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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-08-2525.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2321-2327
NEOPLASIA
Potentiation of TRAIL-induced apoptosis in primary effusion
lymphoma through azidothymidine-mediated inhibition of
NF- B
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, and
William J. Harrington Jr
From the Division of Hematology/Oncology and Department
of Microbiology and Immunology, Sylvester Comprehensive Cancer Center,
University of Miami School of Medicine, FL; Nebraska Center for
Virology and the School of Biological Sciences, University of
Nebraska-Lincoln; and Department of Microbiology and Immunology, State
University of New York Upstate Medical University, Syracuse, NY.
The survival of viral mediated lymphomas depends upon constitutive
nuclear factor kappa B (NF- B) 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- ) 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-; however, signals
transduced by death receptors may also activate an antiapoptotic
response mediated by NF-B. In both the primary tumor cells from our
patient and PEL cell lines, AZT selectively blocked nuclear entry of
the NF-B heterodimer p50 and p65, an effect not seen with other
nonthymidine antiviral nucleosides. AZT monophosphate, the principal
intracellular metabolite, inhibited phosphorylation and degradation of
IB by the IB kinase complex. AZT- and IFN--mediated apoptosis
was blocked by expression and nuclear localization of an
IB-resistant form of NF-B (the p50 subunit linked to the
transactivation domain of herpes simplex virus VP16). The proapoptotic
effect of AZT and IFN- in PEL occurs through the concomitant
activation of TRAIL and blockade of NF-B and represents a novel
antiviral therapy for a virally mediated tumor.
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