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



This study sought to investigate the therapeutic use of AA in preclinical models of ACC.



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.



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.



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.



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.
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Chiara
C
Fiorentini
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Martina
M
Fragni
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Paola
P
Perego
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Sara
S
Vezzoli
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Sara A
SA
Bonini
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Monica
M
Tortoreto
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Diego
D
Galli
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Melanie
M
Claps
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Guido A
GA
Tiberio
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Massimo
M
Terzolo
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Cristina
C
Missale
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Maurizio
M
Memo
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Giuseppe
G
Procopio
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Nadia
N
Zaffaroni
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Alfredo
A
Berruti
Section of Pharmacology, Department of Molecular and Translational Medicine (C.F., M.F., S.V., S.A.B., D.G., C.M., M.M., S.S.), University of Brescia, 25123 Brescia, Italy; Molecular Pharmacology Unit (P.P., M.T., N.Z.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health (M.C., A.B.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Surgical Clinic, Department of Clinical and Experimental Sciences (G.A.T.), University of Brescia and ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Internal Medicine 1, Department of Clinical and Biological Sciences (M.T.), University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy; and Medical Oncology I, Genitourinary Unit (G.P.), Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Sandra
S
Sigala
D000069501:Abiraterone Acetate / Q000494:pharmacology*; D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy*; D018268:Adrenocortical Carcinoma / Q000188:drug therapy*; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D051379:Mice; D011374:Progesterone / Q000378:metabolism*
D000728:Androgens; D000970:Antineoplastic Agents; D011374:Progesterone; D000069501:Abiraterone Acetate; D006854:Hydrocortisone