Diethyldithiocarbamate can induce two different type of death: Apoptosis and necrosis mediating the differential MAP kinase activation and redox regulation in HL60 cells

Abstract

Although apoptosis and necrosis have been considered different pathways to cell death, only one compound induces both types of cell death. Diethyldithiocarbamate (DDC) has been shown to have antioxidant or prooxidant effects in several different systems. We observed in our present study that DDC induced not only apoptosis but also necrosis depending on its dosage in HL60 premyelocytic leukemia cells. Moreover, in hypoxia cell culture conditions, DDC-induced necrotic cells decreased but DDC-induced apoptosis continued. We investigated the DDC-induced different cell death mechanisms as they are correlated with reactive oxygen species (ROS). High-dose DDC-induced necrotic cell death is thought to depend on the increase of intracellular ROS, while low-dose DDC-induced apoptosis is thought to depend on changes of the intracellular redox state by the transporting of external metal ions. There was no sequential or quantitative change of Bcl-2 family proteins in DDC-induced apoptotic or necrotic pathways. However, the mitochondrial transmembrane potential was remarkably decreased in the DDC-induced necrosis. Finally, duration of c-Jun N-terminal kinase (JNK) activation resulted in different types of cell death.

Antioxidant Inhibitors Potentiate the Cytotoxicity of Photodynamic Therapy

“…2-ME and 3-AT have previously been shown to increase the ROS levels in different cell lines (40,41) and our results demonstrated a slight increase in ROS levels in the presence of 3-AT (using DCF) and 2-ME (using DHE) when compared with AlPcS 2 alone. DDC, on the other hand, consistently yielded reduced ROS levels compared with AlPcS 2 alone with both ROS assays and this agreed with results obtained by Han et al (20) and Kimoto-Kinoshita et al (42) who also observed a decrease in ROS in the presence of DDC. DDC is known to have both antioxidant and pro-oxidant effects in different cell systems (42,43).…”

“…(20) and Kimoto‐Kinoshita et al. (42) who also observed a decrease in ROS in the presence of DDC. DDC is known to have both antioxidant and pro‐oxidant effects in different cell systems (42,43).…”

Targeting of Nuclear Factor-κB and Proteasome by Dithiocarbamate Complexes with Metals

“…From other findings, it appears that zinc is an integral element in PDTC-mediated bovine cerebral endothelial cell death [138] and that PDTC-mediated accumulation of intracellular zinc may affect cell viability by modulating several signaling pathways in embryonic hippocampal progenitor cells [139]. These results put together, it is not surprising that dithiocarbamate-induced apoptosis depends on cell type, density and the presence of copper and zinc in medium [140][141] or that, moreover, it is biphasic [142]. Finally it must be noted that dithiocarbamates apparently trigger the release of cytochrome c into the cytosol [143][144].…”

The effects of sodium diethyldithiocarbamate in fibroblasts V79 cells in relation to cytotoxicity, antioxidative enzymes, glutathione, and apoptosis

“…However, Dumay et al (2006) showed antiapoptotic activity of DETC. On the other hand, Kimoto-Kinoshita et al (2004) observed that DETC induces two different types of death: apoptosis and necrosis in human promyelocytic leukemia (HL60) cells depending on the drug concentrations used. Various effects of DETC on cell death are mediated by intracellular redox regulation and/or the different MAP kinase activation.…”