Cushing's disease or pituitary-dependent hypercortisolism (PDH) is a common endocrine disorder in dogs. At present, medical management of canine PDH consists of either trilostane or mitotane therapy. Both treatments have disadvantages associated with the induction of hypoadrenocorticism. Therefore, a more specific inhibition of glucocorticoid synthesis is desirable. Our recent studies indicate that the steroidogenic enzyme cytochrome P-450c17 (CYP17) could be an interesting target for selective inhibition of cortisol production without impeding the synthesis of aldosterone. Abiraterone acetate (AA), a highly selective irreversible CYP17-inhibitor, is already available on the market and successfully used for the treatment of castration-resistant prostate cancer in humans. In addition, the registration for human application will probably enable a relatively straightforward implementation into veterinary clinical practice. As side effects of AA are mostly related to hypocortisolism, this approach seems interesting as a novel medical treatment option for canine hypercortisolism.

The aim of this study was to determine the effects of AA on cortisol synthesis; on mRNA expression of steroidogenic genes encoding for CYP17, 3β-hydroxysteroid dehydrogenase (3β-HSD) and Ki67, a cellular marker for proliferation; and on adrenocortical cell viability.

Canine primary adrenocortical cell cultures from adrenal glands of seven healthy dogs were incubated with various concentrations of AA. PDH was mimicked by co-incubation with synthetic ACTH (Synacthen®). After 48 hours of incubation, RNA was isolated to evaluate gene expression using real-time quantitative PCR (RT-qPCR). Culture medium was removed for measurement of cortisol after 72 hours of incubation. In addition, cell viability was assessed using alamarBlue® assay.

AA dose-dependently decreased cortisol concentration in ACTH-stimulated adrenocortical cells with an IC50 value of 24.2 nM (p<0.0001). At the highest AA concentration of 10 µM, the average suppression of cortisol synthesis was 92.5% (SEM±3.5). The mRNA expression of CYP17, 3β-HSD and Ki67 was not significantly altered after incubation with AA. Finally, AA did not significantly affect adrenocortical cell viability.

We conclude that AA is effective in reducing cortisol synthesis in vitro without affecting adrenocortical cell viability and proliferation. Therefore, AA seems to be a promising future treatment option in the medical management of canine Cushing's disease. To ascertain this, further in vivo studies are warranted.

Disclosures

No disclosures to report.