Diethyldithiocarbamate can induce two different type of death: apoptosis and necrosis mediating the differential MAP kinase activation and redox regulation in HL60 cells.
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.
Kimoto-Kinoshita
Saori
S
Department of Biochemistry & Oncology, Kinki University School of Medicine, Osaka-sayama, Osaka 589-8511, Japan.
Nishida
Shozo
S
Tomura
Takanori T
TT
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D002614:Chelating Agents / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D000860:Hypoxia; D007425:Intracellular Membranes / Q000378:metabolism; D007477:Ions; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008564:Membrane Potentials; D008670:Metals / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D010084:Oxidation-Reduction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
D002614:Chelating Agents; D007477:Ions; D008670:Metals; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D004050:Ditiocarb; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases; D000111:Acetylcysteine