Copper ions regulate cytotoxicity of disulfiram to myeloid leukemia cells

Abstract

White blood cell (WBC) count is considered a prognostic risk factor in acute myeloid leukemia. As density of leukemic cells increases, the cytotoxic activity of certain anticancer drugs, such as vincristine and doxorubicin, progressively decreases. In this study, we investigated the cell density-dependent induction of apoptosis of human acute myeloid leukemia U937 and ML-1 cells by disulfiram (DSF), the dithiocarbamate drug recently proposed for treatment of human cancers. This effect is dependent on uptake of extra-cellular copper and its intracellular accumulation. High-density cells cannot uptake and accumulate this metal to a sufficient level that would allow induction of apoptosis due to progressive decrease of its extracellular concentration. Simple addition of copper can resume sensitivity of high-density leukemic cells to DSF and improve efficiency of anti-leukemic therapies using this drug, thus providing benefit to patients with high WBC count.