Interferon-beta is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane

Adrenocortical carcinoma (ACC) is an aggressive tumor with very poor prognosis. Novel medical treatment opportunities are required. We investigated the effects of interferon-beta (IFN-beta), alone or in combination with mitotane, on cell growth and cortisol secretion in primary cultures of 13 human ACCs, three adrenal hyperplasias, three adrenal adenomas, and in two ACC cell lines. Moreover, the interrelationship between the effects of IGF2 and IFN-beta was evaluated. Mitotane inhibited cell total DNA content/well (representing cell number) in 7/11 (IC50: 38 +/- 9.2 mu M) and cortisol secretion in 5/5 ACC cultures (IC50: 4.5 +/- 0.1 mu M). IFN-beta 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-beta on cell number included the induction of apoptosis. IFN-beta strongly inhibited mRNA expression of STAR, CYP11A1, CYP17A1, and CYP11B1. Mitotane and IFN-beta induced an additive inhibitory effect on cell number and cortisol secretion. IGF2 (10 nM) inhibited apoptosis and increased cell number and cortisol secretion. These effects were counteracted by IFN-beta treatment. Finally, IFN-beta inhibited IGF2 secretion and mRNA expression. In conclusion, IFN-beta is a potent inhibitor of ACC cell growth in human primary ACC cultures, partially mediated by an inhibition of the effects of IGF2, as well as its production. The increased sensitivity of ACC cells to mitotane induced by treatment with IFN-beta may open the opportunity for combined treatment regimens with lower mitotane doses. The inhibition of the expression of steroidogenic enzymes by IFN-beta is a novel mechanism that may explain its inhibitory effect on cortisol production.