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Inhibition of Adrenocortical Carcinoma Cell Proliferation by Steroidogenic Factor-1 Inverse Agonists

Institut de Pharmacologie Moléculaire et Cellulaire Centre National de la Recherche Scientifique Unité Mixte de Recherche 6097 and Université de Nice-Sophia Antipolis (M.D., J.C., D.D., E.L.), 06560 Valbonne, France; and Scripps Research Molecular Screening Center and Molecular Therapeutics (F.M., P.H.), The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458

Address all correspondence and requests for reprints to: Enzo Lalli, M.D., Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6097, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France. E-mail: ninino{at}ipmc.cnrs.fr.

Context: Transcription factor steroidogenic factor-1 (SF-1) plays a pivotal role in the control of adrenocortical cell steroidogenesis and proliferation. SF-1 amplification and overexpression are found in most cases of childhood adrenocortical tumors (ACTs).

Objective: Our objective was to investigate the effect of SF-1 inverse agonists of the alkyloxyphenol and isoquinolinone classes on the proliferation of human adrenocortical cell lines expressing SF-1 (H295R), in conditions of basal and increased SF-1 expression, or negative for SF-1 expression (SW-13).

Main Outcome Measures: Proliferation assays, immunoblots, flow cytometric analyses, steroid hormone assays, and reverse transcription quantitative PCR were used.

Results: SF-1 inhibitors of the alkyloxyphenol class displayed a dose-dependent inhibitory effect on both SF-1-positive and -negative ACT cells, whereas SF-1 inverse agonists of the isoquinolinone class selectively inhibited cell proliferation elicited by SF-1 overexpression. These drugs also inhibited stimulated steroid hormone secretion and CYP21 and CYP17 mRNA expression.

Conclusion: SF-1 inhibitors may represent a useful tool in the chemotherapy of ACTs.