Upregulation of NAD(P)H:quinone oxidoreductase by radiation potentiates the effect of bioreductive β-lapachone on cancer cells

Eun K. Choi, Kaoru Terai, In Mi Ji, Yeon H. Kook, Kyung H. Park, Eun T. Oh, Robert J. Griffin, Byung U. Lim, Jin Seok Kim, Doo S. Lee, David A. Boothman, Melissa Loren, Chang W. Song, Joo Park Heon

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

We found that β-lapachone (β-lap), a novel bioreductive drug, caused rapid apoptosis and clonogenic cell death in A549 human lung epithelial cancer cells in vitro in a dose-dependent manner. The clonogenic cell death caused by β-lap could be significantly inhibited by dicoumarol, an inhibitor of NAD(P)H:quinone oxidoreductase (NQO1), and also by siRNA for NQO1, demonstrating that NQO1-induced bioreduction of β-lap is an essential step in β-lap-induced cell death. Irradiation of A549 cells with 4 Gy caused a long-lasting upregulation of NQO1, thereby increasing NQO1-mediated β-lap-induced cell deaths. Although the direct cause of β-lap-induced apoptosis is not yet clear, β-lap treatment reduced the expression of p53 and NF-κB, whereas it increased cytochrome C release, caspase-3 activity, and γH2AX foci formation. Importantly, β-lap treatment immediately after irradiation enhanced radiation-induced cell death, indicating that β-lap sensitizes cancer cells to radiation, in addition to directly killing some of the cells. The growth of A549 tumors induced in immunocompromised mice could be markedly suppressed by local radiation therapy when followed by β-lap treatment. This is the first study to demonstrate that combined radiotherapy and β-lap treatment can have a significant effect on human tumor xenografts.

Original languageEnglish (US)
Pages (from-to)634-642
Number of pages9
JournalNeoplasia
Volume9
Issue number8
DOIs
StatePublished - Aug 2007

Keywords

  • A549 cells
  • Bioreductive drug
  • NQO1
  • Radiation
  • β-lapachone

ASJC Scopus subject areas

  • Cancer Research

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  • Cite this

    Choi, E. K., Terai, K., Ji, I. M., Kook, Y. H., Park, K. H., Oh, E. T., Griffin, R. J., Lim, B. U., Kim, J. S., Lee, D. S., Boothman, D. A., Loren, M., Song, C. W., & Heon, J. P. (2007). Upregulation of NAD(P)H:quinone oxidoreductase by radiation potentiates the effect of bioreductive β-lapachone on cancer cells. Neoplasia, 9(8), 634-642. https://doi.org/10.1593/neo.07397