Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-kappa B.
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.
Ghosh
Subrata K
SK
Division of Hematology/Oncology and Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, FL 33136, USA.
Wood
Charles
C
Boise
Lawrence H
LH
Mian
Abdul M
AM
Deyev
Vadim V
VV
Feuer
Gerold
G
Toomey
Ngoc L
NL
Shank
Nicole C
NC
Cabral
Lisa
L
Barber
Glen N
GN
Harrington
William J
WJ
D000328:Adult; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D054306:Dideoxynucleotides; D015870:Gene Expression; D019288:Herpesvirus 8, Human; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D016898:Interferon-alpha / Q000627:therapeutic use; D016483:Lymphoma, AIDS-Related / Q000737:chemistry / Q000473:pathology* / Q000628:therapy / Q000821:virology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012074:Remission Induction; D053221:TNF-Related Apoptosis-Inducing Ligand; D013942:Thymine Nucleotides / Q000032:analysis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000032:analysis / Q000627:therapeutic use*
D051017:Apoptosis Regulatory Proteins; D054306:Dideoxynucleotides; D020672:I-kappa B Proteins; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D013942:Thymine Nucleotides; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D015215:Zidovudine; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human