NADPH quinone oxidoreductase 1 mediates breast cancer cell resistance to thymoquinone-induced apoptosis

Sutton, Kimberly M.; Doucette, Carolyn D.

doi:10.1016/j.bbrc.2012.08.111

Cited by 28 publications

(17 citation statements)

References 34 publications

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“…Thymoquinone (TQ) causes the production of superoxide radicals which induce apoptosis in breast cancer cells. Inhibition of NQO1 prevents it from scavenging these radicals [68]. The stabilization of the p.P187S variant by pharmacological chaperones has been suggested as a therapy for patients who are homozygous for the corresponding mutation [46,69].…”

Section: Discussionmentioning

confidence: 99%

Cancer-associated variants of human NQO1: impacts on inhibitor binding and cooperativity

Megarity

Timson

2019

Bioscience Reports

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Human NAD(P)H quinone oxidoreductase (DT-diaphorase, NQO1) exhibits negative cooperativity towards its potent inhibitor, dicoumarol. Here, we addressed the hypothesis that the effects of the two cancer-associated polymorphisms (p.R139W and p.P187S) may be partly mediated by their effects on inhibitor binding and negative cooperativity. Dicoumarol stabilized both variants and bound with much higher affinity for p.R139W than p.P187S. Both variants exhibited negative cooperativity towards dicoumarol; in both cases, the Hill coefficient (h) was approximately 0.5 and similar to that observed with the wild-type protein. NQO1 was also inhibited by resveratrol and by nicotinamide. Inhibition of NQO1 by resveratrol was approximately 10,000-fold less strong than that observed with the structurally similar enzyme, NRH quinine oxidoreductase 2 (NQO2). The enzyme exhibited non-cooperative behaviour towards nicotinamide, whereas resveratrol induced modest negative cooperativity (h = 0.85). Nicotinamide stabilized wild-type NQO1 and p.R139W towards thermal denaturation but had no detectable effect on p.P187S. Resveratrol destabilized the wild-type enzyme and both cancer-associated variants. Our data suggest that neither polymorphism exerts its effect by changing the enzyme’s ability to exhibit negative cooperativity towards inhibitors. However, it does demonstrate that resveratrol can inhibit NQO1 in addition to this compound’s well-documented effects on NQO2. The implications of these findings for molecular pathology are discussed.

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Section: Discussionmentioning

confidence: 99%

Cancer-associated variants of human NQO1: impacts on inhibitor binding and cooperativity

Megarity

Timson

2019

Bioscience Reports

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“…For instance, miRNAs-15a/16 cluster, considered a tumor suppressor found deleted in different malignancies [63,64], or miR-155 reported as repressor of JUN in human dermal fibroblasts in vitro [65]. Interestingly, the up-regulation of Jun TF in MCF7 is connected to the activation of TIMP1, a mettallopeptidase inhibitor whose overexpression contributes to antimetastatic effect in BC [66], and to the activation of NQO1 (NADPH quinone oxidoreductase 1), playing a cytoprotective role and found associated to increase cell-sensitivity to BC anticancer treatment [67]. …”

Section: Resultsmentioning

confidence: 99%

Pathway landscapes and epigenetic regulation in breast cancer and melanoma cell lines

Baroudi

Sala

Cinti

et al. 2014

Theor Biol Med Model

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BackgroundEpigenetic variation is a main regulation mechanism of gene expression in various cancer histotypes, and due to its reversibility, the potential impact in therapy can be very relevant.MethodsBased on a selected pair, breast cancer (BC) and melanoma, we conducted inference analysis in parallel on a few cell lines (MCF-7 for BC and A375 for melanoma). Starting from differential expression after treatment with a demethylating agent, the 5-Aza-2'-deoxycytidine (DAC), we provided pathway enrichment analysis and gene regulatory maps with cross-linked microRNAs and transcription factors.ResultsSeveral oncogenic signaling pathways altered upon DAC treatment were detected with significant enrichment. We represented the association between these cancers by depicting the landscape of common and specific variation affecting them.

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“…It plays an important role in the body's defense against oxidative stress in part by detoxifying quinones and their derivatives, thereby preventing their participation in redox cycling (Riley and Workman, 1992;Ross et al, 2000;Han et al, 2009). NQO1 metabolizes thymoquinone, presumably because of its structural similarity to ubiquinone, the natural electron carrier in mitochondria (Sutton et al, 2012). Indeed, thymoquinone can act as an electron acceptor during the oxidation of NADH to NAD 1 (Staniek and Gille, 2010).…”

Section: Discussionmentioning

confidence: 99%

Endothelium-Dependent Contractions of Isolated Arteries to Thymoquinone Require Biased Activity of Soluble Guanylyl Cyclase with Subsequent Cyclic IMP Production

Detremmerie

Chen

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Preliminary experiments on isolated rat arteries demonstrated that thymoquinone, a compound widely used for its antioxidant properties and believed to facilitate endothelium-dependent relaxations, as a matter of fact caused endothelium-dependent contractions. The present experiments were designed to determine the mechanisms underlying this unexpected response. Isometric tension was measured in rings (with and without endothelium) of rat mesenteric arteries and aortae and of porcine coronary arteries. Precontracted preparations were exposed to increasing concentrations of thymoquinone, which caused concentration-dependent, sustained further increases in tension (augmentations) that were prevented by endothelium removal, Nv-nitro-L-arginine methyl ester [L-NAME; nitric oxide (NO) synthase inhibitor], and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; soluble guanylyl cyclase [sGC] inhibitor). In L-NAME-treated rings, the NO-donor diethylenetriamine NONOate restored the thymoquinone-induced augmentations; 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol (sGC activator) and cyclic IMP (cIMP) caused similar restorations. By contrast, in ODQ-treated preparations, the cell-permeable cGMP analog did not restore the augmentation by thymoquinone. The compound augmented the content (measured with ultra-high performance liquid chromatography-tandem mass spectrometry) of cIMP, but not that of cGMP; these increases in cIMP content were prevented by endothelium removal, L-NAME, and ODQ. The augmentation of contractions caused by thymoquinone was prevented in porcine arteries, but not in rat arteries, by 1-(5-isoquinolinylsulfonyl)homopiperazine dihydrochloride and trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride (Rho-kinase inhibitors); in the latter, but not in the former, it was reduced by 3,5-dichloro-N-[[(1a,5a,6-exo,6a)-3-(3,3-dimethylbutyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl]-benzamide hydrochloride (T-type calcium channel inhibitor), demonstrating species/vascular bed differences in the impact of cIMP on calcium handling. Thymoquinone is the first pharmacological agent that causes endothelium-dependent augmentation of contractions of isolated arteries, which requires endothelium-derived NO and biased sGC activation, resulting in the augmented production of cIMP favoring the contractile process.

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NADPH quinone oxidoreductase 1 mediates breast cancer cell resistance to thymoquinone-induced apoptosis

Cited by 28 publications

References 34 publications

Cancer-associated variants of human NQO1: impacts on inhibitor binding and cooperativity

Cancer-associated variants of human NQO1: impacts on inhibitor binding and cooperativity

Pathway landscapes and epigenetic regulation in breast cancer and melanoma cell lines

Endothelium-Dependent Contractions of Isolated Arteries to Thymoquinone Require Biased Activity of Soluble Guanylyl Cyclase with Subsequent Cyclic IMP Production

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