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J Biol Chem, Vol. 275, Issue 8, 5416-5424, February 25, 2000
From the
NAD(P)H:Quinone Oxidoreductase Activity Is the Principal
Determinant of
-Lapachone Cytotoxicity*
,,,,¶
Department of Radiation Oncology, Laboratory
of Molecular Stress Responses, Ireland Comprehensive Cancer Center,
Case Western Reserve University, Cleveland, Ohio 44106-4942 and the
§ Department of Pharmaceutical Sciences, School of Pharmacy
and Cancer Center, University of Colorado Health Sciences Center,
Denver, Colorado 80262
-Lapachone activates a novel apoptotic
response in a number of cell lines. We demonstrate that the enzyme
NAD(P)H:quinone oxidoreductase (NQO1) substantially enhances the
toxicity of -lapachone. NQO1 expression directly correlated with
sensitivity to a 4-h pulse of -lapachone in a panel of breast cancer
cell lines, and the NQO1 inhibitor, dicoumarol, significantly protected
NQO1-expressing cells from all aspects of -lapachone toxicity.
Stable transfection of the NQO1-deficient cell line, MDA-MB-468, with
an NQO1 expression plasmid increased apoptotic responses and lethality
after -lapachone exposure. Dicoumarol blocked both the apoptotic
responses and lethality. Biochemical studies suggest that reduction of
-lapachone by NQO1 leads to a futile cycling between the quinone and
hydroquinone forms, with a concomitant loss of reduced NAD(P)H. In
addition, the activation of a cysteine protease, which has
characteristics consistent with the neutral
calcium-dependent protease, calpain, is observed after
-lapachone treatment. This is the first definitive elucidation of an
intracellular target for -lapachone in tumor cells. NQO1 could be
exploited for gene therapy, radiotherapy, and/or chemopreventive
interventions, since the enzyme is elevated in a number of tumor types
(i.e. breast and lung) and during neoplastic transformation.
*
This work was supported by United States Army Medical
Research and Materiel Command Breast Cancer Initiative Grant
DAMD17-98-1-8260 (to D. A. B.) and Postdoctoral Fellowship
DAMD17-97-1-7221 (to J. J. P.) and National Institutes of Health
Grant CA51210 (to D. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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