Azidothymidine inhibits NF-kappaB and induces Epstein-Barr virus gene expression in Burkitt lymphoma.
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.
Kurokawa
Motoki
M
Department of Dermatology, Medical College, University of Miyazaki, Japan.
Ghosh
Subrata K
SK
Ramos
Juan Carlos
JC
Mian
Abdul M
AM
Toomey
Ngoc L
NL
Cabral
Lisa
L
Whitby
Denise
D
Barber
Glen N
GN
Dittmer
Dirk P
DP
Harrington
William J
WJ
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*
D016328:NF-kappa B; D018894:Reverse Transcriptase Inhibitors; D051996:Transcription Factor RelA; D015215:Zidovudine; D006918:Hydroxyurea