Involvement of 27-Hydroxycholesterol in Mitotane Action on Adrenocortical Carcinoma.

Antonina Germano,Fiorella Biasi,Laura Saba,Daniela Rossin,Valerio Leoni,Soraya Puglisi,Giuseppe Poli,Noemi Iaia,Claudio Caccia,Vittoria Basile,Massimo Terzolo

doi:10.3390/cells9040885

Antonina Germano, Fiorella Biasi + Show 9 more

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https://doi.org/10.3390/cells9040885

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Abstract

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Mitotane, the standard treatment for ACC, impairs adrenocortical steroid biosynthesis and cholesterol metabolism. In the H295R cell line, a standard ACC in vitro model, mitotane was previously reported to enhance the production of some oxysterols. To verify the possible mechanistic involvement of oxysterols in the anti-ACC effect of mitotane, a gas chromatography mass spectrometry (GC-MS) profiling of oxysterols and the main cholesterol precursors was carried out in H295R cells. Among the oxysterols detected in mitotane-treated cells, 27OHC was markedly produced, as well as lanosterol and lathosterol cholesterol precursors. In this cell model, mitotane was confirmed to affect mitochondrial transmembrane potential and induce apoptosis. Such cytotoxic effects were perfectly matched by H295R cell treatment with a single identical micromolar amount of 27OHC. The mitotane-dependent strong increase in 27OHC was confirmed in vivo, in the plasma of ACC patients under treatment with the drug. Moreover, lanosterol, lathosterol, desmosterol and, to a minor extent, 24-hydroxycholesterol and 25-hydroxycholesterol plasma levels were significantly increased in those patients. The cytotoxic effect of mitotane on ACC cells may be partly related to the increased intracellular level of 27OHC induced by the drug itself.

Highlights

Adrenocortical carcinoma (ACC) is a rare, aggressive endocrine tumor usually associated with hypercortisolism and characterized by a poor prognosis [1]
With regard to the side chain oxysterol of major relevance detectable in human peripheral blood, 24OHC and 25OHC were practically undetectable in H295R cells both mitotane-treated or not
As far as human adrenal cancer cells are concerned, this paper provides solid evidence of specific cytotoxic and pro-apoptotic actions of 27OHC, which matches the in vitro effect exerted by an identical micromolar amount of mitotane (Figure 2)

Summary

Introduction

Adrenocortical carcinoma (ACC) is a rare, aggressive endocrine tumor usually associated with hypercortisolism and characterized by a poor prognosis [1]. The only approved treatment of ACC relies on an old adrenolytic drug, mitotane, a derivate of the insecticide dichlorodiphenyltrichloroethane (DDT). Mitotane has shown to be effective both in adjuvant settings and in the treatment. It was reported that an increase in mevalonic acid during mitotane administration was associated with increased cholesterol synthesis [7]. These authors have shown that this effect is due to the known drug ability to block CYP450-mediated reactions, influencing formation of cholesterol oxidized metabolites responsible for down-regulating hepatic cholesterol synthesis

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