Adrenocortical carcinoma (ACC) is an aggressive tumor with very poor prognosis. Novel medical treatment opportunities are required. We investigated the effects of interferon-β (IFN-β), alone or in combination with mitotane, on cell growth and cortisol secretion in primary cultures of 13 human ACC, 3 adrenal hyperplasias, 3 adrenal adenomas and in 2 ACC cell lines. Moreover, the interrelationship between the effects of IGF-II and IFN-β was evaluated. Mitotane inhibited cell total DNA content/well (representing cell number) in 7/11 (IC50: 38±9.2 µM), and cortisol secretion in 5/5 ACC cultures (IC50: 4.5±0.1 µM). IFN-β reduced cell number in 10/11 (IC50: 83±18 IU/mL) and cortisol secretion in 5/5 ACC cultures (IC50: 7.3±1.5 IU/mL). The effect of IFN-β on cell number included the induction of apoptosis. IFN-β strongly inhibited mRNA expression of STAR, CYP11A1, CYP17A1 and CYP11B1. Mitotane and IFN-β induced an additive inhibitory effect on cell number and cortisol secretion. IGF-II (10nM) inhibited apoptosis and increased cell number and cortisol secretion. These effects were counteracted by IFN-β treatment. Finally, IFN-β inhibited IGF-II secretion and mRNA expression. In conclusion, IFN-β is a potent inhibitor of ACC cell growth in human primary ACC cultures, partially mediated by an inhibition of the effects of IGF-II, as well as its production. The increased sensitivity of ACC cells to mitotane induced by treatment with IFN-β may open the opportunity for combined treatment regimens with lower mitotane doses. The inhibition of the expression of steroidogenic enzymes by IFN-β is a novel mechanism that may explain its inhibitory effect on cortisol production
Interferon-beta is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane / P.M. van Koetsveld, G. Vitale, R.A. Feelders, M.M. Waaijers, D. Sprij-Mooij, R.R. de Krijger, E-J. M. Speel, J. Hofland, S.W. Lamberts, W.W. de Herder, L. Hofland. - In: ENDOCRINE-RELATED CANCER. - ISSN 1351-0088. - 20:3(2013 May), pp. 443-454. [10.1530/ERC-12-0217]
Interferon-beta is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane
G. VitaleSecondo
;
2013
Abstract
Adrenocortical carcinoma (ACC) is an aggressive tumor with very poor prognosis. Novel medical treatment opportunities are required. We investigated the effects of interferon-β (IFN-β), alone or in combination with mitotane, on cell growth and cortisol secretion in primary cultures of 13 human ACC, 3 adrenal hyperplasias, 3 adrenal adenomas and in 2 ACC cell lines. Moreover, the interrelationship between the effects of IGF-II and IFN-β was evaluated. Mitotane inhibited cell total DNA content/well (representing cell number) in 7/11 (IC50: 38±9.2 µM), and cortisol secretion in 5/5 ACC cultures (IC50: 4.5±0.1 µM). IFN-β reduced cell number in 10/11 (IC50: 83±18 IU/mL) and cortisol secretion in 5/5 ACC cultures (IC50: 7.3±1.5 IU/mL). The effect of IFN-β on cell number included the induction of apoptosis. IFN-β strongly inhibited mRNA expression of STAR, CYP11A1, CYP17A1 and CYP11B1. Mitotane and IFN-β induced an additive inhibitory effect on cell number and cortisol secretion. IGF-II (10nM) inhibited apoptosis and increased cell number and cortisol secretion. These effects were counteracted by IFN-β treatment. Finally, IFN-β inhibited IGF-II secretion and mRNA expression. In conclusion, IFN-β is a potent inhibitor of ACC cell growth in human primary ACC cultures, partially mediated by an inhibition of the effects of IGF-II, as well as its production. The increased sensitivity of ACC cells to mitotane induced by treatment with IFN-β may open the opportunity for combined treatment regimens with lower mitotane doses. The inhibition of the expression of steroidogenic enzymes by IFN-β is a novel mechanism that may explain its inhibitory effect on cortisol productionPubblicazioni consigliate
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