Different basal NAD levels determine opposite effects of poly(ADP-ribosyl)polymerase inhibitors on H2O2-induced apoptosis

Exp Cell Res. 1995 Dec;221(2):462-9. doi: 10.1006/excr.1995.1397.

Abstract

We have recently described that poly(ADP-ribosyl)-polymerase (PARP) inhibitors rescue U937 cells from apoptosis induced by 1 mM H2O2 oxidative stress; PARP activation leads to a reversible drop in NAD level, which could be blocked by PARP inhibitors (Nos-seri et al., 1994, Exp. Cell Res. 212, 367-373). A phenotypic variant of U937 is characterized by a lower basal NAD level (low NAD, LN U937, as opposed to the original high NAD, HN U937). In LN cells treatment with 1 mM H2O2, although activating PARP, does not lower NAD concentration; puzzlingly, PARP inhibitors increase (instead of decreasing, as occurs in HN cells) the extent of stress-induced apoptosis, leading to a reduced cell survival. NAD concentration could be increased in LN cells by adding nicotinamide (5-and 25-fold increase) to the culture medium. These cells (LN+) behaved as HN U937: oxidative stress induced a NAD drop, the extent of which is dependent on the cells' basal NAD level; moreover, PARP inhibitors could rescue LN+ cells from peroxide-induced apoptosis. H2O2-induced apoptosis is not triggered by NAD depletion, but instead it takes place only when NAD levels have been preserved or have recovered: on HN U937, peroxide doses (5 and 10 mM) which lead to necrosis induce an irreversible NAD drop, whereas apoptosis occurs only at lower doses, where NAD depletion is reversible; on LN cells NAD levels do not drop even upon 10 mM H2O2 treatment, and these cells die only by apoptosis; moreover, in HN cells apoptosis is not detectable until 8 h posttreatment, when NAD levels recover, whereas in LN cells, where NAD is always present, apoptosis begins to take place as early as 3 h after stress.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Benzamides / pharmacology
  • Cell Death / drug effects
  • Cell Line
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Kinetics
  • Monocytes / cytology
  • Monocytes / enzymology
  • NAD / analysis
  • NAD / metabolism*
  • Niacinamide / pharmacology
  • Oxidative Stress / physiology
  • Poly(ADP-ribose) Polymerase Inhibitors*

Substances

  • Benzamides
  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • NAD
  • Niacinamide
  • 3-aminobenzamide
  • Hydrogen Peroxide