ECE2017 Eposter Presentations: Pituitary and Neuroendocrinology Pituitary - Basic (13 abstracts)
Ketoconazole induces inhibition of cell viability and apoptosis in an ACTH-secreting tumour cell line model
Roberta Patalano 1 , Claudia Pivonello 1 , Domenico Solari 2 , Francesca Vitulli 2 , Davide Iacuaniello 1 , Monica De Leo 1 , Mariarosaria Negri 1 , Donatella Paola Provvisiero 1 , Luigi Maria Cavallo 2 , Paolo Cappabianca 2 , Annamaria Colpo 1 & Rosario Pivonello 1
1Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy; 2Dipartimento di Neuroscienze, Scienze Riproduttive e Odontostomatologiche, Sezione di Neurochirurgia, Università Federico II di Napoli, Naples, Italy.
Chronic cortisol excess as a consequence of ACTH overproduction from a pituitary tumour is responsible for the development of Cushing’s disease (CD). The first-line treatment for CD is pituitary surgery, but medical treatment is an alternative second-line approach to control cortisol excess. Among pharmacological agents, the adrenal-blocking drug ketoconazole (KT), is able to control cortisol excess in the majority of patients with CD. During KT treatment, the adrenal block of cortisol production is expected to induce increase in ACTH levels, but conflicting data demonstrated ACTH to be increased, unchanged or decreased, suggesting a possible direct KT effect on the pituitary tumour. The aim of the current study was to evaluate the effects of KT on cell viability and apoptosis in mouse corticotroph tumour cell line (AtT20-D16). MTT assay was assessed to evaluate cell viability and to evaluate the induction of cell apoptosis the study of mitochondrial membrane potential by JC-1 assay and of PARP cleavage by western blot were performed. KT induced a dose- (from 10–12 M to 6×10–5 M, concentrations covering KT therapeutic range of 200–1200 mg/daily) and time – (from 24 h to 144 h) dependent inhibition of cell viability (82.4%, P<0.0001 at 6×10–5M, 84.4% P<0.0001 at 4×10–5 M, 81.1% P<0.0001 at 2×10–5 M and 34% P<0.01 at 10–5 M after 144 h). KT treatment at 24 and 48 h induced depolarization of mitochondrial membrane potential (108%, P<0.027 at IC50 2.5×10–5 M) followed by PARP cleavage, confirming the activation of apoptosis. In conclusion, these preliminary data suggest that KT has a direct effect on pituitary tumour significantly reducing cell viability and inducing apoptosis on a corticotroph tumour cell model, shedding new light on the possible mechanisms by which KT may control cortisol excess in CD.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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