S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization

Bouillaud, Frédéric; Janda, Elżbieta; Szikora, István; Guillaumet, Gérald; Hirsch, Étienne C.; Kane, Daniel A.; Nepveu, Françoise; Reybier, Karine; Dupuis, Philippe; Bertrand, Marc; Chhour, Monivan; Diguarher, Thierry Le; Antoine, Mathias; Brebner, Karen; Costa, Hervé Da; Ducrot, Pierre; Giganti, Adeline; Goswami, Vishalgiri; Guedouari, Hala; Michel, Patrick P.; Patel, Anjni; Paysant, Jérôme; Stojko, Johann; Viaud‐Massuard, Marie‐Claude; Ferry, Gilles

doi:10.1124/mol.118.114231

Cited by 22 publications

(17 citation statements)

References 84 publications

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“…This result was further confirmed by the detection of the glucuronide form of menadiol. In a more general context, after having pointed out the ambiguous role of NQO2 as a detoxifying enzyme (Boutin et al, 2019;Janda et al, 2020), we present data clearly showing that in more relevant conditions, for example in the presence of the conjugating enzyme(s), NQO2 would recuperate its detoxifying role, in line with the NQO1 one. In this pathway, NQO2 acts as a drug metabolizing Phase I enzyme, leading to an 'activated' molecule that can be conjugated by Phase II enzymes of the next step of drug metabolizing machinery.…”

Section: Discussionmentioning

confidence: 61%

Association of NQO2 With UDP-Glucuronosyltransferases Reduces Menadione Toxicity in Neuroblastoma Cells

Chhour

Pério

Gayon³

et al. 2021

Front. Pharmacol.

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The balance between detoxification and toxicity is linked to enzymes of the drug metabolism Phase I (cytochrome P450 or oxidoreductases) and phase II conjugating enzymes (such as the UGTs). After the reduction of quinones, the product of the reaction, the quinols—if not conjugated—re-oxidizes spontaneously to form the substrate quinone with the concomitant production of the toxic reactive oxygen species (ROS). Herein, we documented the modulation of the toxicity of the quinone menadione on a genetically modified neuroblastoma model cell line that expresses both the quinone oxidoreductase 2 (NQO2, E.C. 1.10.5.1) alone or together with the conjugation enzyme UDP-glucuronosyltransferase (UGT1A6, E.C. 2.4.1.17), one of the two UGT isoenzymes capable to conjugate menadione. As previously shown, NQO2 enzymatic activity is concomitant to massive ROS production, as previously shown. The quantification of ROS produced by the menadione metabolism was probed by electron-paramagnetic resonance (EPR) on cell homogenates, while the production of superoxide was measured by liquid chromatography coupled to mass spectrometry (LC-MS) on intact cells. In addition, the dysregulation of the redox homeostasis upon the cell exposure to menadione was studied by fluorescence measurements. Both EPR and LCMS studies confirmed a significant increase in the ROS production in the NQO2 overexpressing cells due to the fast reduction of quinone into quinol that can re-oxidize to form superoxide radicals. However, the effect of NQO2 inhibition was drastically different between cells overexpressing only NQO2 vs. both NQO2 and UGT. Whereas NQO2 inhibition decreases the amount of superoxide in the first case by decreasing the amount of quinol formed, it increased the toxicity of menadione in the cells co-expressing both enzymes. Moreover, for the cells co-expressing QR2 and UGT the homeostasis dysregulation was lower in presence of menadione than for the its counterpart expressing only QR2. Those results confirmed that the cooperation of the two enzymes plays a fundamental role during the cells’ detoxification process. The fluorescence measurements of the variation of redox homeostasis of each cell line and the detection of a glucuronide form of menadiol in the cells co-expressing NQO2 and UGT1A6 enzymes further confirmed our findings.

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Section: Discussionmentioning

confidence: 61%

Association of NQO2 With UDP-Glucuronosyltransferases Reduces Menadione Toxicity in Neuroblastoma Cells

Chhour

Pério

Gayon³

et al. 2021

Front. Pharmacol.

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“…Notably, Compounds 1 , 3 , 4 and 6 produced radicals, whereas no radicals were detected for 2 , 5 and 7 . For the first three compounds ( 1 , 3 and 4 ), the radical production decreased after adding the specific NQO2 inhibitor S29434 [17], confirming that radicals originate in part from the autoxidation of the enzymatically reduced quinone.…”

Section: Resultsmentioning

confidence: 99%

“…We measured the ability of the selected compounds to produce superoxide radicals during the redox cycle of NQO2 by EPR spectroscopy. The following compounds were used as molecular tools: Menadione (Figure 1) as a reference compound and NQO2 substrate, S29434 as a specific NQO2 inhibitor [17] and dimethyl-pyrroline- N -oxide (DMPO) as a spin trap reagent to characterize ROS. Different EPR profiles were obtained, depending on the compound structures as illustrated in Figure 2 for menadione and Compounds 1 and 3 .…”

Section: Resultsmentioning

confidence: 99%

“…The [2-(2-methoxy-5 H -1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434) was prepared as described by Boutin et al [17], and menadione, Dulbecco’s phosphate buffered saline, Tris-HCL, octyl β- d -glucopyranoside were from Sigma-Aldrich (Saint Quentin Fallavier, France). 5,5′-Dimethyl-1-pyrroline N -oxide (DMPO) was from Dojindo (Kumamoto, Japan).…”

Section: Methodsmentioning

confidence: 99%

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Antimalarial Properties of Dunnione Derivatives as NQO2 Substrates

et al. 2019

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Dunnione, a natural product isolated from the leaves of Streptocarpus dunnii (Gesneriaceae), acts as a substrate for quinone-reductases that may be associated with its antimalarial properties. Following our exploration of reactive oxygen species-producing compounds such as indolones, as possible new approaches for the research of new ways to treat this parasitosis, we explored derivatives of this natural product and their possible antiplasmodial and antimalarial properties, in vitro and in vivo, respectively. Apart from one compound, all the products tested had weak to moderate antiplasmodial activities, the best IC50 value being equal to 0.58 µM. In vivo activities in the murine model were moderate (at a dose of 50 mg/kg/mice, five times higher than the dose of chloroquine). These results encourage further pharmacomodulation steps to improve the targeting of the parasitized red blood cells and antimalarial activities.

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“…The abovementioned comments address some of the controversies and/or difficulties concerning fundamental aspects of the MLT field 137 . It would be pretentious to claim to know the answer to all these questions that have occupied researchers in the field for decades.…”

Section: Conclusion and Tentative Guidelinesmentioning

confidence: 99%

Melatonin controversies, an update

Boutin

Jockers

2020

Journal of Pineal Research

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Melatonin was discovered more than 60 years ago. Since then, several seminal discoveries have allowed us to define its function as a neuroendocrine hormone and its molecular targets in mammals and many other species. However, many fundamental issues have not yet been solved such as the subcellular localization of melatonin synthesis and the full spectrum of its molecular targets. In addition, a considerable number of controversies persist in the field, mainly concerning how many functions melatonin has. Altogether, this illustrates how “immature” the field still is. The intention of this opinion article is to note the controversies and limitations in the field, to initiate a discussion and to make proposals/guidelines to overcome them and move the field forward.

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S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization

Cited by 22 publications

References 84 publications

Association of NQO2 With UDP-Glucuronosyltransferases Reduces Menadione Toxicity in Neuroblastoma Cells

Association of NQO2 With UDP-Glucuronosyltransferases Reduces Menadione Toxicity in Neuroblastoma Cells

Antimalarial Properties of Dunnione Derivatives as NQO2 Substrates

Melatonin controversies, an update

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