Oxidative stress inhibits apoptosis in human lymphoma cells.
Apoptosis and necrosis are two forms of cell death that are induced under different conditions and that differ in morphological and biochemical features. In this report, we show that, in the presence of oxidative stress, human B lymphoma cells are unable to undergo apoptosis and die instead by a form of necrosis. This was established using the chemotherapy drug VP-16 or the calcium ionophore A23187 to induce apoptosis in Burkitt's lymphoma cell lines and by measuring classical markers of apoptotic death, including cell morphology, annexin V binding, DNA ladder formation, and caspase activation. In the presence of relatively low levels of H2O2 (75-100 microM), VP-16 and A23187 were unable to induce apoptosis in these cells. Instead, the cells underwent non-apoptotic cell death with mild cytoplasmic swelling and nuclear shrinkage, similar to the death observed when they were treated with H2O2 alone. We found that H2O2 inhibits apoptosis by depleting the cells of ATP. The effects of H2O2 can be overcome by inhibitors of poly(ADP)-ribosylation, which also preserve cellular ATP levels, and can be mimicked by agents such as oligomycin, which inhibit ATP synthesis. The results show that oxidants can manipulate cell death pathways, diverting the cell away from apoptosis. The potential physiological ramifications of this finding will be discussed.
Division of Hematologic Products, Food and Drug Administration, Center for Biologics Evaluation and Research, Bethesda, Maryland 20892-4555, USA.
Y J
YJ
Lee
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E
Shacter
D000255:Adenosine Triphosphate / Q000378:metabolism; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D002051:Burkitt Lymphoma; D000001:Calcimycin / Q000494:pharmacology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009840:Oligomycins / Q000494:pharmacology; D018384:Oxidative Stress; D011485:Protein Binding / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D052999:Quinazolinones; D014407:Tumor Cells, Cultured
D017304:Annexin A5; D001549:Benzamides; D061945:Caspase Inhibitors; D009840:Oligomycins; D011799:Quinazolines; D052999:Quinazolinones; D000001:Calcimycin; D005047:Etoposide; C061339:4-hydroxyquinazoline; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D020169:Caspases