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Mitochondrial production of reactive oxygen species mediate dicumarol-induced cytotoxicity in cancer cells
Journal article   Open access   Peer reviewed

Mitochondrial production of reactive oxygen species mediate dicumarol-induced cytotoxicity in cancer cells

Juan Du, David H Daniels, Carla Asbury, Sujatha Venkataraman, Jingru Liu, Douglas R Spitz, Larry W Oberley and Joseph J Cullen
The Journal of biological chemistry, Vol.281(49), pp.37416-37426
12/08/2006
DOI: 10.1074/jbc.M605063200
PMID: 17040906
url
https://doi.org/10.1074/jbc.M605063200View
Published (Version of record) Open Access

Abstract

Dicumarol is a naturally occurring anticoagulant derived from coumarin that induces cytotoxicity and oxidative stress in human pancreatic cancer cells (Cullen, J. J., Hinkhouse, M. M., Grady, M., Gaut, A. W., Liu, J., Zhang, Y., Weydert, C. J. D., Domann, F. E., and Oberley, L. W. (2003) Cancer Res. 63, 5513-5520). Although dicumarol has been used as an inhibitor of the two-electron reductase NAD(P)H:quinone oxidoreductase (NQO1), dicumarol is also thought to affect quinone-mediated electron transfer reactions in the mitochondria, leading to the production of superoxide (O2*-) and hydrogen peroxide (H(2)O(2)). We hypothesized that mitochondrial production of reactive oxygen species mediates the increased susceptibility of pancreatic cancer cells to dicumarol-induced metabolic oxidative stress. Dicumarol decreased clonogenic survival equally in both MDA-MB-468 NQO1(-) and MDA-MB-468 NQO1+ breast cancer cells. Dicumarol decreased clonogenic survival in the transformed fibroblast cell line IMRSV-90 compared with the IMR-90 cell line. Dicumarol, with the addition of mitochondrial electron transport chain blockers, decreased clonogenic cell survival in human pancreatic cancer cells and increased superoxide levels. Dicumarol with the mitochondrial electron transport chain blocker antimycin A decreased clonogenic survival and increased superoxide levels in cells with functional mitochondria but had little effect on cancer cells without functional mitochondria. Overexpression of manganese superoxide dismutase and mitochondrial-targeted catalase with adenoviral vectors reversed the dicumarol-induced cytotoxicity and reversed fluorescence of the oxidation-sensitive probe. We conclude mitochondrial production of reactive oxygen species mediates the increased susceptibility of cancer cells to dicumarol-induced cytotoxicity.
 Electron Transport - drug effects Pancreatic Neoplasms - metabolism Reactive Oxygen Species - metabolism Uncoupling Agents - pharmacology Humans Breast Neoplasms - metabolism Pancreatic Neoplasms - drug therapy Dicumarol - pharmacology Female Antineoplastic Agents - pharmacology Superoxide Dismutase - metabolism Recombinant Proteins - metabolism Cell Line Cell Survival - drug effects Tumor Stem Cell Assay Pancreatic Neoplasms - pathology Mitochondria - metabolism Mitochondria - drug effects Breast Neoplasms - drug therapy Hydrogen Peroxide - metabolism Catalase - metabolism Breast Neoplasms - pathology Cell Line, Tumor NAD(P)H Dehydrogenase (Quinone) - metabolism Kinetics Oxidative Stress - drug effects Cell Line, Transformed

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