Dithiocarbamates inhibit hematopoiesis via a copper-dependent mechanism.
Dithiocarbamates (DTC), an important class of therapeutic and industrial chemicals, have alternatively been reported to be either beneficial or toxic to the hematopoietic and immune systems. In the present study, we investigated the potential of dimethyl- and diethyl-dithiocarbamate to alter clonogenic response of primary human CD34(+) bone marrow cells in vitro. Our results demonstrate that both compounds are potent inhibitors of clonogenic response in human CD34(+) bone marrow cells, suppressing cytokine-induced colony formation at concentrations between 100 and 500 nM. Pretreatment of bone marrow cells for 1 h with very high doses of DTC (30 microM) had no effect on colony formation. DTCs are known inhibitors of nuclear factor-kappa B (NF-kappa B); however, data presented herein demonstrate that DTC do not inhibit cytokine activation of NF-kappa B in CD34(+) bone marrow cells. Additional experiments demonstrate that DTCs induce a dose-related increase in apoptosis, potentially acting via a cytotoxic mechanism. We further demonstrate that the addition of copper sulfate greatly potentiates the hematotoxicity of DTC and that the addition of a copper-specific chelator completely abrogates DTC clonogenic suppression. These data support a role for copper in DTC-induced hematotoxicity.
Molecular Toxicology and Environmental Health Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, 80262, USA.
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Pyatt
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Yang
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Stillman
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D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D004125:Dimethyldithiocarbamate / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D020287:In Situ Nick-End Labeling; D016328:NF-kappa B / Q000378:metabolism
D018952:Antigens, CD34; D002614:Chelating Agents; D004125:Dimethyldithiocarbamate; D016328:NF-kappa B; D003300:Copper; D004050:Ditiocarb