Steroidogenic factor-1 inverse agonists as a treatment option for canine hypercortisolism: in vitro study

K. Sanders, J. A. Mol, A. Slob, H. S. Kooistra, S. Galac

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

Hypercortisolism is one of the most commonly diagnosed endocrinopathies in dogs, and new targeted medical treatment options are desirable. Steroidogenic factor-1 (SF-1), an orphan nuclear hormone receptor, is a key regulator of adrenal steroidogenesis, development, and growth. In pituitary-dependent hypercortisolism (PDH), high plasma ACTH concentrations increase the transcriptional activity of SF-1. In adrenal-dependent hypercortisolism, SF-1 expression is significantly greater in dogs with recurrence after adrenalectomy than in those without recurrence. Inhibition of SF-1 could therefore be an interesting treatment option in canine spontaneous hypercortisolism. We determined the effects of 3 SF-1 inverse agonists, compounds IsoQ A, #31, and #32, on cortisol production, on the messenger RNA (mRNA) expression of steroidogenic enzymes and SFs, and on cell viability, in primary adrenocortical cell cultures of 8 normal adrenal glands and of 3 cortisol-secreting adrenocortical tumors (ATs). To mimic PDH, the normal adrenocortical cell cultures were stimulated with ACTH. The results show that only compound #31 inhibited cortisol production and SF-1 target gene expression in non–ACTH-stimulated and ACTH-stimulated normal adrenocortical cells but did not affect cell viability. In the AT cell cultures, the effects of #31 on cortisol production and target gene expression were variable, possibly caused by a difference in the SF-1 mRNA expressions of the primary tumors. In conclusion, inhibition of SF-1 activity shows much promise as a future treatment for canine hypercortisolism.
Originele taal-2Engels
Pagina's (van-tot)23-30
Aantal pagina's8
TijdschriftDomestic Animal Endocrinology
Volume63
DOI's
StatusGepubliceerd - 1 apr. 2018
Extern gepubliceerdJa

Trefwoorden

  • ACTH
  • Ad4BP
  • Adrenal
  • Cushing's syndrome
  • NR5A1
  • Pituitary

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