Beta-lapachone suppresses radiation-induced activation of nuclear factor-kappaB.

Eun Taex Oh,Guang Zhi Dong,Hyemi Lee,Chang Won Song,Moon Taek Park,Heon Joo Park

doi:10.3858/emm.2010.42.5.034

Eun Taex Oh, Guang Zhi Dong + Show 4 more

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https://doi.org/10.3858/emm.2010.42.5.034

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Abstract

Anticancer effects of beta-lapachone (beta-lap) are due to generation of ROS and metabolic catastrophes as a result of NAD(P)H:quinone oxidoreductase (NQO1)-mediated futile cycling between the oxidized and reduced forms of beta-lap. It has been shown that NQO1 is also essential for the TNF-induced activation of NF-kappaB and that beta-lap suppresses the TNF-induced NF-kappaB activation. We investigated whether or not NQO1 is involved and beta-lap suppresses the radiation-induced NF-kappaB activation using A549 human lung cancer cells and NQO1-knock down A549 cells (shNQO1 A549 cells). Irradiation with 4 Gy markedly increased the DNA binding activity of NF-kappaB in A549 cells, but not in the shNQO1 A549 cells, thus demonstrating that NQO1 plays a pivotal role in irradiation-induced NF-kappaB activation. Treatment with 10 micronM beta-lap for 4 h almost completely abrogated the radiation-induced increase in NF-kappaB activation and the transcription of NF-kappaB target genes such as bcl2, gadd45beta and cyclinD1. Moreover, beta-lap markedly suppressed the activation of IkappaB kinase gamma (IKKgamma) and the subsequent phosphorylation of IkappaBalpha, thereby inhibiting NF-kappaB activation. It is concluded that beta-lap suppresses the radiation-induced activation of NF-kappaB by interrupting the involvement of NQO1 in the activation of NF-kappaB, thereby inhibiting the transcription of survival signals. The radiosensitization caused by beta-lap may, in part, be attributed to beta-lap-induced suppression of NF-kappaB activation.

Highlights

Introduction βLapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho [1,2-b]pyran-5,6-dione) (β-lap), is novel bio-reductive anti-cancer drug (Planchon et al, 1995; Wuerzberger et al, 1998; Planchon et al, 2001)
The clonogenic survival of A549 cells decreased to 27.2%, 4.0% and 0.2% when treated with irradiation alone, β-lap or a combination of β-lap treatment with irradiation, respectively (Figure 1B)
The clonogenic survival of shNQO1 A549 cells was 36.7%, 18.7% and 6.1% after treatment with β-lap alone, irradiation alone or a combination of irradiation and β-lap, respectively (Figure 1B). These results demonstrated that shNQO1 A549 cells were resistant to β-lap treatment or to the combined treatment of β-lap and irradiation as compared with the wild-type A549 cells

Summary

Introduction

Introduction βLapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho [1,2-b]pyran-5,6-dione) (β-lap), is novel bio-reductive anti-cancer drug (Planchon et al, 1995; Wuerzberger et al, 1998; Planchon et al, 2001). The anti-tumor activity and the radiosensitizing activity of β-lap are dependent on the cytosolic flavoenzyme NAD(P)H:quinone oxidoreductase (NQO1, E>C>1.6.99.2), which catalyzes the two-electron reduction of endogenous as well as exogenous quinone compounds to their corresponding hydroquinone forms using H+ from NADH or NADPH (Boothman et al, 1993; Trush et al, 1996; Pink et al, 2000; Planchon et al, 2001; Tagliarino et al, 2001; Park et al, 2005a, 2005b; Suzuki et al, 2006; Bey et al, 2007; Choi et al, 2007; Song et al, 2008). Treatment of cells with dicoumarol, an inhibitor of NQO1

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