ECE2020 Oral Communications Endocrine-related Cancer (7 abstracts)
Differential adrenal toxicity of SOAT1-inhibitors
Isabel Weigand 1 , Silviu Sbiera 1,2 , Sabine Kendl 1 , Urlaub Hanna 1 , Hantel Constanze 3,4 , Kiseljak-Vassiliades Katja 5,6 , Wierman Margaret E 5,6 , Martin Fassnacht 1,2 & Matthias Kroiss 1,2
1University Hospital, University of Würzburg, Department of Internal Medicine I, Würzburg, Germany; 2Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany; 3Department of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland; 4Medizinische Klinik und Poliklinik III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany; 5University of Colorado School of Medicine, Division of Endocrinology, Aurora, CO, United States; 6Research Service Veterans Affairs Medical Center, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, United States
Background: Mitotane is the only approved treatment for advanced adrenocortical carcinoma and was shown to inhibit Sterol-O-Acyl transferase 1 (SOAT1) which leads to the depletion of cholesterol esters and increase of free cholesterol in the ACC cell line H295R. Downstream activation of the endoplasmic reticulum stress (ER-stress) pathway results in decreased adrenocortical cell viability.
Aim: To better characterize the effects of SOAT1 inhibition in ACC, four human cell lines (H295R, MUC-1, CU-ACC1 and CU-ACC2) were treated with the SOAT1 inhibitors SOATi) mitotane, nevasimibe, AZD 3988 and Sandoz 58-035.
Methods: SOAT1 inhibition was quantified in vitro, ER-stress marker expression by qPCR and WB, cell viability by cell titer glo-assay, SOAT1 knockdown (KD) by siRNA and steroid hormone synthesis by LC-MS/MS.
Results: Mitotane, nevasimibe, AZD 3988 and Sandoz 58-035 inhibited SOAT1 in NCI-H295R cells with IC50 of 1.3 µM, 3.1 nM, 0.9 nM and 13 nM, respectively. Expression of ER-stress markers was activated by mitotane, nevasimibe, only poorly by AZD 3988 and not at all by Sandoz 58-035. Sandoz58-035 did not impair viability of any ACC cell line. H295R cells were most responsive to SOAT1 inhibition, while MUC-1 cells were least responsive, with EC50 > 100 µM for all inhibitors. Only mitotane efficiently blocked cortisol secretion in the two highly cortisol-secreting cell lines H295R and CU-ACC1. KD of SOAT1 in NCI-H295R cells did not affect the response to mitotane treatment.
Conclusion: Although SOAT1 inhibition was confirmed for all compounds, downstream effects on ER-stress markers and cell viability exhibit marked differences. SOAT1 expression does not affect mitotane responsiveness in H295R cells, suggesting targets different from SOAT1 are relevant for in vitro cytotoxicy. Their identification may lead to novel ACC treatments.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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