Context:Patients with adrenocortical carcinoma (ACC) frequently suffer from cortisol excess, which portends a negative prognosis. Rapid control of cortisol hypersecretion and tumor growth are the main goals of ACC therapy. Abiraterone acetate (AA) is a potent inhibitor of 17alpha-hydroxylase/17,20-lyase, a key enzyme of adrenal steroidogenesis. Objective:To investigate the therapeutic use of AA in preclinical models of ACC. Design:AA antisecretive and antiproliferative effects were investigated in vitro using NCI-H295R and SW13 ACC cell lines and human primary ACC cell cultures, as well as in vivo using immunodeficient mice. Methods:Steroid secretion, cell viability and proliferation were analyzed in untreated and AA-treated ACC cells. The ability of AA to affect the Wnt/beta-catenin pathway in NCI-H295R cells was also analyzed. Progesterone receptor (PgR) gene was silenced by the RNA interference approach. The antitumor efficacy of AA was confirmed in vivo in NCI-H295R cells xenografted in immunodeficient mice. Results:AA reduced the secretion of both cortisol and androgens, increased production of progesterone and induced a concentration-dependent decrease of cell viability in the NCI-H295R cells and primary secreting ACC cultures. AA also reduced beta-catenin nuclear accumulation in NCI-H295R cells. AA administration to NCI-H295R-bearing mice enhanced progesterone levels and inhibited tumor growth. The cytotoxic effect of AA was prevented by either blocking PgR or by gene silencing. Conclusion:AA is able to inhibit hormone secretion and growth of ACC both in vitro and in vivo. It also reduces beta-catenin nuclear accumulation. The cytotoxic effect of AA appears to require PgR.

Antisecretive and Antitumor Activity of Abiraterone Acetate in Human Adrenocortical Cancer: A Preclinical Study.

TERZOLO, Massimo;BERRUTI, Alfredo;
2016-01-01

Abstract

Context:Patients with adrenocortical carcinoma (ACC) frequently suffer from cortisol excess, which portends a negative prognosis. Rapid control of cortisol hypersecretion and tumor growth are the main goals of ACC therapy. Abiraterone acetate (AA) is a potent inhibitor of 17alpha-hydroxylase/17,20-lyase, a key enzyme of adrenal steroidogenesis. Objective:To investigate the therapeutic use of AA in preclinical models of ACC. Design:AA antisecretive and antiproliferative effects were investigated in vitro using NCI-H295R and SW13 ACC cell lines and human primary ACC cell cultures, as well as in vivo using immunodeficient mice. Methods:Steroid secretion, cell viability and proliferation were analyzed in untreated and AA-treated ACC cells. The ability of AA to affect the Wnt/beta-catenin pathway in NCI-H295R cells was also analyzed. Progesterone receptor (PgR) gene was silenced by the RNA interference approach. The antitumor efficacy of AA was confirmed in vivo in NCI-H295R cells xenografted in immunodeficient mice. Results:AA reduced the secretion of both cortisol and androgens, increased production of progesterone and induced a concentration-dependent decrease of cell viability in the NCI-H295R cells and primary secreting ACC cultures. AA also reduced beta-catenin nuclear accumulation in NCI-H295R cells. AA administration to NCI-H295R-bearing mice enhanced progesterone levels and inhibited tumor growth. The cytotoxic effect of AA was prevented by either blocking PgR or by gene silencing. Conclusion:AA is able to inhibit hormone secretion and growth of ACC both in vitro and in vivo. It also reduces beta-catenin nuclear accumulation. The cytotoxic effect of AA appears to require PgR.
2016
101
12
4594
4602
http://press.endocrine.org/doi/10.1210/jc.2016-2414
Chiara, Fiorentini; Fragni, Martina; Perego, Paola; Vezzoli, Sara; Bonini, Sara A.; Tortoreto, Monica; Galli, Diego; Claps, Melanie; Tiberio, Guido A.; Terzolo, Massimo; Missale, Cristina; Memo, Maurizio; Procopio, Giuseppe; Zaffaroni, Nadia; Berruti, Alfredo; Sigala, Sandra
File in questo prodotto:
File Dimensione Formato  
ANTISECRETIVE AND ANTITUMOR ACTIVITY OF ABIRATERONE ACETATE IN HUMAN ADRENOCORTICAL CANCER.pdf

Accesso aperto

Descrizione: Articolo principale
Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 491.72 kB
Formato Adobe PDF
491.72 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1597096
Citazioni
  • ???jsp.display-item.citation.pmc??? 15
  • Scopus 30
  • ???jsp.display-item.citation.isi??? 30
social impact