Dithiocarbamates inhibit hematopoiesis via a copper-dependent mechanism

Dithiocarbamates (DTC), an important class of therapeutic and industrial ch emicals, have alternatively been reported to be either beneficial or toxic to the hematopoietic and immune systems. In the present study, me investiga ted the potential of dimethyl- and diethyl-dithiocarbamate to alter clonoge nic response of primary human CD34(+) bone marrow cells in vitro. Our resul ts demonstrate that both compounds are potent inhibitors of clonogenic resp onse in human CD34(+) bone marrow cells, suppressing cytokine-induced colon y formation at concentrations between 100 and 500 nM. Pretreatment of bone marrow cells for 1 h with very high doses of DTC (30 mu M) 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 inhibi t cytokine activation of NF-kappa B in CD34(+) bone marrow cells. Additiona l experiments demonstrate that DTCs induce a dose-related increase in apopt osis, 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 abrog ates DTC clonogenic suppression. These data support a role for copper in DT C-induced hematotoxicity. (C) 2000 Academic Press.