Antisecretive and antitumor activity of abiraterone acetate in human adrenocortical cancer: A preclinical study

Chiara Fiorentini, Martina Fragni, Paola Perego, Sara Vezzoli, Sara A. Bonini, Monica Tortoreto, Diego Galli, Melanie Claps, Guido A. Tiberio, Massimo Terzolo, Cristina Missale, Maurizio Memo, Giuseppe Procopio, Nadia Zaffaroni, Alfredo Berruti, Sandra Sigala

Research output: Contribution to journalArticlepeer-review

Abstract

Context: Patients with adrenocortical carcinoma (ACC) frequently sufferfromcortisol 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: This study sought 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 AAtreated 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 NCIH295R 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 ofAAseems to require PgR.

Original languageEnglish
Pages (from-to)4594-4602
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume101
Issue number12
DOIs
Publication statusPublished - Dec 1 2016

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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