Abstract
Simple SummaryMitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma and for postoperative adjuvant therapy. It is known that mitotane destroys the adrenal cortex impairing steroidogenesis, although its exact molecular mechanism is still unclear. However, confounding factors affecting in vitro experiments could reduce the relevance of the studies. In this review, we explore in vitro studies on mitotane effects, highlighting how different experimental conditions might contribute to the controversial findings. On this basis, it may be necessary to re-evaluate the experiments taking into account their potential confounding factors such as cell strains, culture serum, lipoprotein concentration, and culture passages, which could hide important molecular results. As a consequence, the identification of novel pharmacological molecular pathways might be used in the future to implement personalized therapy, maximizing the benefit of mitotane treatment while minimizing its toxicity.Mitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma and is increasingly used for postoperative adjuvant therapy. Mitotane action involves the deregulation of cytochromes P450 enzymes, depolarization of mitochondrial membranes, and accumulation of free cholesterol, leading to cell death. Although it is known that mitotane destroys the adrenal cortex and impairs steroidogenesis, its exact mechanism of action is still unclear. The most used cell models are H295-derived cell strains and SW13 cell lines. The diverging results obtained in presumably identical cell lines highlight the need for a stable in vitro model and/or a standard methodology to perform experiments on H295 strains. The presence of several enzymatic targets responsive to mitotane in mitochondria and mitochondria-associated membranes causes progressive alteration in mitochondrial structure when cells were exposed to mitotane. Confounding factors of culture affecting in vitro experiments could reduce the significance of any molecular mechanism identified in vitro. To ensure experimental reproducibility, particular care should be taken in the choice of culture conditions: aspects such as cell strains, culture serum, lipoproteins concentration, and culture passages should be carefully considered and explicated in the presentation of results. We aimed to review in vitro studies on mitotane effects, highlighting how different experimental conditions might contribute to the controversial findings. If the concerns pointed out in this review will be overcome, the new insights into mitotane mechanism of action observed in-vitro could allow the identification of novel pharmacological molecular pathways to be used to implement personalized therapy.
Highlights
Mitotane, 1,1-(o,p0 -Dichlorodiphenyl)-2,2-dichloroethane (o,p0 -DDD), commercially available as Lysodren® (HRA Pharma Rare Diseases, Paris, France), is a parent compound of the insecticide dichlorodiphenyltrichloroethane (DDT). o,p0 -DDD is metabolized by the mitochondria of adrenal cells in DDE (1,1-(o,p0 -Dichlorodiphenyl)-2,2 dichloroethene) and DDA (1,1-(o,p0 -Dichlorodiphenyl) acetic acid) through α-hydroxylation and β-hydroxylation, respectively
Several molecular mechanisms have been identified in vitro and involve: deregulation of key mitochondrial genes, such as those encoding the P450 family of cytochromes, both at the transcriptional and functional level; depolarization and rupture of mitochondrial membranes; reduction in interactions between mitochondria and endoplasmic reticulum by altering the integrity of Mitochondria-associated membranes (MAM); reduction in the expression of proteins, such as STAR and SOAT1, involved in cellular uptake and cholesterol metabolism leading to the accumulation of free cholesterol and cell death
The divergent results obtained in presumably identical cell lines highlight the need for a stable in vitro model and/or a standard methodology to perform experiments on H295 strains
Summary
1,1-(o,p0 -Dichlorodiphenyl)-2,2-dichloroethane (o,p0 -DDD), commercially available as Lysodren® (HRA Pharma Rare Diseases, Paris, France), is a parent compound of the insecticide dichlorodiphenyltrichloroethane (DDT). o,p0 -DDD is metabolized by the mitochondria of adrenal cells in DDE (1,1-(o,p0 -Dichlorodiphenyl)-2,2 dichloroethene) and DDA (1,1-(o,p0 -Dichlorodiphenyl) acetic acid) through α-hydroxylation and β-hydroxylation, respectively. Mitotane produces dose-related cellular toxicity causing the rupture of mitochondrial membranes mainly on the zona fasciculata and reticularis, whereas a minimal effect on the zona glomerulosa has been observed [13]. This differential action explains why aldosterone secretion is less affected by mitotane treatment [14,15]. The mechanism of action of mitotane remains poorly defined at a molecular level due to controversial results generated by in vitro studies addressing its anticancer effect. We will review these in vitro studies on mitotane action highlighting how different experimental conditions might contribute to the controversial results. Further elucidation of mitotane action after a reappraisal of the in vitro experimental conditions may contribute to the implementation of patient-tailored treatment
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