CYP17 inhibitor abiraterone acetate as a promising future treatment for canine Cushing’s syndrome: in vitro investigations

Abstract

INTRODUCTION: Cushing’s syndrome or hypercortisolism is one of the most frequently diagnosed endocrinopathies in dogs. At present, medical management of canine hypercortisolism consists of either trilostane or mitotane. Both treatments have disadvantages associated with undesired hypoadrenocorticism. Therefore, a more specific inhibition of cortisol production is desirable. The steroidogenic enzyme cytochrome P-450c17 (CYP17) could be an interesting target for selective inhibition of cortisol production without impeding the production of aldosterone. Abiraterone acetate (AA), a highly selective, irreversible CYP17-inhibitor, is already successfully used in the treatment of prostate cancer in humans. As side effects of AA are mostly related to hypocortisolism, this approach seems interesting as a novel medical treatment option for canine hypercortisolism. OBJECTIVES: The aim of this in vitro study was to determine the effects of AA on 1) steroidogenesis, 2) mRNA expression of steroidogenic enzymes, steroidogenic factors and proliferation markers, and 3) cell viability in both normal adrenocortical cells and adrenocortical tumor cells. MATERIAL AND METHODS: Canine primary adrenocortical cell cultures from adrenal glands of 10 healthy dogs and from cortisol-secreting adrenocortical tumors of 4 dogs were incubated with AA. ACTH-dependent hypercortisolism was mimicked by co-incubation with synthetic ACTH. The mRNA expression was studied with RT-qPCR and steroid concentrations were determined by RIA (cortisol) and LC-MS (whole steroid profile). The alamarBlue® assay was carried out to determine cell viability. RESULTS: AA dose-dependently decreased cortisol production in normal adrenocortical cell cultures. Aldosterone levels remained fairly constant, whereas the production of progesterone dose-dependently increased. In canine adrenocortical tumor cells, cortisol levels decreased as well. No significant alterations were found in the mRNA expression of steroidogenic enzymes, steroidogenic factors and proliferation markers, with the exception of CYP11A1, which was upregulated in non-stimulated normal adrenocortical cells. No negative influence of AA on cell viability was noted. CONCLUSION: We conclude that in normal adrenocortical cell cultures, AA effectively inhibits cortisol production in vitro without impeding aldosterone production and without decreasing adrenocortical cell viability. The upregulated progesterone production requires further studies. Concerning the adrenocortical tumors, a larger sample size is needed to draw reliable conclusions. On the whole, AA seems to be a promising future treatment option in the medical management of canine Cushing’s syndrome.