Retinoic acid prevents experimental Cushing syndrome

Páez-Pereda, Marcelo; Kovalovsky, Damián; Hopfner, Úrsula; Theodoropoulou, Marily; Pagotto, Uberto; Uhl, Eberhard; Losa, Marco; Stalla, Johanna; Grübler, Yvonne; Missale, Cristina; Arzt, Eduardo; Stalla, Günter

doi:10.1172/jci11098

Cited by 175 publications

(167 citation statements)

References 52 publications

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“…Upon glucocorticoid receptor binding, glucocorticoids exert their negative effect by binding on the glucocorticoid responding element (GRE) situated on the POMC promoter and thus, inhibiting ACTH synthesis. inhibiting the transcriptional activity of the transcription factors AP1 and Nur on the POMC gene, which encodes ACTH [46]. However, this inhibitory action of retinoic acid seems to be restricted to ACTH-secreting tumor cells, since, in rat normal pituitary cells, neither ACTH, prolactin nor growth hormone are affected by the treatment, demonstrating a specific effect on tumor cells probably related to the distinct differentiation degree of normal cells versus tumor cells.…”

Section: Retinoic Acid Receptorsmentioning

confidence: 98%

“…However, this inhibitory action of retinoic acid seems to be restricted to ACTH-secreting tumor cells, since, in rat normal pituitary cells, neither ACTH, prolactin nor growth hormone are affected by the treatment, demonstrating a specific effect on tumor cells probably related to the distinct differentiation degree of normal cells versus tumor cells. COUP-TF1 (chicken ovalbumin upstream promotertranscription factor 1), an orphan receptor that belongs to the steroid/thyroid hormone receptor superfamily, with a hypothetical role in the differentiation of ACTH-secreting cells [46][47][48],was described to inhibit the retinoic acid response pathways [48][49][50]. In this direction, in normal ACTH-secreting cells-the corticotrophs-COUP-TF1 was expressed and cells remained unaffected by the retinoic acid treatment.…”

Section: Retinoic Acid Receptorsmentioning

confidence: 99%

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Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

Labeur

Paez-Pereda²,

Arzt

et al. 2008

Rev Endocr Metab Disord

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Cushing's disease is a severe clinical condition caused by hypersecretion of corticosteroids due to excessive ACTH secretion from a pituitary adenoma. This complex endocrine disorder still represents a major challenge for the physician in terms of efficient treatment. In the last years there was only little progress in elucidating the molecular mechanisms responsible for the constitutive and autonomous ACTH secretion of pituitary corticotrophinomas. As a consequence, no effective drug therapy is currently available, particularly if surgical excision is not successful. In the present article we examine recent studies that have investigated the therapeutic potential of retinoic acid receptors as nuclear receptor targets for the treatment of Cushing's disease. Retinoic acid is an efficient drug used for the treatment of different types of cancers and it proved to act in animal models of Cushing's disease. The efficiency of this treatment in patients with this disorder still needs to be tested in clinical trials.

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Section: Retinoic Acid Receptorsmentioning

confidence: 98%

Section: Retinoic Acid Receptorsmentioning

confidence: 99%

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

Labeur

Paez-Pereda²,

Arzt

et al. 2008

Rev Endocr Metab Disord

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“…Retinoic acid is a ligand for Nur77/Nurr1 receptor which is involved in the physiological stimulation of ACTH by CRH (108). Retinoic acid inhibits cell proliferation and induces cell death in ACTH secreting tumours but not in normal pituitary cells.…”

Section: Retinoic Acidmentioning

confidence: 99%

“…In the adrenal cortex it inhibits corticosterone secretion and cell proliferation, while in a mouse model, it blocks tumour growth and reduces circulating ACTH and cortisol. The dose was 10 mg/kg which is within the dose range in human cancer therapy (108). Studies in rodents and dogs models of Cushing's disease have been successful but there is now a need for studies in human (108,109).…”

Section: Retinoic Acidmentioning

confidence: 99%

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Pharmacological management of Cushing's syndrome: an update

Dang

Trainer

2007

Arq Bras Endocrinol Metab

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The treatment of choice for Cushing's syndrome remains surgical. The role for medical therapy is twofold. Firstly it is used to control hypercortisolaemia prior to surgery to optimize patient's preoperative state and secondly, it is used where surgery has failed and radiotherapy has not taken effect. The main drugs used inhibit steroidogenesis and include metyrapone, ketoconazole, and mitotane. RESUMOManejo Farmacológico da Síndrome de Cushing: Uma Atualização. O tratamento de escolha para a síndrome de Cushing ainda é a cirurgia. O papel da terapia medicamentosa é duplo: ele é usado para controlar o hipercortisolismo antes da cirurgia e otimizar o estado pré-operatório do paciente e, adicionalmente, quando ocorre falha cirúrgica e a radioterapia ainda não se mostrou efetiva. Os principais medicamentos são empregados para inibir a esteroidogênese e incluem: metirapona, cetoconazol e mitotano. Medicamentos visando o eixo hipotálamo-hipofisário têm sido investigados, mas seu papel na prática clínica permanece limitado, embora o agonista PPAR-γ e análogo de somatostatina, som-230 (pasireotídeo), requeira estudos adicionais. A única droga que age perifericamente no receptor glicocorticóide é a mifepristona (RU486). O manejo da síndrome de Cushing deve envolver uma combinação terapêutica atuando em diferentes vias da hipercortisolemia, mas o monitoramento dessa terapia ainda permanece um desafio. (Arq Bras Endocrinol Metab

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Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Stoney

Helfer

Rodrigues

et al. 2015

Glia

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Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)‐synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA‐responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1‐expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus. GLIA 2016;64:425–439

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Retinoic acid prevents experimental Cushing syndrome

Cited by 175 publications

References 52 publications

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

Pharmacological management of Cushing's syndrome: an update

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

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