Mitotane Revisited: A New Target for an Old Drug.

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