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• W1767025218 abstract "Adrenocortical carcinoma (ACC) is among the deadliest endocrine malignancies. Radical surgical resection of a localized tumor is the only curative option for ACC, but in many patients cancer is diagnosed already at an advanced stage, needing pharmacological treatment. The mainstay of the medical therapy for metastatic ACC is mitotane (o,p -DDD), a derivative of the insecticide dichlorodiphenyl-trichloroethane, which is also used as an adjuvant treatment in patients resected for localized ACC but at a high risk of relapse. Mitotane is an old drug. More than 60 years ago, Nelson and Woodard showed that technical-grade dichlorodiphenildichloroethane caused selective atrophy of the adrenal cortex in the dog (1). Subsequent studies demonstrated that the active substance was o,p -DDD, an impurity in the technical-grade product, which was then introduced in the treatment of ACC (2). Today mitotane is the only approved drug for ACC treatment, even if controversies remain concerning its long-term efficacy (reviewed in reference 3). Mitotane has both an adrenolytic action on ACC cells and inhibits steroid hormone synthesis, with beneficial effects in patients with Cushing’s syndrome. However, mitotane therapy often has important side effects that limit its use in the clinic. Furthermore, for many patients it is difficult to attain and maintain the therapeutic levels of plasma mitotane (between 14 and 20 mg/L) (4). A better knowledge of the mechanism of action of mitotane is then required to develop new drugs that are more efficient and better tolerated by ACC patients. Recent studies showed that mitotane treatment negatively affects mitochondrial respiratory chain activity (5) and induces mitochondrial morphofunctional changes in ACC cells (6), but the mechanisms of those effects remained elusive. A breakthrough in our understanding of how mitotane works as a selective toxic agent for adrenal cells is represented by the study of Sbiera et al (7) published in this issue of Endocrinology. Here the authors show compelling evidence that mitotane treatment rapidly induces endoplasmic reticulum (ER) stress in ACC cells but not in cancer cell lines from tissues other than the adrenal. ER stress generates protein misfolding in the ER, which is sensed by several signaling cascades and triggers a response targeted to limit the effects of ER stress. Collectively this phenomenon is termed the unfolded protein response (UPR) (8). Mitotane-induced ER stress is correlated with the accumulation of toxic lipids inside ACC cells. In particular, increase in free cholesterol and decrease of cholesteryl esters pinpointed the inhibition of sterol-Oacyl-transferase (SOAT) (also known as acyl-coenzyme A cholesterol acyltransferase) activity as a potential mechanism of action of mitotane. In the adrenal, this enzyme has the role to produce stores of esterified cholesterol protecting cells from the damaging effects of free cholesterol. Cholesterol esters can be rapidly made available as substrates for steroidogenesis after ACTH stimulation by the action of hormone-sensitive lipase (9). Consistently with its important role in steroidogenesis, SOAT1 has been shown to be a target for steroidogenic factor-1, an essential transcriptional regulator of steroidogenic genes (10). Based on those results, Sbiera et al (7) show that mitotane indeed inhibits SOAT1 activity in vitro and that its effect correlates with" @default.
• W1767025218 created "2016-06-24" @default.
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• W1767025218 date "2015-11-01" @default.
• W1767025218 modified "2023-10-18" @default.
• W1767025218 title "Mitotane Revisited: A New Target for an Old Drug" @default.
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• W1767025218 doi "https://doi.org/10.1210/en.2015-1796" @default.
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