Upregulation of NAD(P)H:quinone Oxidoreductase by Radiation Potentiates the Effect of Bioreductive Beta-lapachone on Cancer Cells

Overview

Journal Neoplasia

Publisher Elsevier

Specialty Oncology

Date 2007 Sep 6

PMID 17786182

Citations 28

Authors

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

Heon Joo Park

Affiliations

Soon will be listed here.

Abstract

We found that beta-lapachone (beta-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 beta-lap could be significantly inhibited by dicoumarol, an inhibitor of NAD(P)H:quinone oxido-reductase (NQO1), and also by siRNA for NQO1, demonstrating that NQO1-induced bioreduction of beta-lap is an essential step in beta-lap-induced cell death. Irradiation of A549 cells with 4 Gy caused a long-lasting upregulation of NQO1, thereby increasing NQO1-mediated beta-lap-induced cell deaths. Although the direct cause of beta-lap-induced apoptosis is not yet clear, beta-lap treatment reduced the expression of p53 and NF-kappaB, whereas it increased cytochrome C release, caspase-3 activity, and gammaH2AX foci formation. Importantly, beta-lap treatment immediately after irradiation enhanced radiation-induced cell death, indicating that beta-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 beta-lap treatment. This is the first study to demonstrate that combined radiotherapy and beta-lap treatment can have a significant effect on human tumor xenografts.

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