Involvement of 27-Hydroxycholesterol in Mitotane Action on Adrenocortical Carcinoma
Antonina Germano1,2, Daniela Rossin1, Valerio Leoni3
1Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano (Turin), Italy.
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.
Insights
Mitotane, a treatment for adrenocortical carcinoma (ACC), increases oxysterol 27OHC levels, inducing cancer cell death. This finding was observed in cell models and ACC patients, suggesting 27OHC contributes to mitotane
Area of Science:
- Endocrinology
- Oncology
- Biochemistry
Background:
- Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options and poor prognosis.
- Mitotane is the standard therapy for ACC, primarily affecting steroid biosynthesis and cholesterol metabolism.
- Previous studies indicated mitotane may alter oxysterol production in ACC cell lines.
Purpose of the Study:
- To investigate the role of oxysterols in the anti-cancer effects of mitotane on adrenocortical carcinoma.
- To analyze oxysterol and cholesterol precursor profiles in mitotane-treated ACC cells and patients.
Main Methods:
- Gas chromatography-mass spectrometry (GC-MS) profiling of oxysterols and cholesterol precursors in H295R cells and patient plasma.
- Assessment of mitochondrial transmembrane potential and apoptosis induction in H295R cells.
- Correlation analysis between drug treatment, oxysterol levels, and cytotoxic effects.
Main Results:
- Mitotane treatment markedly increased 27-hydroxycholesterol (27OHC) and cholesterol precursors (lanosterol, lathosterol) in H295R cells.
- Mitotane induced apoptosis and affected mitochondrial potential in H295R cells, effects mimicked by 27OHC.
- Elevated plasma 27OHC levels were confirmed in ACC patients treated with mitotane, along with increased levels of other sterols.
Conclusions:
- The cytotoxic effect of mitotane on adrenocortical carcinoma cells is potentially mediated by drug-induced elevation of intracellular 27OHC.
- Oxysterol modulation represents a possible mechanism underlying mitotane's therapeutic action in ACC.
- Further research into oxysterol pathways could reveal novel therapeutic strategies for ACC.
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