Regulation of apoptosis/necrosis execution in cadmium-treated human promonocytic cells under different forms of oxidative stress

Apoptosis. 2006 May;11(5):673-86. doi: 10.1007/s10495-006-5879-3.


Pulse-treatment of U-937 human promonocytic cells with cadmium chloride followed by recovery caused caspase-9/caspase-3-dependent, caspase-8-independent apoptosis. However, pre-incubation with the glutathione (GSH)-suppressing agent DL-buthionine-(S,R)-sulfoximine (cadmium/BSO), or co-treatment with H2O2 (cadmium/H2O2), switched the mode of death to caspase-independent necrosis. The switch from apoptosis to necrosis did not involve gross alterations in Apaf-1 and pro-caspase-9 expression, nor inhibition of cytochrome c release from mitochondria. However, cadmium/H2O2-induced necrosis involved ATP depletion and was prevented by 3-aminobenzamide, while cadmium/BSO-induced necrosis was ATP independent. Pre-incubation with BSO increased the intracellular cadmium accumulation, while co-treatment with H2O2 did not. Both treatments caused intracellular peroxide over-accumulation and disruption of mitochondrial transmembrane potential (delta psi m). However, while post-treatment with N-acetyl-L-cysteine or butylated hydroxyanisole reduced the cadmium/BSO-mediated necrosis and delta psi m disruption, it did not reduce the effects of cadmium/H2O2. Bcl-2 over-expression, which reduced peroxide accumulation without affecting the intracellular GSH content, attenuated necrosis generation by cadmium/H2O2 but not by cadmium/BSO. By contrast, AIF suppression, which reduced peroxide accumulation and increased the GSH content, attenuated the toxicity of both treatments. These results unravel the existence of two different oxidation-mediated necrotic pathways in cadmium-treated cells, one of them resulting from ATP-dependent apoptosis blockade, and the other involving the concurrence of multiple regulatory factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Adenosine Triphosphate / analysis
  • Adenosine Triphosphate / metabolism
  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis / drug effects*
  • Benzamides / pharmacology
  • Buthionine Sulfoximine / pharmacology
  • Cadmium / analysis
  • Cadmium / pharmacology*
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism
  • Drug Interactions
  • Glutathione / analysis
  • Glutathione / metabolism
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Membrane Potentials / drug effects
  • Mitochondria / drug effects
  • Monocytes / drug effects*
  • Necrosis / chemically induced
  • Necrosis / pathology
  • Oxidants / pharmacology
  • Oxidative Stress*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / metabolism
  • Transfection
  • U937 Cells


  • Antimetabolites, Antineoplastic
  • Benzamides
  • Oxidants
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Cadmium
  • Buthionine Sulfoximine
  • 3-aminobenzamide
  • Adenosine Triphosphate
  • Hydrogen Peroxide
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases
  • Glutathione
  • Acetylcysteine