Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-κB

Subrata K. Ghosh, Charles Wood, Lawrence H. Boise, Abdul M. Mian, Vadim V. Deyev, Gerold Feuer, Ngoc L. Toomey, Nicole C. Shank, Lisa Cabral, Glen N. Barber, William J. Harrington

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

The survival of viral mediated lymphomas depends upon constitutive nuclear factor kappa B (NF-κB) activity. AIDS-related human herpesvirus type 8-associated primary effusion lymphoma (PEL) responds poorly to chemotherapy and is almost invariably fatal. We have previously demonstrated that the antiviral combination of interferon alpha (IFN-α) and azidothymidine (AZT) induces apoptosis in PEL cell lines. We therefore used these agents as therapy for an AIDS patient with PEL. The patient had a dramatic response, with complete resolution of his malignant effusion in 5 days. In PEL cells, the death receptor ligand known as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is markedly up-regulated by IFN-α; however, signals transduced by death receptors may also activate an antiapoptotic response mediated by NF-κB. In both the primary tumor cells from our patient and PEL cell lines, AZT selectively blocked nuclear entry of the NF-κB heterodimer p50 and p65, an effect not seen with other nonthymidine antiviral nucleosides. AZT monophosphate, the principal intracellular metabolite, inhibited phosphorylation and degradation of IκB by the IκB kinase complex. AZT- and IFN-α-mediated apoptosis was blocked by expression and nuclear localization of an IκB-resistant form of NF-κB (the p50 subunit linked to the transactivation domain of herpes simplex virus VP16). The proapoptotic effect of AZT and IFN-α in PEL occurs through the concomitant activation of TRAIL and blockade of NF-κB and represents a novel antiviral therapy for a virally mediated tumor.

Original languageEnglish (US)
Pages (from-to)2321-2327
Number of pages7
JournalBlood
Volume101
Issue number6
DOIs
StatePublished - Mar 15 2003

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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