Targeting initiation and progression of Cushing disease by protecting levels of cell cycle inhibitor (p27) in veterinary medicine

Cushing disease (CD), due to pituitary corticotroph tumor ACTH hypersecretion, drives excess adrenal cortisol production with adverse morbidity and mortality. Loss of glucocorticoid negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis leads to autonomous transcription of the corticotroph precursor hormone proopiomelanocortin (POMC), consequent ACTH over-production and adrenal hypercortisolism. We previously reported that R-roscovitine (CYC202, seliciclib), a 2,6,9-trisubstituted purine analogue, suppresses CDK2/cyclin E, and inhibits ACTH in mice and zebrafish. We hypothesized that intra-pituitary cyclin E signaling regulates corticotroph tumor POMC transcription independently of cell cycle progression. The aim was to investigate whether R-roscovitine inhibits human ACTH in corticotroph tumors by targeting the CDK2/cyclin E signaling pathway. Primary cell cultures of surgically resected human corticotroph tumors were treated with or without R-roscovitine, ACTH measured...