Diminished heme oxygenase potentiates cell death: pyrrolidinedithiocarbamate mediates oxidative stress

Exp Biol Med (Maywood). 2003 May;228(5):459-65. doi: 10.1177/15353702-0322805-06.


Pyrrolidinedithiocarbamate (PDTC) is a metal-chelating compound that exerts both pro-oxidant and antioxidant effects and is widely used as an antitumor and anti-inflammatory agent. Heme oxygenase-1 (HO-1) is a redox-sensitive-inducible protein that provides efficient cytoprotection against oxidative stress. Because it has been reported that several angiogenic stimulating factors upregulating HO-1 in endothelial cells cause a significant increase in angiogenesis, we investigated the effect of PDTC on cell proliferation and angiogenesis and the effect of overexpression and underexpression of HO-1. The evaluation of PDTC (20 or 50 micro M) in endothelial cells resulted in significant increase in HO-1 mRNA and protein (P < 0.001), but a decrease in cell proliferation. Pretreatment of endothelial cells with SnCl(2) (10 micro M), an inducer of HO-1 attenuated the PDTC-mediated decrease in cell proliferation (P < 0.05). In contrast, pretreatment with SnMP, an inhibitor of HO activity, magnified the inhibiting effect of PDTC on cell proliferation. Upregulation of HO-1 gene expression by retrovirus-mediated delivery of the human HO-1 gene also attenuated the PDTC-induced decrease in cell proliferation. Underexpression of HO-1, by delivery of the human HO-1 in antisense orientation, enhanced the PDTC-mediated decrease in cell proliferation. The decrease, by PDTC, in proliferation of cells underexpressing HO-1 is related to an increase in O(-)(2) production. Collectively, these results demonstrate that upregulation of HO-1 was able to attenuate the PDTC-mediated cell proliferation, but was unable to reverse the high concentration of PDTC-induced decrease in angiogenesis.

MeSH terms

  • Antioxidants / metabolism*
  • Cell Death / physiology*
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cells, Cultured
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Gene Expression Regulation, Enzymologic
  • Gene Transfer Techniques
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Heme Oxygenase-1
  • Humans
  • Membrane Proteins
  • Neovascularization, Physiologic / drug effects
  • Oxidative Stress*
  • Pyrrolidines / pharmacology*
  • Superoxides / metabolism
  • Thiocarbamates / pharmacology*


  • Antioxidants
  • Membrane Proteins
  • Pyrrolidines
  • Thiocarbamates
  • Superoxides
  • pyrrolidine dithiocarbamic acid
  • HMOX1 protein, human
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1