early-passage, Epstein-Barr virus-positive Burkitt lymphoma (EBV+ BL) lines and has clinical activity in EBV+ BL. We report here a mechanism of AZT's antitumor activity. The nuclei of these cells contain activated nuclear factor-kappaB (NF-kappaB) subunits p50, c-Rel, RelB, and p52, but not p65. Treatment of primary EBV+ BL lines with AZT inhibited NF-kappaB within 1 to 2 hours. This was followed by up-regulation of EBV gene expression including viral thymidine kinase (vTK) and apoptosis. Subclones of EBV+ BL cells that demonstrated activated p65 were resistant to AZT. In EBV+ BLs, AZT but not ganciclovir (GCV) was highly phosphorylated to its monophosphate form (AZT-MP). Phosphorylation, as well as apoptosis, was markedly enhanced in the presence of hydroxyurea. AZT inhibits NF-kappaB and up-regulates EBV gene expression in primary EBV+ BLs. AZT with hydroxyurea may represent an inexpensive, targeted regimen for endemic BL.
authors.affiliation: Department of Dermatology, Medical College, University of Miyazaki, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Subrata K
authors.initials: SK
authors.lastname: Ghosh
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Ramos
authors.forename: Abdul M
authors.initials: AM
authors.lastname: Mian
authors.forename: Ngoc L
authors.initials: NL
authors.lastname: Toomey
authors.forename: Lisa
authors.initials: L
authors.lastname: Cabral
authors.forename: Denise
authors.initials: D
authors.lastname: Whitby
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.forename: Dirk P
authors.initials: DP
authors.lastname: Dittmer
authors.forename: William J
authors.initials: WJ
authors.lastname: Harrington
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000188:drug therapy*; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016679:Genome, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D018894:Reverse Transcriptase Inhibitors; D051996:Transcription Factor RelA; D015215:Zidovudine; D006918:Hydroxyurea