Inhibition of Cholesterol Esterification in the Adrenal Gland by ATR101/PD132301-2, A Promising Case of Drug Repurposing.

Abstract

Adrenocortical carcinoma (ACC) is a malignancy that harbors a significant risk of recurrence even after complete resection and has a particularly unfavorable prognosis in advanced stages (1, 2). Current treatment is challenging due to unsatisfactory efficacy of most regimens. Despite remarkable international efforts aiming at a better understanding of the disease at the molecular level (3) and collaborative international clinical trials (4, 5), the prognosis of patients has improved little during the past few years. In the current issue of Endocrinology, LaPensee et al (7) report on preclinical investigations supporting the repurposing of the small molecule compound PD132301–2 (6) as a therapy for ACC (7). PD132301–2, now renamed ATR-101, an N-phenylN -(1-phenylcycloalkyl)urea, was developed by ParkeDavis in the 1990s for treatment of hypercholesterolemia and atherosclerosis. At the time, several pharmaceutical companies pursued development of acyl-CoA (coenzyme A):cholesterol acyl transferases (ACATs) inhibitors (8) but eventually discontinued clinical development (9). ACAT enzymes (EC 2.3.1.26) catalyze the esterification of cholesterol but also other sterols (10) with activated fatty acids to form sterol esters and are hence also referred to as sterol-O-acyl transferases (SOATs). Inhibition of SOAT/ACAT activity had emerged as a strategy to reduce atherosclerosis for 2 reasons (8). First, foam cell macrophages in the arterial wall require this enzymatic activity to esterify and store cholesterol in the form of cholesteryl esters (11). Second, inhibition of SOAT was shown to reduce low density lipoprotein-cholesterol levels through reduced intestinal uptake of cholesterol. Cloning of the first human SOAT enzyme (12) and subsequent investigations (see Ref. 13 for review) revealed that indeed 2 different SOAT enzymes exist with isoformspecific tissue distribution and function (14). Although SOAT1 is involved in formation of intracellular deposits of lipid droplets in the adrenal cortex, kidney epithelial cells, and macrophages, SOAT2 plays an eminent role in the intestinal absorption of cholesterol and hepatic lipoprotein secretion (15). Interestingly, adrenal cortical degeneration has been described with several high-affinity ACAT/SOAT inhibitors (16, 17) but has been best documented for PD132301–2/ATR-101 (18–20). It is yet unexplained why this effect is not observed in mice and rats but particularly apparent in dogs. Only recently the idea emerged that this tissue-specific cytotoxic impact on the adrenal cortex observed with SOAT inhibitors may be beneficial for the treatment of ACC. This has been investigated in the present article. It is remarkable, that coming from a very different perspective, the orphan drug mitotane, a cornerstone of contemporary ACC treatment, recently has been discovered to be an inhibitor of adrenal SOAT1 (21). In the same study, we also demonstrated that inhibition of SOAT1 is likely a key molecular mechanism of action of mitotane and transduced through endoplasmic reticulum stress pathways.