Identification of novel subtype selective RAR agonists

Piu, Fabrice; Gauthier, Natalie K; Olsson, Roger; Currier, Erika A.; Lund, Birgitte W.; Croston, Glenn; Hacksell, Uli; Brann, Mark R.

doi:10.1016/j.bcp.2005.10.025

Cited by 29 publications

(20 citation statements)

References 19 publications

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“…In contrast, the Am80-AC55649 group did not lead to fully restored neurite length, compared with 7 days of Am80 treatment. According to the present results, RARß 2 pathway was involved in ATRA-induced neuronal differentiation, which was consistent with previous reports (15,16,21). In contrast, Am80 may not activate RARß 2 pathway but presented potent of neurite outgrowth effect.…”

Section: Discussionsupporting

confidence: 93%

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Am80 induces neuronal differentiation in a human neuroblastoma NH-12 cell line

Shiohira

Kitaoka²,

Shirasawa³

et al. 2010

Int J Mol Med

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Abstract. Retinoids including natural vitamin A, its derivatives and synthetic compounds work as transcription factors through the retinoic acid receptors (RAR, RXR). All-trans retinoic acid (ATRA), a family of retinoids, is an internal ligand of RAR and well known as a useful differentiation inducer to treat acute promyelocytic leukemia (APL). ATRA therapy is now established as an initial treatment for APL. Recently, to improve therapeutic potency and reduce adverse effects of ATRA, a novel synthetic selective agonist for RAR· and ß, Am80, was developed and applied to APL treatment.In this study, we tested whether Am80 was capable of inducing neuronal differentiation in a human neuroblastoma cell line, NH-12 and compared the differentiation effects between Am80 and ATRA. Morphological studies demonstrated that Am80 induced more potent neurite outgrowth and also proved lesser cell toxicity than ATRA. Am80 upregulated the expression of tropomyosin-related kinase B as well as ATRA. Moreover, Am80 increased the expression of the neuronal marker, growth-associated protein 43. These findings suggest that Am80 induces neuronal differentiation to a greater extent than ATRA and thus may help establishing therapeutic strategies against neuronal degenerative disorders such as Parkinson's disease. IntroductionAll-trans retinoic acid (ATRA), a natural derivative of vitamin A, is known as a differentiation inducer and has been utilized for the initial therapy to successfully treat acute promyelocytic leukemia (APL) by itself or in combination with other chemotherapies (1-3). A number of synthetic retinoids have been developed to improve its therapeutic potency. Among them, Am80 (Tamibarotene), which is a retinoic acid receptor · (RAR·)-and RARß-specific synthetic agonist, exhibits greater potency than ATRA in differentiation assays of tumor cells in vitro (4,5) and a clinical trial (6).ATRA-induced cell differentiation effect is dependent on the RARs and retinoid X receptor (RXR) pathways (7). RARs and RXRs are members of the nuclear hormone receptor superfamily acting as transcription factors and can regulate gene transcription associated with neuronal differentiation (8-10). Therefore, ATRA is commonly used to induce neuronal differentiation (11)(12)(13)(14). RARß pathway has been shown to be involved in neuronal differentiation (15,16). More specifically, ATRA has been shown to induce the expression of tropomyosin-related kinase B (TrkB) and to increase sensitivity against brain-derived neurotrophic factor (BDNF) as well as neuronal markers such as growth-associated protein-43 (GAP43) (17)(18)(19). In this study, we investigated whether Am80 could induce neuronal differentiation in NH-12 human neuroblastoma cells. We also compared the effect of Am80 with that of ATRA in morphological and biochemical cell differentiation analyses. Materials and methodsCell lines and cell culture. Human neuroblastoma cell line, NH-12, was kindly provided by the Cell Resource Center for Biomedical Research Institute of Development Aging and ...

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Section: Discussionsupporting

confidence: 93%

“…Therefore, we investigated, using AC55649, a RARß 2 selective agonist (21), whether the RARß 2 pathway contributed to Am80-induced neuronal differentiation. As shown in Fig.…”

Section: Involvement Of Rarß 2 In Am80-induced Morphological Differenmentioning

confidence: 99%

Am80 induces neuronal differentiation in a human neuroblastoma NH-12 cell line

Shiohira

Kitaoka²,

Shirasawa³

et al. 2010

Int J Mol Med

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“…Therefore subtype selective RAR agonists are of great interest as pharmacological tools. 29 In Figure 5b a RAR-a specific antagonist CID445091 and the RAR-c specific agonist BMS184394 are shown as reference. The area where RAR-c prefers lipophilic groups (marked with an arrow) could explain the opposite specificity of the two compounds and could be important for the design of selective RAR ligands.…”

Section: Rar Subtypes (Nr1b)mentioning

confidence: 99%

Field‐based comparison of ligand and coactivator binding sites of nuclear receptors

2009

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A structure-based comparison of the ligand-binding domains of 35 nuclear receptors from five different subfamilies is presented. Their ligand and coactivator binding sites are characterized using knowledge-based contact preference fields for hydrophobic and hydrophilic interactions implemented in the MOE modeling environment. Additionally, for polar knowledge-based field points the preference for negative or positive electrostatic interactions is estimated using the Poisson-Boltzmann equation. These molecular-interaction fields are used to cluster the nuclear receptor family based on similarities of their binding sites. By analyzing the similarities and differences of hydrophobic and polar fields in binding pockets of related receptors it is possible to identify conserved interactions in ligand and coactivator binding pockets, which support e.g. design of specific ligands during lead optimization or virtual screening as docking filter. Examples of remarkable similarities between ligand binding sites of members from phylogenetically different nuclear receptor families (RXR, RAR, HNF4, NR5) and differences between closely related subtypes (LXR, RAR, TR) are discussed in more detail. Significant similarities and differences of coactivator binding sites are shown for NR3Cs, LXRs and PPARs.

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“…The RA system is the best studied and well-documented reproducible and nonsophisticated in vitro model for ND and therefore deserves comparative proteomic testing and can be even used for pharmacological testing of candidate compounds modifying the ND process [14,15].…”

Section: Introductionmentioning

confidence: 99%

Proteins involved in neuronal differentiation of neuroblastoma cell line N1E‐115

Freilinger

Gelpí

et al. 2007

Electrophoresis

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Neuronal differentiation (ND) represents a well-defined phenomenon in biological terms but proteins involved have not been studied systematically. We therefore aimed to study ND by retinoic acid (RA) in a widely used neuroblastoma cell line by comparative proteomics. The ND was induced in the N1E-115 cell line by serum deprivation and RA treatment. Undifferentiated cells and cells undergoing serum deprivation served as controls. Protein extracts were run on 2-DE followed by MALDI-TOF or MALDI-TOF-TOF analysis. Quantification was carried out using specific software and stringent statistical analysis was performed. Tubulin beta 5, cat eye syndrome critical region protein 5 homolog, putative GTP-binding protein PTD004 homolog, and the metabolic proteins glyceraldehyde-3-phosphate dehydrogenase and transketolase were differentially regulated. Differential protein levels of cytoskeleton proteins including tubulins and metabolic proteins have been reported to be regulated by ND. Herein, specific signaling differences as reflected by putative GTP-binding protein PTD004 changes in differentiated cells are shown and a possible role for the Cat eye syndrome critical region protein 5 homolog is proposed. The protein disulfide isomerase associated 3 protein fits the already proposed findings of chaperon regulation by ND. The study forms the molecular basis for further evaluation of the functional roles of the differentially expressed proteins in ND.

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Identification of novel subtype selective RAR agonists

Cited by 29 publications

References 19 publications

Am80 induces neuronal differentiation in a human neuroblastoma NH-12 cell line

Am80 induces neuronal differentiation in a human neuroblastoma NH-12 cell line

Field‐based comparison of ligand and coactivator binding sites of nuclear receptors

Proteins involved in neuronal differentiation of neuroblastoma cell line N1E‐115

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