Dicoumarol alters cellular redox state and inhibits nuclear factor kappa B to enhance arsenic trioxide-induced apoptosis.
The effects of a number of cytotoxic drugs are influenced by cellular reduction/oxidation (redox) state. In the present study, we attempt to explore if dicoumarol, an inhibitor of NADPH: quinone oxidoreductase (NQO1), alters the cellular redox state and how this alteration affects the redox-related apoptosis. Flow cytometry was used to assess the reactive oxygen species (ROS) level and apoptotic rates of HeLa cells treated with arsenic trioxide (As2O3) alone or in combination with natural anthraquinone emodin and dicoumarol or plus N-acetyl-cysteine. Western blot, immunofluorescence, electrophoretic mobility shift assay and luciferase assay were used to detect Nuclear Factor kappa B (NF-kappaB) activation. The results showed that dicoumarol synergized with emodin to sensitize HeLa cells to As2O3-induced apoptosis through raising the ROS level. More notably, this enhanced susceptibility was associated with a ROS-mediated inhibition of NF-kappaB activation in which the combinative treatment with dicoumarol prevented NF-kappaB from binding to target DNA. It was suggested that dicoumarol in combination with anthraquinones might be a novel strategy to expand the chemotherapeutic spectrum of As2O3 by means of interfering the cellular redox state.
Jing
Ya-Wu
YW
Department of Cell Biology, Shanghai Second Medical University, Shanghai 200025, China.
Yi
Jing
J
Chen
Yu-Ying
YY
Hu
Qing-Shen
QS
Shi
Gui-Ying
GY
Li
Hue
H
Tang
Xue-Ming
XM
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001728:Dicumarol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004642:Emodin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D001152:Arsenicals; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D010087:Oxides; D017382:Reactive Oxygen Species; D001728:Dicumarol; D004642:Emodin; D000077237:Arsenic Trioxide