Synergistic Effects of Radiation and β-Lapachone in DU-145 Human Prostate Cancer Cells<i>In Vitro</i>

Suzuki, Minoru; Amano, Morikazu; Choi, Ji-Hyung; Park, Heon Joo; Williams, Brent; Ono, Koji; Song, Chang W.

doi:10.1667/rr3554.1

Cited by 48 publications

(41 citation statements)

References 22 publications

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“…In good agreement with previous reports (Boothman et al, 1993;Planchon et al, 1995Planchon et al, , 2001Wuerzberger et al, 1998;Pink et al, 2000;Park et al, 2005a;Suzuki et al, 2006;Choi et al, 2007;Song et al, 2008), we have observed in the present study that not only the apoptosis and clonogenic cell death caused by β-lap but also the synergistic interaction between β-lap and irradiation in causing cell death occurred preferentially in the NQO1-positive A549 cells relative to NQO1-null shNQO1 A549 cells (Figure 1). These results clearly demonstrated that the effect of β-lap and NQO1 activity is closely related.…”

Section: Discussionsupporting

confidence: 94%

“…Furthermore, NQO1 expression in cancer cells can be increased by a number of different types of stresses such as ionizing radiation (Choi et al, 2007), heat shock (Park et al, 2005b) and certain chemotherapeutic drugs such as cisplatin (Terai et al, 2009). These observations strongly indicated that conventional cancer treatments may increase the sensitivity of the cancer to β-lap treatment by increasing NQO1 activity in the target tumor cells (Park et al, 2005b;Suzuki et al, 2006;Choi et al, 2007;Song et al, 2008).…”

Section: Introductionmentioning

confidence: 83%

“…A549 cells grown in flasks were washed twice with ice-cold PBS, scraped from the dishes and lysed with RIPA buffer (Park et al, 2005b;Suzuki et al, 2006;Choi et al, 2007). The lysates were centrifuged, and an equal amount of protein from each sample was resolved using an 8 to 10% SDS-polyacrylamide gel electrophoresis and transferring to a Hybond-P (Amersham Life Sciences) membrane.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…In addition to killing a variety of cancer cells, β-lap has been shown to sensitize cancer cells to radiation by inhibiting the repair of sublethal radiation damage (Boothman et al, 1993;Park et al, 2005b;Suzuki et al, 2006;Choi et al, 2007). 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, 2005aPark et al, , 2005bSuzuki et al, 2006;Bey et al, 2007;Choi et al, 2007;Song et al, 2008). Boothman and his colleagues (Trush et al, 1996;Pink et al, 2000;Planchon et al, 2001;Tagliarino et al, 2001;Park et al, 2005b;Bentle et al, 2006;Bey et al, 2007) proposed that NQO1 mediates the two-electron reduction of β-lap and that the reduced form of β-lap is unstable and thus immediately oxidized to the original oxidized form.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the futile cycling between the oxidized and reduced forms of β-lap causes depletion of ATP, the elevation of cytosolic Ca 2+ and the release of cytochrome C, thereby inducing cell death. Treatment of cells with dicoumarol, an inhibitor of NQO1 (Boothman et al, 1993;Park et al, 2005b;Suzuki et al, 2006; Song et al, 2008), or with the small interfering RNA (siRNA)-NQO1 (Choi et al, 2007) have been shown to effectively suppress the cytotoxic and radiosensitizing effects of β-lap. Furthermore, NQO1-null-cells were resistant to β-lap and this resistance could be reversed by administration of exogenous NQO1 (Pink et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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β-Lapachone suppresses radiation-induced activation of nuclear factor-κB

Dong

Lee

et al. 2010

Exp Mol Med

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Anticancer effects of β-lapachone (β-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 β-lap. It has been shown that NQO1 is also essential for the TNF-induced activation of NF-κB and that β-lap suppresses the TNF-induced NF-κB activation. We investigated whether or not NQO1 is involved and β-lap suppresses the radiation-induced NF-κB 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-κB in A549 cells, but not in the shNQO1 A549 cells, thus demonstrating that NQO1 plays a pivotal role in irradiation-induced NF-κB activation. Treatment with 10 μM β-lap for 4 h almost completely abrogated the radiation-induced increase in NF-κB activation and the transcription of NF-κB target genes such as bcl2, gadd45β and cyclinD1. Moreover, β-lap markedly suppressed the activation of IκB kinase γ (IKKγ) and the subsequent phosphorylation of IκBα, thereby inhibiting NF-κB activation. It is concluded that β-lap suppresses the radiation-induced activation of NF-κB by interrupting the involvement of NQO1 in the activation of NF-κB, thereby inhibiting the transcription of survival signals. The radiosensitization caused by β-lap may, in part, be attributed to β-lap-induced suppression of NF-κB activation.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 83%

Section: Western Blot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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β-Lapachone suppresses radiation-induced activation of nuclear factor-κB

Dong

Lee

et al. 2010

Exp Mol Med

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Asymmetrische Iminiumionenkatalyse: ein enantioselektiver Zugang zu Pyranonaphthochinonen und β‐Lapachonen

2008

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Naphthochinone sind weit verbreitete Pflanzenstoffe, die aufgrund ihrer charakteristischen Redoxeigenschaften zahlreiche regulatorische zelluläre Prozesse beeinflussen. Ihre cytotoxische Aktivität ist auf das Chinongrundgerüst zurückzuführen, das als wichtiges Pharmakophor fungiert. [1] Mehrere natürlich vorkommende 1,4-und 1,2-Naphthochinone zeigen eine Reihe weiterer biologischer Aktivitäten [2] und sind Bestandteil von antibakteriellen, fungiziden, antimalarialen, antiparasitären und antitumoralen Wirkstoffen. [3] Mit ihren biologischen und strukturellen Eigenschaften zählen die 1,2-und 1,4-Naphthochinone daher zu den privilegierten Substraten in der medizinischen Chemie.In Anlehnung an frühere Studien zur Aktivierung von Aldiminen und Carbonylverbindungen mit chiralen Brøn-sted-Säuren [4] haben wir versucht, eine enantioselektive Brønsted-Säure-katalysierte Synthese von 1,2-Pyranonaphthochinonen ausgehend von Hydroxynaphthochinon und a,b-ungesättigten Aldehyden zu entwickeln [Gl. (1)]. Hierbei konnten jedoch keine zufriedenstellenden Ergebnisse in Hinblick auf Reaktivität und Selektivität erzielt werden.Daher entschlossen wir uns, eine andere organokatalytische Reaktionsführung mit einem sekundären Amin als Katalysator zu untersuchen. Aus früheren Studien war bekannt, dass primäre Amine ausschließlich das Kondensationsprodukt dieser Reaktion ergeben, [5] wir nahmen aber an, dass eine Aktivierung der a,b-ungesättigten Aldehyde 2 mit sekundären Aminen durch Bildung eines intermediären Iminiumions [6] möglich sein sollte. Nachfolgende 1,4-Addition an das 2-Hydroxy-1,4-naphthochinon 1 und Acetalisierung sollten dann zum enantiomerenangereicherten 1,4-Pyranonaphthochinon 3 führen. Bereits erste Versuche ergaben, dass die Reaktion von 1 mit dem a,b-ungesättigten Aldehyd 2 a unter Verwendung der Diarylprolinolether [7] 4 a oder 4 b in Dimethylsulfoxid (DMSO) gelingt. Das 1,4-Pyranonaphthochinon 3 a wurde in guten Ausbeuten und mit exzellenten Enantioselektivitäten erhalten (Tabelle 1, Nr.

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