ES936 stimulates DNA synthesis in HeLa cells independently on NAD(P)H:quinone oxidoreductase 1 inhibition, through a mechanism involving p38 MAPK

González-Aragón, David; Alcaı́n, Francisco J.; Ariza, Julia; Jódar, Laura; Barbarroja, Nuria; López‐Pedrera, Chary; Villalba, José M.

doi:10.1016/j.cbi.2010.04.022

Cited by 5 publications

(3 citation statements)

References 43 publications

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“…ES936 is a potent mechanism based inhibitor which alkylates key tyrosine residues within the NQO1 active site . While neither compound has perfect specificity for NQO1, − both DIC and ES936 are widely used in studies of NQO1-mediated cell death, ,,,, as incubation of cells with these inhibitors is effective in blocking the enzymatic activity of NQO1. ,− As shown in Figure A and B, coincubation with DIC and ES936 dramatically protects A549 cells from DNQ-mediated cell death, shifting the IC 50 53-fold and >170-fold, respectively (the fold is the ratio of the IC 50 of cotreatment with quinone and inhibitor to the IC 50 of treatment with only quinone, and a higher ratio indicates greater protection and greater NQO1 selectivity). DIC and ES936 also protect cells from β-lap-induced cell death, shifting the IC 50 10-fold and 6-fold (Figure A and B).…”

Section: Resultsmentioning

confidence: 99%

Efficient NQO1 Substrates are Potent and Selective Anticancer Agents

et al. 2013

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A major goal of personalized medicine in oncology is the identification of drugs with predictable efficacy based on a specific trait of the cancer cell, as has been demonstrated with gleevec (presence of Bcr-Abl protein), herceptin (Her2 overexpression), and iressa (presence of a specific EGFR mutation). This is a challenging task, as it requires identifying a cellular component that is altered in cancer, but not normal cells, and discovering a compound that specifically interacts with it. The enzyme NQO1 is a potential target for personalized medicine, as it is overexpressed in many solid tumors. In normal cells NQO1 is inducibly expressed, and its major role is to detoxify quinones via bioreduction; however, certain quinones become more toxic after reduction by NQO1, and these compounds have potential as selective anticancer agents. Several quinones of this type have been reported, including mitomycin C, RH1, EO9, streptonigrin, β-lapachone, and deoxynyboquinone (DNQ). However, no unified picture has emerged from these studies, and the key question regarding the relationship between NQO1 processing and anticancer activity remains unanswered. Here, we directly compare these quinones as substrates for NQO1 in vitro, and for their ability to kill cancer cells in culture in an NQO1-dependent manner. We show that DNQ is a superior NQO1 substrate, and we use computationally guided design to create DNQ analogues that have a spectrum of activities with NQO1. Assessment of these compounds definitively establishes a strong relationship between in vitro NQO1 processing and induction of cancer cell death and suggests these compounds are outstanding candidates for selective anticancer therapy.

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Section: Resultsmentioning

confidence: 99%

Efficient NQO1 Substrates are Potent and Selective Anticancer Agents

et al. 2013

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“…These agents deactivate NQO1 and NQO2 by alkylation of their active sites. However, this attractive mechanism-based approach also has limitations regarding target selectivity (46). The work of Nolan etal (3,22,23) and that reported here was undertaken with the specific objective of identifying novel inhibitors of NQO2 that might have therapeutic properties on the basis of the impact of NQO2 on NFκB mediated gene transcription that was previously suggested from genetic deletion studies (21,30).…”

Section: Discussionmentioning

confidence: 99%

In Silico Screening Reveals Structurally Diverse, Nanomolar Inhibitors of NQO2 That Are Functionally Active in Cells and Can Modulate NF-κB Signaling

Nolan

Dunstan

Caraher

et al. 2012

Molecular Cancer Therapeutics

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The National Cancer Institute chemical database has been screened using in silico docking to identify novel nanomolar inhibitors of NRH:quinone oxidoreductase 2 (NQO2). The inhibitors identified from the screen exhibit a diverse range of scaffolds and the structure of one of the inhibitors, NSC13000 cocrystalized with NQO2, has been solved. This has been used to aid the generation of a structure-activity relationship between the computationally derived binding affinity and experimentally measured enzyme inhibitory potency. Many of the compounds are functionally active as inhibitors of NQO2 in cells at nontoxic concentrations. To show this, advantage was taken of the NQO2-mediated toxicity of the chemotherapeutic drug CB1954. The toxicity of this drug is substantially reduced when the function of NQO2 is inhibited, and many of the compounds achieve this in cells at nanomolar concentrations. The NQO2 inhibitors also attenuated TNFa-mediated, NF-kB-driven transcriptional activity. The link between NQO2 and the regulation of NF-kB was confirmed by using short interfering RNA to NQO2 and by the observation that NRH, the cofactor for NQO2 enzyme activity, could regulate NF-kB activity in an NQO2-dependent manner. NF-kB is a potential therapeutic target and this study reveals an underlying mechanism that may be usable for developing new anticancer drugs.

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“…In this inhibition study, 100 nm enzyme inhibitors were added to MCF-7 breast cancer cells for 2 h; this treatment reduces the levels of these enzymes by more than 95% without impacting cell viability. [38] Then the cells were lysed and the total protein of cells admixed with HAuCl 4 for analysis of gold formation through measurements of absorption spectra. The inhibitions of NADH and QOH-1 resulted in a significant decrease of nanoparticle plasmonic peak intensities (Figure 5A), indicating potential role of these enzymes in cellular GNP biomineralization.…”

Section: Nadh Dehydrogenase Flavoprotein 2 and Quinone Oxidoreductase...mentioning

confidence: 99%

Prospecting Cellular Gold Nanoparticle Biomineralization as a Viable Alternative to Prefabricated Gold Nanoparticles

Schwartz-Duval

Sokolov

2022

Advanced Science

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Gold nanoparticles (GNPs) have shown considerable potential in a vast number of biomedical applications. However, currently there are no clinically approved injectable GNP formulations. Conversely, gold salts have been used in the clinic for nearly a century. Further, there is evidence of GNP formation in patients treated with gold salts (i.e., chrysiasis). Recent reports evaluating this phenomenon in human cells and in murine models indicate that the use of gold ions for in situ formation of theranostic GNPs could greatly improve the delivery within dense biological tissues, increase efficiency of intracellular gold uptake, and specificity of GNP formation within cancer cells. These attributes in combination with safe clinical application of gold salts make this process a viable strategy for clinical translation. Here, the first summary of the current knowledge related to GNP biomineralization in mammalian cells is provided along with critical assessment of potential biomedical applications of this newly emergent field.

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ES936 stimulates DNA synthesis in HeLa cells independently on NAD(P)H:quinone oxidoreductase 1 inhibition, through a mechanism involving p38 MAPK

Cited by 5 publications

References 43 publications

Efficient NQO1 Substrates are Potent and Selective Anticancer Agents

Efficient NQO1 Substrates are Potent and Selective Anticancer Agents

In Silico Screening Reveals Structurally Diverse, Nanomolar Inhibitors of NQO2 That Are Functionally Active in Cells and Can Modulate NF-κB Signaling

Prospecting Cellular Gold Nanoparticle Biomineralization as a Viable Alternative to Prefabricated Gold Nanoparticles

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