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Potent inhibition of breast cancer by bis-indole-derived nuclear receptor 4A1 (NR4A1) antagonists.

ABSTRACT: BACKGROUND:Nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors, and the methylene-substituted bis-indole derivative 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) acts as an NR4A1 antagonist (inverse agonist) and inhibits NR4A1-regulated pro-oncogenic pathways/genes in breast and other cancer cells. METHODS:Buttressed analogs of DIM-C-pPhOH were synthesized by condensation of the substituted p-hydroxybenzaldehydes with indole. Breast cancer cell growth, survival, and migration assays were carried out by cell counting, Annexin V staining, and Boyden chamber assays, respectively. Changes in RNA and protein expression were determined by RT-PCR and western blots, respectively. Analysis of RNAseq results was carried out using Ingenuity Pathway Analysis, and in vivo potencies of NR4A1 antagonists were determined in athymic nude mice bearing MDA-MB-231 cells in an orthotopic model. RESULTS:Ingenuity Pathway analysis of common genes modulated by NR4A1 knockdown or treatment with DIM-C-pPhOH showed that changes in gene expression were consistent with the observed decreased functional responses, namely inhibition of growth and migration and increased apoptosis. DIM-C-pPhOH is rapidly metabolized and the effects and potencies of buttressed analogs of DIM-C-pPhOH which contain one or two substituents ortho to the hydroxyl groups were investigated using NR4A1-regulated gene/gene products as endpoints. The buttressed analogs were more potent than DIM-C-pPhOH in both in vitro assays and as inhibitors of mammary tumor growth. Moreover, using 1,1-bis(3'-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (DIM-C-pPhOh-3-Cl-5-OCH3) significant tumor growth inhibition was observed at doses as low as 2 mg/kg/d which was at least an order of magnitude more potent than DIM-C-pPhOH. CONCLUSIONS:These buttressed analogs represent a more potent set of second generation NR4A1 antagonists as inhibitors of breast cancer.

SUBMITTER: Hedrick E

PROVIDER: S-EPMC6681651 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Potent inhibition of breast cancer by bis-indole-derived nuclear receptor 4A1 (NR4A1) antagonists.

Hedrick Erik E Li Xi X Cheng Yating Y Lacey Alexandra A Mohankumar Kumaravel K Zarei Mahsa M Safe Stephen S

Breast cancer research and treatment 20190522 1

<h4>Background</h4>Nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors, and the methylene-substituted bis-indole derivative 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) acts as an NR4A1 antagonist (inverse agonist) and inhibits NR4A1-regulated pro-oncogenic pathways/genes in breast and other cancer cells.<h4>Methods</h4>Buttressed analogs of DIM-C-pPhOH were synthesized by condensation of the substituted p-hydroxybenzaldehydes with indole. Breast cancer cell growth, s ...[more]

PMID: 31119568

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Project description:Resveratrol is a polyphenolic phytochemical found in fruits, nuts and vegetables that contributes to the remarkable dietary effects of polyphenolic as inhibitors aging and multiple aging related diseases. In addition, resveratrol has been extensively investigated as an inhibitor of inflammatory diseases including cancer, however, the underlying mechanisms of these chemotherapeutic effects of resveratrol are not completely understood. In cancer cells resveratrol inhibits cell growth, survival, migration and invasion, and many of the effects of resveratrol resemble those observed for bis-indole derived (CDIM) compounds that bind the pro-oncogenic nuclear receptor 4A1 (NR4A1, Nur77) and act as receptor antagonists. Using an isothermal titration calorimetry binding assay, we observed that resveratrol bound to the ligand binding domain of NR4A1 with a KD value of 2.4 µM and a ΔG of -32.2 kJ/mol. Resveratrol also inhibited NR4A1-dependent transactivation in H460 and H1299 lung cancer cells suggesting that resveratrol is an NR4A1 antagonist. This observation was confirmed in a series of functional (cell proliferation, survival, migration and invasion) and gene expression assays in H460 and H1299 cells showing that treatment with resveratrol mimicked the effects of NR4A1 knockdown and were similar to results of previous studies using CDIM/NR4A1 antagonists. These data indicate that applications of resveratrol may be more effective in patients that overexpress NR4A1 which is a negative prognostic factor for patients with some solid tumor-derived cancers. Significance Statement We have examined the mechanism of action of resveratrol and show binding to NR4A1 (KD = 2.4 µM) and inhibition of NR4A1-dependent transactivation in lung cancer cells. Treatment of H460 and H1299 lung cancer cells with resveratrol inhibits cell growth, survival, migration/invasion and related genes, and acts as an NR4A1 antagonist. Resveratrol can now be used more effectively in cancer chemotherapy by targeting patients that overexpress NR4A1 in lung cancer.

Dataset Information

Potent inhibition of breast cancer by bis-indole-derived nuclear receptor 4A1 (NR4A1) antagonists.

Publications

Potent inhibition of breast cancer by bis-indole-derived nuclear receptor 4A1 (NR4A1) antagonists.

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