A novel combined glucocorticoid-mineralocorticoid receptor selective modulator markedly prevents weight gain and fat mass expansion in mice fed a high-fat diet

Mammi, Caterina; Marzolla, Vincenzo; Armani, Andrea M.; Feraco, Alessandra; Antelmi, Antonella; Maślak, Edyta; Chłopicki, Stefan; Cinti, Francesca; Hunt, Hazel; Fabbri, Andrea; Caprio, Massimiliano

doi:10.1038/ijo.2016.13

Cited by 29 publications

(18 citation statements)

References 34 publications

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“…For in vitro experiments concentrations were based on human PK studies with mifepristone (40,41), and on previous studies utilizing CORT118335 (42). For in vivo experiments, we tested the SGRMs at concentrations based on mifepristone use in previous mouse studies (11,40,43).…”

Section: Discussionmentioning

confidence: 99%

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Kach

Long

Selman

et al. 2017

Molecular Cancer Therapeutics

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Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here we report that two novel non-steroidal and highly selective GR modulators (SGRMs), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer (PC) and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect AR signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR-expressing, but not in low GR-expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective non-steroidal SGRMs potently inhibit GR activity and PC growth despite AR pathway inhibition demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC.

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Section: Discussionmentioning

confidence: 99%

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Kach

Long

Selman

et al. 2017

Molecular Cancer Therapeutics

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“…Moreover, these cells have been used to describe the effect of melatonin [ 37 ], reactive oxygen species (ROS), or antioxidants [ 38 ] on adipogenic differentiation [ 39 ], and also, the role of some androgens such as testosterone that inhibit the adipogenic differentiation by activation of androgen receptor/β-catenin/T-cell factor 4 interaction in 3T3-L1 adipocytes [ 40 ]. Apart from that, 3T3-L1 cells have been useful to study the mechanisms of action during the differentiation process of several compounds or nutrients that have previously been shown in vivo to inhibit obesity [ 41 ]. Additionally, several endocrine disruptors and obesogenic compounds have also been evaluated during the differentiation of 3T3-L1 cells [ 42 ].…”

Section: Animal Cell Modelsmentioning

confidence: 99%

Cell Models and Their Application for Studying Adipogenic Differentiation in Relation to Obesity: A Review

Ruiz‐Ojeda

Rupérez

Gómez-Llorente

et al. 2016

IJMS

293

221

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Over the last several years, the increasing prevalence of obesity has favored an intense study of adipose tissue biology and the precise mechanisms involved in adipocyte differentiation and adipogenesis. Adipocyte commitment and differentiation are complex processes, which can be investigated thanks to the development of diverse in vitro cell models and molecular biology techniques that allow for a better understanding of adipogenesis and adipocyte dysfunction associated with obesity. The aim of the present work was to update the different animal and human cell culture models available for studying the in vitro adipogenic differentiation process related to obesity and its co-morbidities. The main characteristics, new protocols, and applications of the cell models used to study the adipogenesis in the last five years have been extensively revised. Moreover, we depict co-cultures and three-dimensional cultures, given their utility to understand the connections between adipocytes and their surrounding cells in adipose tissue.

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“…An additional advantage of new compounds -whether they are SGRMs of full GR antagonists -is that they lack affinity for androgen and progesterone receptors that is a characteristic of mifepristone (45)(46)(47)(48). Of note, the compound C118335 does act as an antagonist for the mineralocorticoid receptor, at a lower affinity than for GR (26), and this may be responsible for some it its effects (49).…”

mentioning

confidence: 99%

Glucocorticoid receptor modulators

Meijer

Koorneef

Kroon

2018

Annales d'Endocrinologie

109

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The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects. Selective glucocorticoid receptor modulators are ligands that induce a receptor conformation that allows activation of only a subset of downstream signaling pathways. Such molecules thereby combine agonistic and antagonistic properties. Here we discuss the mechanisms underlying selective receptor modulation and their promise in treating diseases in several organ systems where cortisol signaling plays a role.

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A novel combined glucocorticoid-mineralocorticoid receptor selective modulator markedly prevents weight gain and fat mass expansion in mice fed a high-fat diet

Cited by 29 publications

References 34 publications

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Cell Models and Their Application for Studying Adipogenic Differentiation in Relation to Obesity: A Review

Glucocorticoid receptor modulators

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