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

• Published in: Journal of medicinal chemistry Vol. 53; no. 4; pp. 1627 - 1635
• Main Authors: Rhenals, Maricela Viola, Strasberg-Rieber, Mary, Rieber, Manuel
• Format: Journal Article
• Language: English
• Published: United States 25.02.2010
• Subjects: 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; Mitochondria - metabolism; Nitric Oxide - biosynthesis; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase Type II - biosynthesis; Nitrites - metabolism; Nitroprusside - pharmacology; Nitroso Compounds - pharmacology; Organometallic Compounds - metabolism; Organometallic Compounds - pharmacology; Poly(ADP-ribose) Polymerases - metabolism; S-Nitroso-N-Acetylpenicillamine - pharmacology; Sodium Nitrite - pharmacology
• ISSN: 1520-4804
• DOI: 10.1021/jm901314r

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.