TY - JOUR
T1 - Antisecretive and antitumor activity of abiraterone acetate in human adrenocortical cancer
T2 - A preclinical study
AU - Fiorentini, Chiara
AU - Fragni, Martina
AU - Perego, Paola
AU - Vezzoli, Sara
AU - Bonini, Sara A.
AU - Tortoreto, Monica
AU - Galli, Diego
AU - Claps, Melanie
AU - Tiberio, Guido A.
AU - Terzolo, Massimo
AU - Missale, Cristina
AU - Memo, Maurizio
AU - Procopio, Giuseppe
AU - Zaffaroni, Nadia
AU - Berruti, Alfredo
AU - Sigala, Sandra
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
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U2 - 10.1210/jc.2016-2414
DO - 10.1210/jc.2016-2414
M3 - Article
AN - SCOPUS:85003721868
VL - 101
SP - 4594
EP - 4602
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 12
ER -