Oxidized analogs of Di(1<i>H</i>-indol-3-yl)methyl-4-substituted benzenes are NR4A1-dependent UPR inducers with potent and safe anti-cancer activity

Sanchez, Marisa; Xia, Zebin; Rico-Bautista, Elizabeth; Cao, Xihua; Cuddy, Michael; Castro, David J.; Correa, Ricardo G.; Chen, Liqun; Yu, Jinghua; Bobkov, Andrey A.; Ruvolo, Vivian; Andreeff, Michael; Oshima, Robert G.; Matsuzawa, Shu Ichi; Reed, John C.; Zhang, Xiao Kun; Hansel, Donna E.; Wolf, Dieter A; Dawson, Marcia I.

doi:10.18632/oncotarget.25285

Cited by 5 publications

(2 citation statements)

References 34 publications

(56 reference statements)

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“…This response was blocked by leptomycin B, a nuclear export inhibitor, and it was shown that AHPN-induced apoptosis was due to nuclear export of NR4A1 and mitochondrial targeting of the receptor (111). Similar effects were observed in cancer cells treated with many other structurally diverse compounds including phobol esters, etoposide, cadmium, cholic acid derivatives, etoposide, HDAC inhibitors, dibutyltin derivatives, coumarin analogues, bile acids, oxidized analogues of bis-indole derived compounds, acetylshikonin analogues, and n-butylenephthalide and related compounds (111)(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123)(124). Many of these agents not only induced nuclear export and apoptosis in cancer cells but also increased overall levels of NR4A1.…”

Section: Extranuclear Nr4a Actionmentioning

confidence: 73%

The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer

Safe

Karki

2021

Molecular Cancer Research

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The three-orphan nuclear receptor 4A genes are induced by diverse stressors and stimuli, and there is increasing evidence that NR4A1 (Nur77), NR4A2 (Nurr1), and NR4A3 (Nor1) play an important role in maintaining cellular homeostasis and in pathophysiology. In blood-derived tumors (leukemias and lymphomas), NR4A expression is low and NR4A1−/−/NR4A3−/− double knockout mice rapidly develop acute myelocytic leukemia, suggesting that these receptors exhibit tumor suppressor activity. Treatment of leukemia and most lymphoma cells with drugs that induce expression of NR4A1and NR4A3 enhances apoptosis, and this represents a potential clinical application for treating this disease. In contrast, most solid tumor–derived cell lines express high levels of NR4A1 and NR4A2, and both receptors exhibit pro-oncogenic activities in solid tumors, whereas NR4A3 exhibits tumor-specific activities. Initial studies with retinoids and apoptosis-inducing agents demonstrated that their cytotoxic activity is NR4A1 dependent and involved drug-induced nuclear export of NR4A1 and formation of a mitochondrial proapoptotic NR4A1–bcl-2 complex. Drug-induced nuclear export of NR4A1 has been reported for many agents/biologics and involves interactions with multiple mitochondrial and extramitochondrial factors to induce apoptosis. Synthetic ligands for NR4A1, NR4A2, and NR4A3 have been identified, and among these compounds, bis-indole derived (CDIM) NR4A1 ligands primarily act on nuclear NR4A1 to inhibit NR4A1-regulated pro-oncogenic pathways/genes and similar results have been observed for CDIMs that bind NR4A2. Based on results of laboratory animal studies development of NR4A inducers (blood-derived cancers) and NR4A1/NR4A2 antagonists (solid tumors) may be promising for cancer therapy and also for enhancing immune surveillance.

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Section: Extranuclear Nr4a Actionmentioning

confidence: 73%

The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer

Safe

Karki

2021

Molecular Cancer Research

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“…The experiment was performed blindly in triplicates with positive and negative controls to ensure reproducibility. 25 26 27 …”

Section: Methodsmentioning

confidence: 99%

In Vitro Evaluation of Candida albicans Adhesion and Related Surface Properties of CAD/CAM Denture Base Resins

Fouda,

Gad,

Abualsaud

et al. 2023

Eur J Dent

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Objective The aim of this study was to evaluate the surface roughness, contact angle, and adhesion of Candida albicans to computer-aided designing/computer-aided manufacturing (CAD/CAM) and heat-polymerized (HP) denture base materials. Materials and Methods Specimens were allocated to six groups based on the composition of studied denture base materials, HP acrylic resin, milled resins (AvaDent and IvoCad), and 3D-printed resins (ASIGA, FormLabs, and NextDent). Ten specimens per group were used for each test (n = 10/test). Surface roughness and contact angles were analyzed using profilometer and goniometer, respectively. Adhesion of C. albicans was counted using colony-forming unit (CFU/mL). Means and standard deviations were calculated, and then one-way analysis of variance (ANOVA), followed by Tukey's post hoc test. Correlation of Candida adhesion and surface parameters was determined by using Pearson's correlation analysis. Results No statistically significant difference was noted in surface roughness between HP, milled, and 3D-printed denture base resins except NextDent, which showed significantly higher roughness in comparison to all other resins (p = 0.001). In terms of contact angle, milled resins had the lowest value, followed by HP, ASIGA, and FormLabs, whereas NextDent showed the highest contact angle (p = 0.001). C. albicans adhesion showed no significant difference between all denture base resins. A positive and significant correlation was found between C. albicans adhesion and contact angle (p = 0.003), while no correlation was reported between C. albicans adhesion and surface roughness (p = 0.523). Conclusion Adhesion of C. albicans was similar in all tested specimens. Surface roughness showed no significant difference between all groups except NextDent, which had the highest value. Milled denture base resins had the lowest contact angle among all groups.

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Metabolic targeting of cancer by a ubiquinone uncompetitive inhibitor of mitochondrial complex I

Jain

Kluza

et al. 2022

Cell Chemical Biology

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Oxidized analogs of Di(1H-indol-3-yl)methyl-4-substituted benzenes are NR4A1-dependent UPR inducers with potent and safe anti-cancer activity

Cited by 5 publications

References 34 publications

The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer

The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer

In Vitro Evaluation of Candida albicans Adhesion and Related Surface Properties of CAD/CAM Denture Base Resins

Metabolic targeting of cancer by a ubiquinone uncompetitive inhibitor of mitochondrial complex I

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