ECE2010 Poster Presentations Adrenal (66 abstracts)
Sunitinib decreases adrenocortical cancer cell proliferation and specifically inhibits adrenal steroidogenesis
Miriam Reuss 1 , Matthias Kroiss 1 , Sarah Johanssen 1 , Melanie Beyer 1 , Martina Zink 1 , Michaela Hartmann 2 , Vivek Dhir 3 , Stefan Wudy 2 , Wiebke Arlt 3 , Silviu Sbiera 1 , Bruno Allolio 1 & Martin Fassnacht 1
1Medicine I, Endocrine and Diabetes Unit, University Hospital Würzburg, Würzburg, Germany; 2Centre for Child and Adolescent Medicine, University Hospital Gießen, Gießen, Germany; 3Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK.
Background: The multi-tyrosine kinase inhibitor sunitinib is approved for advanced renal cell carcinoma and gastrointestinal stroma tumors. It targets both tumor vessels and malignant cells. Animal experiments have pointed to a direct adrenotoxic effect of the drug.
Aims: We hypothesized that sunitinib may inhibit proliferation of adrenocortical cancer (ACC) cells and influence adrenal steroid hormone synthesis.
Results: Sunitinib reduced cell viability in both ACC cell lines NCI-h295 and SW13 in a dose-dependent manner (MTT assays SW13: 96±7% (0.1 μM), 90±9%* (1 μM), 79±9%* (2 μM), 62±9%* (5 μM), and 57±3%* (10 μM) vs 100±9% in control cells, *P<0.01). Analyses of selected steroid hormones in supernatant of NCI-h295-cells indicated a significant decrease of glucocorticoid secretion after incubation with sunitinib, while precursor hormones accumulated. Using isotope dilution gas chromatography mass spectrometry a complete steroid profile exhibited an increased ratio of DHEA/androstenedione (0.1 μM: 1.02±0.04; 1 μM: 1.30±0.06*; 5 μM: 1.50±0.05*; *P<0.01) and 17-OH-pregnenolone/17-OH-progesterone. This suggested a dose-dependent inhibition of 3β-hydroxysteroid dehydrogenase (HSD3B) catalyzing these reactions. Whilst no direct inhibition of HSD3B activity by sunitinib was detected in yeast microsome assays, we found a dose-dependent down-regulation of HSD3B in real time PCR and western blot after 24 h incubation with sunitinib (relative RNA expression: 1 μM 47±7%*; 5 μM 33±7%*; 10 μM 27±6%*; protein expression: 1 μM 82±8%; 5 μM 62±8%*; 10 μM 55±9%*; *P<0.05), whereas the expression of other adrenal enzymes like CYP11A1 remained unaffected.
Conclusion: Our data demonstrate a specific blockade of adrenal steroidogenesis by sunitinib via downregulation of HSD3B. Studies in patients treated with sunitinib are warranted to assess the clinical impact of this finding. Whether inhibition of ACC cell proliferation by sunitinib is clinically relevant is currently investigated in the SIRAC-trial.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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