Upregulation of NAD(P)H:quinone oxidoreductase by radiation potentiates the effect of bioreductive beta-lapachone on cancer cells.
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.
Choi
Eun K
EK
Department of Therapeutic Radiology, College of Medicine, University of Ulsan, Seoul, South Korea.
Terai
Kaoru
K
Ji
In-Mi
IM
Kook
Yeon H
YH
Park
Kyung H
KH
Oh
Eun T
ET
Griffin
Robert J
RJ
Lim
Byung U
BU
Kim
Jin-Seok
JS
Lee
Doo S
DS
Boothman
David A
DA
Loren
Melissa
M
Song
Chang W
CW
Park
Heon Joo
HJ
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis* / Q000502:physiology / Q000528:radiation effects*; D009285:Naphthoquinones / Q000494:pharmacology*; D011839:Radiation, Ionizing; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects*; D023041:Xenograft Model Antitumor Assays / Q000379:methods