Inhibition of NF-κB activation sensitizes U937 cells to 30-azido-30-deoxythymidine induced apoptosis

C. Matteucci, A. Minutolo, E. Balestrieri, F. Marino-Merlo, P. Bramanti, E. Garaci, B. MacChi, A. Mastino

Research output: Contribution to journalArticle

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Abstract

In this study, we investigated molecular mechanisms underlying low susceptibility to apoptosis induced by the nucleoside analog azidothymidine (AZT) and the role of nuclear factor-κB (NF-κB) activation in these phenomena. A preliminary screening in different cell lines indicated U937 monocytic cell line as suitable to this purpose. Treatment of U937 cells even with suprapharmacological concentrations of AZT induced only moderate levels of apoptosis. Surprisingly, SuperArray analysis showed that AZT induced the transcriptional activity of both pro- and anti-apoptotic genes. Interestingly, moreover, several genes upregulated by AZT were NF-κB related. In fact, AZT, after an initial inhibition of NF-κB activation with respect to control, induced a transient, but consistent, increase in NF-κB-binding activity. Inhibition of NF-κB activation in U937 cells, stably transfected with a dominant-negative IjBa or by pharmacological treatment, sensitized them to apoptosis induced by AZT and impaired the upregulation of anti-apoptotic genes in response to AZT treatment, with respect to control cells. These results indicate that NF-κB activation by AZT has a role in protecting target cells from apoptotic cell death, improving our understanding of the toxicology and the therapeutic usage of this drug.

Original languageEnglish
Article numbere81
JournalCell Death and Disease
Volume1
Issue number10
DOIs
Publication statusPublished - Oct 2010

Fingerprint

U937 Cells
Zidovudine
Thymidine
Apoptosis
Genes
Cell Line
Nucleosides
Toxicology
Cell Death
Up-Regulation
Pharmacology

Keywords

  • Apoptosis
  • AZT
  • Chemotherapy
  • DNA damage
  • NF-κB

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Inhibition of NF-κB activation sensitizes U937 cells to 30-azido-30-deoxythymidine induced apoptosis. / Matteucci, C.; Minutolo, A.; Balestrieri, E.; Marino-Merlo, F.; Bramanti, P.; Garaci, E.; MacChi, B.; Mastino, A.

In: Cell Death and Disease, Vol. 1, No. 10, e81, 10.2010.

Research output: Contribution to journalArticle

Matteucci, C. ; Minutolo, A. ; Balestrieri, E. ; Marino-Merlo, F. ; Bramanti, P. ; Garaci, E. ; MacChi, B. ; Mastino, A. / Inhibition of NF-κB activation sensitizes U937 cells to 30-azido-30-deoxythymidine induced apoptosis. In: Cell Death and Disease. 2010 ; Vol. 1, No. 10.
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