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

Authors
Choi, Eun K.Terai, KaoruJi, In-MiKook, Yeon H.Park, Kyung H.Oh, Eun T.Griffin, Robert J.Lim, Byung U.Kim, Jin-SeokLee, Doo S.Boothman, David A.Loren, MelissaSong, Chang W.Park, Heon Joo
Issue Date
Aug-2007
Publisher
ELSEVIER SCIENCE INC
Keywords
NQO1; radiation; beta-lapachone; A549 cells; bioreductive drug
Citation
NEOPLASIA, v.9, no.8, pp 634 - 642
Pages
9
Journal Title
NEOPLASIA
Volume
9
Number
8
Start Page
634
End Page
642
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/14652
DOI
10.1593/neo.07397
ISSN
1522-8002
1476-5586
Abstract
We found that B-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 oxidoreductase (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-kappa B, whereas it increased cytochrome C release, caspase-3 activity, and; gamma H2AX 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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