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
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 (SN...
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Published in | Journal of medicinal chemistry Vol. 53; no. 4; pp. 1627 - 1635 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
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United States
25.02.2010
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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. |
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AbstractList | 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. |
Author | Rhenals, Maricela Viola Strasberg-Rieber, Mary Rieber, Manuel |
Author_xml | – sequence: 1 givenname: Maricela Viola surname: Rhenals fullname: Rhenals, Maricela Viola organization: Instituto Venezolano de Investigaciones Cientificas (IVIC), Centre for Microbiology & Cell Biology, Tumor Cell Biology Laboratory, Apartado 20632, Caracas 1020-A, Venezuela – sequence: 2 givenname: Mary surname: Strasberg-Rieber fullname: Strasberg-Rieber, Mary – sequence: 3 givenname: Manuel surname: Rieber fullname: Rieber, Manuel |
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SubjectTerms | 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 |
Title | 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 |
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