Rotenone-induced G2/M cell cycle arrest and apoptosis in a human B lymphoma cell line PW.
Concentrations of rotenone (ROT) that block electron flow through mitochondrial complex I (100 nM) did not significantly alter either cell viability or the growth of PW cells. However, 10- to 50-fold higher concentrations (1-5 microM) were found to induce a dose-dependent cell cycle arrest predominantly at the G2/M stage of the cycle and apoptosis. Apoptosis was dependent on the cell cycle arrest, since apoptosis but not the G2/M arrest was prevented with the broad spectrum caspase inhibitor zVADfmk. Biochemical features of apoptosis included mitochondrial cytochrome c release, reactive oxygen species generation, and the activation of procaspase 3. Thus, ROT inhibition of mitochondrial electron transport may be insufficient to induce apoptosis in PW cells. Instead, apoptosis in these cells occurs as a consequence of disruption of the cell cycle and is only indirectly dependent upon mitochondrial electron transport.
Armstrong
J S
JS
Department of Radiation Oncology, Stanford University Medical Center, Stanford, California 94305-5105, USA. jeff30322@lycos.com
Hornung
B
B
Lecane
P
P
Jones
D P
DP
Knox
S J
SJ
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014475:Uncoupling Agents / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D012402:Rotenone