Nitric oxide donors or nitrite counteract copper-[dithiocarbamate](2)-mediated tumor cell death and inducible nitric oxide synthase down-regulation: possible role of a nitrosyl-copper [dithiocarbamate](2) complex.

Abstract

In contrast to other metal-dithiocarbamate [DEDTC] complexes, the copper-DEDTC complex is highly cytotoxic, inducing oxidative stress, preferentially in tumor cells. Because nitric oxide (NO) forms adducts with Cu[DEDTC](2), we investigated whether NO donors like S-nitroso-N-acetyl penicillamine (SNAP) or sodium nitroprusside (SNP), and nitrite, a NO decomposition product, modulate Cu[DEDTC](2) cytotoxicity against human tumor cells. We show that apoptosis-associated PARP cleavage and inducible nitric oxide synthase (iNOS) down-regulation induced by nanomolar Cu[DEDTC](2), are counteracted by 50 muM SNAP, SNP, or CoCl(2), an inducer of hypoxia and NO signaling. Nitrite was stochiometrically effective in antagonizing Cu[DEDTC](2) cytotoxicity and inducing shifts in the absorption spectrum of the binary complex in the 280 and 450 nm regions. Subtoxic concentrations of Cu[DEDTC](2) became lethal when tumor cells were pretreated with c-PTIO, a membrane-impermeable scavenger for extracellular NO. Our results suggest that: (a) reactive oxygen species induced by Cu[DEDTC](2) are scavenged by nitrite released from NO, (b) the extent of lethality of Cu[DEDTC](2) is dependent on the reciprocal formation of an inactive ternary Cu[DEDTC](2)NO copper-nitrosyl complex.

• Authors: Maricela Viola Rhenals, Mary Strasberg-Rieber, Manuel Rieber
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 4 Pg. 1627-35 (Feb 25 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20108933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic N-Oxides
• Free Radical Scavengers
• Imidazoles
• Nitric Oxide Donors
• Nitrites
• Nitroso Compounds
• Organometallic Compounds
• 2,2'-(hydroxynitrosohydrazono)bis-ethanamine
• Nitroprusside
• 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide
• Nitric Oxide
• Cobalt
• S-Nitroso-N-Acetylpenicillamine
• Nitric Oxide Synthase Type II
• Poly(ADP-ribose) Polymerases
• cobaltous chloride
• Sodium Nitrite

Topics

• Cell Death
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cobalt (pharmacology)
• Cyclic N-Oxides (pharmacology)
• Down-Regulation
• Free Radical Scavengers (pharmacology)
• Humans
• Imidazoles (pharmacology)
• Melanoma
• Mitochondria (drug effects, metabolism)
• Nitric Oxide (biosynthesis)
• Nitric Oxide Donors (pharmacology)
• Nitric Oxide Synthase Type II (biosynthesis)
• Nitrites (metabolism)
• Nitroprusside (pharmacology)
• Nitroso Compounds (pharmacology)
• Organometallic Compounds (metabolism, pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• S-Nitroso-N-Acetylpenicillamine (pharmacology)
• Sodium Nitrite (pharmacology)