Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide.
The mechanism of the induction of apoptosis by arsenic trioxide (As2O3), which was demonstrated recently to be an effective inducer of apoptosis in patients with leukemia, was examined in detail in human leukemia U937 cells. Upon treatment of U937 cells with 50 microM of As2O3, complete inactivation of the kinases ERK1 and ERK2 was detected within 30 min. p38 was activated within 3 hr, and the maximum activity was detected at 6 hr, when DNA fragmentation remained undetectable. Experiments with transfected cells that expressed constitutively activated MEK1 and a specific inhibitor of p38 also suggested that inactivation of ERKs and activation of p38 might be associated with the induction of apoptosis by As2O3. In contrast to the inactivation of ERKs and the activation of p38, activation of JNK by As2O3 appeared to protect cells against the induction of apoptosis. Treatment of U937 cells with As2O3 also caused the Ca2+-dependent production of superoxide and intracellular acidification and a decrease in the mitochondrial membrane potential at the early stages of induction of apoptosis by As2O3. These changes preceded the release of cytochrome c from mitochondria and the activation of caspase-3. It should be possible to exploit the unusual characteristics of the mechanism of induction of apoptosis by As2O3 in U937 cells by making use of synergistic effects of this compound with other inducers of apoptosis.
Iwama
K
K
Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Nakajo
S
S
Aiuchi
T
T
Nakaya
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005799:Genes, Dominant; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D048670:MAP Kinase Kinase 4; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D001152:Arsenicals; D003574:Cytochrome c Group; D010087:Oxides; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D013481:Superoxides; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D000077237:Arsenic Trioxide; D002118:Calcium