Inhibitors of ADP-ribose polymerase decrease the resistance of HER2/neu-expressing cancer cells to the cytotoxic effects of tumor necrosis factor.
Four human ovarian and breast tumor lines expressing the HER2/neu oncogene were resistant to the cytotoxic and DNA-degradative activity of TNF. The resistance was not associated with altered TNF receptor function because Scatchard analysis of 125I-rTNF binding to HER2/neu-expressing target cells revealed receptors with normal binding parameters. Furthermore, the TNF receptors on the resistant lines were capable of signal transduction as evidence by the induction of ADP-ribose polymerase activity and MHC expression. TNF resistance was not reversed by coincubation with drugs that interrupted the glutathione redox cycle. In addition, although coincubation of HER2/neu-expressing targets with cycloheximide resulted in significant TNF-induced lysis, when compared to HER2/neu-nonexpressing targets similarly treated with cycloheximide, a significant relative resistance was still present. To investigate the role of ADP-ribosylation in the resistance of these targets, we used nontoxic concentrations of two inhibitors of ADP-ribose polymerase, 3-aminobenzamide, and nicotinamide. Both inhibitors completely reversed the resistance of HER2/neu-expressing targets to TNF-mediated cytotoxicity and DNA injury in a concentration-dependent fashion. These inhibitors of ADP-ribose polymerase did not act by down-regulating expression of HER2/neu oncogenes. In contrast, aminobenzamide and nicotinamide significantly diminished TNF-induced cytotoxicity of L929 targets. These data suggest that the activity of ADP-ribose polymerase may play a pivotal role in determining the fate of the target cell during exposure to TNF.
Lichtenstein
A
A
Department of Medicine, V.A. Wadsworth-UCLA Medical Center.
Gera
J F
JF
Andrews
J
J
Berenson
J
J
Ware
C F
CF
D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004249:DNA Damage; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D009856:Oncogene Proteins, Viral; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha