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

60 Citations (Scopus)

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

Fingerprint

Radiation Effects
NAD
Oxidoreductases
Cell Death
Up-Regulation
Neoplasms
Radiotherapy
Radiation
Dicumarol
Apoptosis
Therapeutics
Cytochromes
Heterografts
Caspase 3
Small Interfering RNA
Lung Neoplasms
Epithelial Cells
benzoquinone
Growth
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Cancer Research

Cite this

Choi, E. K., Terai, K., Ji, I. M., Kook, Y. H., Park, K. H., Oh, E. T., ... 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

Upregulation of NAD(P)H : quinone oxidoreductase by radiation potentiates the effect of bioreductive β-lapachone on cancer cells. / Choi, Eun K.; Terai, Kaoru; Ji, In Mi; Kook, Yeon H.; Park, Kyung H.; Oh, Eun T.; Griffin, Robert J.; Lim, Byung U.; Kim, Jin Seok; Lee, Doo S.; Boothman, David A.; Loren, Melissa; Song, Chang W.; Heon, Joo Park.

In: Neoplasia, Vol. 9, No. 8, 08.2007, p. 634-642.

Research output: Contribution to journalArticle

Choi, EK, Terai, K, Ji, IM, Kook, YH, Park, KH, Oh, ET, Griffin, RJ, Lim, BU, Kim, JS, Lee, DS, Boothman, DA, Loren, M, Song, CW & Heon, JP 2007, 'Upregulation of NAD(P)H: quinone oxidoreductase by radiation potentiates the effect of bioreductive β-lapachone on cancer cells', Neoplasia, vol. 9, no. 8, pp. 634-642. https://doi.org/10.1593/neo.07397
Choi, Eun K. ; Terai, Kaoru ; Ji, In Mi ; Kook, Yeon H. ; Park, Kyung H. ; Oh, Eun T. ; Griffin, Robert J. ; Lim, Byung U. ; Kim, Jin Seok ; Lee, Doo S. ; Boothman, David A. ; Loren, Melissa ; Song, Chang W. ; Heon, Joo Park. / Upregulation of NAD(P)H : quinone oxidoreductase by radiation potentiates the effect of bioreductive β-lapachone on cancer cells. In: Neoplasia. 2007 ; Vol. 9, No. 8. pp. 634-642.
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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.",
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AU - Terai, Kaoru

AU - Ji, In Mi

AU - Kook, Yeon H.

AU - Park, Kyung H.

AU - Oh, Eun T.

AU - Griffin, Robert J.

AU - Lim, Byung U.

AU - Kim, Jin Seok

AU - Lee, Doo S.

AU - Boothman, David A.

AU - Loren, Melissa

AU - Song, Chang W.

AU - Heon, Joo Park

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