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

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.

Analysis of 10 Adrenocortical Carcinoma Patients in the Cohort of the Precision Medicine Platform MONDTI

“…PR and ER overexpression is another typical finding in ACC [16]. The results of a study in a preclinical model suggest that silencing of PR and ER in ACC may have anti-hormone-secretive and antitumor activity, perhaps mediated through inhibition of the Wnt/β-catenin pathway [17]. We did not consider PR or ER inhibition monotherapy as a therapeutic option because of the low evidence for clinical efficacy.…”

Palbociclib inhibits proliferation of human adrenocortical tumor cells

“…Several molecular targets have been recently identified for novel treatment approaches in the management of ACC, including mTOR [17,18], Wnt-beta catenin signaling pathway [13], receptors for different growth factors and the ACAT1 [2] and CYP17A1 [19] steroidogenic enzymes.…”

Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells

“…Despite the constitutive activation of the CTNNB1 gene, however, the Wnt/β-catenin pathway in the NCI-H295R cell model retains, at least partially, the capability to respond to exogenous regulatory stimuli. This was shown to be induced by progesterone in previous studies of our group [25,26] as well as in a study testing the Wnt/β-catenin inhibitor PNU-7654 [24].…”

“…NCI-H295R cells were treated with IC50 value of trabectedin for 4 days. Whole cell lysates were prepared in ice-cold buffer with protease and phosphatase inhibitor cocktails (Roche, Milano, Italy) as previously described [25]. Fractionated cell lysates were prepared according to [47].…”