Journal Article

Histone Deacetylase Inhibitor SAHA Is a Promising Treatment of Cushing Disease

Chittiboina, Prashant, Chatain, Grégoire P, Wang, Xiang, Maric, Dragan, Lu, Jie, Walbridge, Stuart, Zhuang, Zhengping, Bugarini, Alejandro

2017

Overview

ContextRemission failure following transsphenoidal surgery in Cushing disease (CD) from pituitary corticotroph tumors (CtTs) remains clinically challenging. Histone deacetylase inhibitors (HDACis) are antitumor drugs approved for clinical use, with the potential to affect adrenocorticotropin hormone (ACTH) hypersecretion by inhibiting pro-opiomelanocortin (POMC) transcription.ObjectiveTesting the efficacy of suberoylanilide hydroxamic acid (SAHA) on human and murine ACTH-secreting tumor (AtT-20) cells.DesignCell viability, ACTH secretion (enzyme-linked immunosorbent assay), apoptosis, and gene expression profile were investigated on AtT-20 cells. In vivo efficacy was examined in an athymic nude mouse AtT-20 xenograft model. SAHA efficacy against human-derived corticotroph tumor (hCtT) (n = 8) was tested in vitro.SettingNational Institutes of Health.InterventionSAHA (0.5 to 8 µM).Main Outcome MeasuresAtT-20 and hCtT cell survival, in vitro/invivo ACTH measurements.ResultsSAHA (1 µM) reduced AtT-20 viability to 75% at 24 hours, 43% at 48 hours (analysis of variance; P = 0.002). Apoptosis was confirmed with elevated BAX/Bcl2 ratio and FACS. Intriguingly, early (3-hour) significant decline (70%; P < 0.0001) of secreted ACTH and diminished POMC transcription was observed with SAHA (1 µM). Microarray analysis revealed a direct association between liver X receptor alpha (LXRα) and POMC expression. Accordingly, SAHA reduced LXRα in AtT-20 cells but not in normal murine corticotrophs. Xenografted nude-mice tumor involution (126 ± 33/160 ± 35 vs 337 ± 49 mm3; P = 0.0005) was observed with 5-day intraperitoneal SAHA, with reversal of elevated ACTH (P < 0.0001). SAHA did not affect serum ACTH in nontumor mice. Lastly, we confirmed that SAHA (1 µM/24 h) decreased hCtT survival (78.92%; P = 0.0007) and ACTH secretion (83.64%; P = 0.03).ConclusionOur findings demonstrate SAHA’s efficacy in reducing survival and ACTH secretion in AtT-20 and hCtT cells, providing a potential intervention for recurrent/unremitting CD.SAHA efficacy was tested on human/murine ACTH-secreting tumor cells. It successfully reduced survival and ACTH secretion, offering potential novel treatment of recurrent/unremitting Cushing disease.

• Publisher: Endocrine Society,Copyright Oxford University Press,Oxford University Press
• Subject: ACTH-Secreting Pituitary Adenoma - drug therapy / ACTH-Secreting Pituitary Adenoma - secretion / Adenoma - drug therapy / Adenoma - secretion / Adrenocorticotropic hormone / Adrenocorticotropic Hormone - drug effects / Adrenocorticotropic Hormone - secretion / Animals / Apoptosis / Apoptosis - drug effects / BAX protein / Bcl-2 protein / Blotting, Western / Cell Line, Tumor / Cell survival / Cell Survival - drug effects / Cell viability / Clinical s / Corticotrophs - cytology / Corticotrophs - drug effects / Cushing syndrome / Cushing's disease / DNA microarrays / Enzyme-Linked Immunosorbent Assay / Female / Flow Cytometry / Gene expression / Gene Expression Profiling / Histone deacetylase / Histone Deacetylase Inhibitors - pharmacology / Humans / Hydroxamic acid / Hydroxamic Acids - pharmacology / In Vitro Techniques / Liver X receptors / Mice / Mice, Nude / Nervous system diseases / Pituitary / Pituitary (anterior) / Pituitary ACTH Hypersecretion - drug therapy / Pro-Opiomelanocortin - drug effects / Pro-Opiomelanocortin - genetics / Proopiomelanocortin / Real-Time Polymerase Chain Reaction / Remission / Secretion / Surgery / Transcription / Tumor cells / Tumors / Xenograft Model Antitumor Assays / Xenografts