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, 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
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: 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 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 seems to require PgR.
Source: PubMed