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

Autor: Nicole C. Shank, Subrata K. Ghosh, Abdul M. Mian, Vadim Deyev, Ngoc L. Toomey, Lawrence H. Boise, William J. Harrington, Glen N. Barber, Gerold Feuer, Lisa Cabral, Charles E. Wood
Rok vydání: 2003
Předmět:
Adult
Male
viruses
Immunology
Gene Expression
Alpha interferon
Apoptosis
IκB kinase
Protein Serine-Threonine Kinases
Biology
Biochemistry
TNF-Related Apoptosis-Inducing Ligand
chemistry.chemical_compound
Transactivation
NF-KappaB Inhibitor alpha
immune system diseases
Tumor Cells
Cultured
medicine
Humans
Thymine Nucleotides
RNA
Messenger
Phosphorylation
Lymphoma
AIDS-Related
Membrane Glycoproteins
Tumor Necrosis Factor-alpha
Remission Induction
NF-kappa B
Interferon-alpha
virus diseases
NF-κB
Cell Biology
Hematology
biochemical phenomena
metabolism
and nutrition
medicine.disease
Virology
I-kappa B Kinase
chemistry
Cell culture
Herpesvirus 8
Human
Cancer research
I-kappa B Proteins
Tumor necrosis factor alpha
Primary effusion lymphoma
Apoptosis Regulatory Proteins
Zidovudine
Dideoxynucleotides
Zdroj: Blood. 101:2321-2327
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2002-08-2525
Popis: The survival of viral mediated lymphomas depends upon constitutive nuclear factor kappa B (NF-kappaB) 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-alpha) 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-alpha; however, signals transduced by death receptors may also activate an antiapoptotic response mediated by NF-kappaB. In both the primary tumor cells from our patient and PEL cell lines, AZT selectively blocked nuclear entry of the NF-kappaB heterodimer p50 and p65, an effect not seen with other nonthymidine antiviral nucleosides. AZT monophosphate, the principal intracellular metabolite, inhibited phosphorylation and degradation of IkappaB by the IkappaB kinase complex. AZT- and IFN-alpha-mediated apoptosis was blocked by expression and nuclear localization of an IkappaB-resistant form of NF-kappaB (the p50 subunit linked to the transactivation domain of herpes simplex virus VP16). The proapoptotic effect of AZT and IFN-alpha in PEL occurs through the concomitant activation of TRAIL and blockade of NF-kappaB and represents a novel antiviral therapy for a virally mediated tumor.
Databáze: OpenAIRE
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