Endocrine Abstracts

Ectopic Cushing syndrome (EAS) is a rare condition characterized by ACTH-dependent hypercortisolism resistant to normal physiologic suppression by glucocorticoids. EAS is due to an extra-pituitary tumor producing bioactive molecules generated by post-translational cleavage of the proopiomelanocortin gene (POMC). EAS is associated with significant morbidity and mortality and although surgical resection of the primary ACTH-producing tumor remains the mainstay of therapy, not all tumors are easily and rapidly localized or are amenable to complete resection often exacerbating clinical symptoms. In this view pharmacological approach can play a crucial role but a safe and effective therapy is still lacking. Beside inhibitors of adrenal cortisol secretion, somatostatin analogs and dopamine agonists, alone or in combination, have been tried, with acceptable results only in a limited number of patients. 9 cis retinoic acid (RA) is derived from vitamin A showing encouraging effect in regulating ACTH secretion and cortisol levels in patients affected by Cushing’s disease. We demonstrated that RA effect in reducing POMC transcription and ACTH production could be potentiated by the co-treatment with Bromocriptine (Br) as a consequence of the permissive role that RA exert on the dopamine receptor type-2 (DRD2). Aim of the present study was to evaluate whether RA alone or in combination with Br is effective in regulating POMC expression and cell viability in cellular model of EAS – i.e. the SCLC-derived cell line DMS79, and primary cultures from 4 bronchopulmonary carcinoids. In DMS79 RA induced a significant dose-dependent decrease in both POMC promotorial activity (67% of control cells at 1 uM, P = 0.0326) and mRNA steady state level (47% at 100 nM, P = 0.0023). After a prolonged incubation (6 days) 1uM RA induce a 39% reduction in cell viability without changes in cell cycle distribution. Concerning DRD2 expression, RA stimulated DRD2 promotorial activity and RNA expression in a dose dependent manner with maximal effect at 1 uM in both assays (130% P = 0.00035, and 424% of control cells, P = 0.00011, respectively). Interestingly, in 3 out 4 tumor cultures, ACTH secretion was reduced of nearly 30% respect to control cells in presence of the combination of RA (5 nM) and Br (500 nM), while single drugs were less effective. Concluding, the effects of RA on POMC synthesis and cell viability in DMS79, and of the combination RA/Br on ACTH secretion in pulmonary carcinoids may represent a suitable starting point for assessing the potential of this treatment regimen in EAS. and has potentially important implications for novel therapeutic approaches.