Diminished heme oxygenase potentiates cell death: pyrrolidinedithiocarbamate mediates oxidative stress.
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.
Malaguarnera
Lucia
L
Department of Pharmacology, New York Medical College Valhalla, New York 10595, USA.
Quan
Shuo
S
Pilastro
M Rosaria
MR
Abraham
Nader G
NG
Kappas
Attallah
A
D000975:Antioxidants / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D008565:Membrane Proteins; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018384:Oxidative Stress; D011759:Pyrrolidines / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology*
D000975:Antioxidants; D008565:Membrane Proteins; D011759:Pyrrolidines; D013859:Thiocarbamates; D013481:Superoxides; C020972:pyrrolidine dithiocarbamic acid; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1