Comparative evaluation of the biological characteristics of a novel retinoid X receptor agonist and bexarotene
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ABSTRACT:
PROVIDER: PRJNA1181754 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31213808_1.fastq.gz | Fastqsanger.gz | |||
| SRR31213808_2.fastq.gz | Fastqsanger.gz | |||
| SRR31213809_1.fastq.gz | Fastqsanger.gz | |||
| SRR31213809_2.fastq.gz | Fastqsanger.gz | |||
| SRR31213810_1.fastq.gz | Fastqsanger.gz |
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Project description:Retinoid X receptor (RXR) is a crucial and distinctive member of the nuclear receptor superfamily, which is involved in regulating various physiological processes. RXR agonists have the potential to treat Alzheimer’s disease (AD). In this study, we identified a novel RXR agonist superior to existing drugs after extensively exploring the biological properties of 6-hydroxy-3’-propyl-[1,1’-biphenyl]-3-propanoic acid (6OHA), a compound synthesized in our laboratory based on the structure of magnaldehyde B. 6OHA exhibited higher selectivity for RXRα over retinoic acid receptor (RARα) and lower transcriptional activity for RXRg compared to the existing RXR agonist bexarotene (Bex). RNA-sequencing analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggest that 6OHA and Bex exhibit similar gene expression patterns but have distinct transcriptional effects; 6OHA was more closely associated with chemotaxis and response to stimuli compared to Bex. Pharmacokinetic studies revealed that 6OHA exhibited faster intestinal absorption, reached higher concentrations in the brain and liver shortly after oral dministration, and was cleared from the body more rapidly than Bex, subsequently inducing target gene transcription in the brain. Bex increased serum triglyceride and decreased serum thyrotropin and free thyroxine levels, whereas 6OHA did not induce these adverse effects, attributable to the distinct properties of 6OHA as an RXR agonist compared to Bex. Our results highlight 6OHA as a promising RXR agonist for treating AD without any adverse effects.
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Project description:Retinoid X receptor (RXR) is a crucial and distinctive member of the nuclear receptor superfamily, which is involved in regulating various physiological processes. RXR agonists have the potential to treat Alzheimer’s disease (AD). In this study, we identified a novel RXR agonist superior to existing drugs after extensively exploring the biological properties of 6-hydroxy-3’-propyl-[1,1’-biphenyl]-3-propanoic acid (6OHA), a compound synthesized in our laboratory based on the structure of magnaldehyde B. 6OHA exhibited higher selectivity for RXRα over retinoic acid receptor (RARα) and lower transcriptional activity for RXRg compared to the existing RXR agonist bexarotene (Bex). RNA-sequencing analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggest that 6OHA and Bex exhibit similar gene expression patterns but have distinct transcriptional effects; 6OHA was more closely associated with chemotaxis and response to stimuli compared to Bex. Pharmacokinetic studies revealed that 6OHA exhibited faster intestinal absorption, reached higher concentrations in the brain and liver shortly after oral dministration, and was cleared from the body more rapidly than Bex, subsequently inducing target gene transcription in the brain. Bex increased serum triglyceride and decreased serum thyrotropin and free thyroxine levels, whereas 6OHA did not induce these adverse effects, attributable to the distinct properties of 6OHA as an RXR agonist compared to Bex. Our results highlight 6OHA as a promising RXR agonist for treating AD without any adverse effects.
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Project description:Comparative evaluation of the biological characteristics of a novel retinoid X receptor agonist and bexarotene II
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Project description:Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Differentiation can attenuate or block tumor growth; thus, phenotypic screenings were performed to search for drugs inducing differentiational morphological changes in mesenchymal recurrent GBM, a temozolomide (TMZ)-resistant brain cancer. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured GBM stem cells. Bexarotene decreased nestin expression and significantly increased GFAP expression. Gene expression changes by bexarotene and all-trans retinoic acid (ATRA), a well-known differentiation inducer, were compared. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). Both drugs also induced a potential oncogene, transglutaminase 2 (TG2), but the fold-change induced by bexarotene was considerably lesser than that by ATRA. Consistently, the TG2 activity in GBM was elevated several folds by ATRA. Because TG2 upregulation is correlated with tumor transformation and resistance, it is important to control its overexpression. Bexarotene does not upregulate TG2 as much as ATRA, and bexarotene showed in vivo tumoricidal effects in a GBM xenograft mouse model. Thus, these findings strongly suggest that bexarotene is more beneficial than ATRA and should be considered as a differentiation therapeutic agent for mesenchymal GBM.
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2015-11-04 | E-GEOD-66988 | biostudies-arrayexpress
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Project description:While skeletal myogenesis is tightly coordinated by myogenic regulatory factors including MyoD and myogenin, chromatin modifications have emerged as vital mechanisms of myogenic regulation. We have previously established that bexarotene, a clinically approved agonist of retinoid X receptor, promotes the specification and differentiation of skeletal muscle lineage. Here, we examine a genome-wide impact of rexinoids on myogenic differentiation through integral RNA-seq and ChIP-seq analyses. We found that bexarotene promotes myoblast differentiation through the coordination of exit from the cell cycle and the activation of muscle-related genes. We uncovered a new mechanism of rexinoid action which is mediated by the nuclear receptor and largely reconciled through a direct regulation of MyoD gene expression. In addition, we determined a rexinoid-responsive residue-specific histone acetylation at a distinct chromatin state associated to MyoD and myogenin. Thus, we provide novel molecular insights into the interplay between retinoid X receptor signaling and chromatin states pertinent to myogenic programs in early myoblast differentiation.
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Project description:Acquired drug resistance represents a major challenge in chemo-therapy treatment for various types of cancers. We have found that the retinoid X receptorâselective agonist bexarotene (LGD1069, Targretin) was efficacious in treating chemo-resistant cancer cells. The goal of this microarray study was to understand the mechanism of bexaroteneâs role in overcoming acquired drug resistance using human breast cancer cells MDA-MB-231 as a model system and paclitaxel as model compound. After MDA-MB-231 cells were repeatedly treated with paclitaxel for 8 cycles with each cycle including a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium, MDA cells resistant to paclitaxel were developed and their growth was no longer inhibited by paclitaxel treatment. Those MDA cells with acquired drug resistance, when treated with paclitaxel and bexarotene in combination, could regain their sensitivity and their growth were again inhibited. Therefore, RNA samples from parental MDA-MB-231 cells, paclitaxel-resistant MDA cells treated with vehicle, paclitaxel alone or in combination with bexarotene, were used for perform global gene expression profiling with Affymetrix HG-U133A gene chips. Keywords: Drug Treatment MDA-MB-231 cells were exposed to regimens on a 10-day cycle: a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium. Paclitaxel resistant MDA-MB-231 cells (MDA-PR) were established within 8 cycles of such treatment (80 days). These MDA-PR cells were then treated with vehicle control, paclitaxel along, or the combination of 30 nM paclitaxel ( 3 days on and 7 days off) and 1 µM Targretin (10 days on) in a new 10-day cycle for 3 months. Thus, there are four treatment groups, parent MDA cells, MDA-PR, MDA-PR treated with paclitaxel, MDA-PR treated with paclitaxel and bexarotene, and each group had four biological replicates.
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