NAD(P)H:quinone oxidoreductase activity is the principal determinant of β-lapachone cytotoxicity

John J. Pink, Sarah M. Planchon, Colleen Tagliarino, Marie E. Varnes, David Siegel, David A. Boothman

Research output: Contribution to journalArticlepeer-review

308 Scopus citations

Abstract

β-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 β-lapachone. NQO1 expression directly correlated with sensitivity to a 4-h pulse of β-lapachone in a panel of breast cancer cell lines, and the NQO1 inhibitor, dicoumarol, significantly protected NQO1-expressing cells from all aspects of β-lapachone toxicity. Stable transfection of the NQO1-deficient cell line, MDA-MB-468, with an NQO1 expression plasmid increased apoptotic responses and lethality after β- lapachone exposure. Dicoumarol blocked both the apoptotic responses and lethality. Biochemical studies suggest that reduction of β-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 β-lapachone treatment. This is the first definitive elucidation of an intracellular target for β-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.

Original languageEnglish (US)
Pages (from-to)5416-5424
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number8
DOIs
StatePublished - Feb 25 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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