Adrenocortical carcinoma (ACC) is a rare aggressive tumor with a poor prognosis. At present, early diagnosis followed by total surgical tumor resection is the only valuable option for ACC cure and mitotane (MTT) is the only specific drug available for pharmacological treatment. However, its effects seem to be mainly due to its adrenocortical cytotoxicity and its bioavailability and cellular mechanism of action are still unknown, making it difficult to develop less toxic multidrug strategies for ACC treatment. We investigated MTT metabolism and effects on cell activity and proliferation in the human ACC line H295R and in an in vivo xenograft model obtained by s.c. injection of H295R cells in athymic mice. MTT and its metabolite DDA dose-dependently accumulated intracellularly in H295R with a peak at 24 h administration, resulting in a dose- and time-dependent inhibition of cell proliferation, evaluated by MTS assay (inhibition: 50.0±2.1% at 48 h, 85.0±2.5% at 5 days, P<0.001, 20 μM MTT) and cell count (inhibition: 54.0±3.2% at 48 h, 89.0±2.2% at 5 days, P<0.001, 20 μM MTT). We demonstrated that MTT interferes with MAPK signalling pathways. In vivo oral/i.p. administration of MTT resulted in a significant accumulation of MTT in adrenals and in the ACC xenograft model determined a significant inhibition of tumor growth versus the untreated control animals (tumor growth fold decrease following 21 day treatment: 0.74±0.20, P<0.01, n=10), accompanied with a reduced expression of angiogenic, vascular and proliferation genes in tumors of MTT treated mice. In prevention experiments where MTT was started contemporarily with H295R inoculation, we observed an even greater reduction in tumor growth compared with the untreated control animals (tumor growth fold decrease following 21 day treatment: 0.38±0.10, P<0.001, n=10). In conclusion, we contributed to elucidated MTT kinetics in vitro and in vivo highlighting the antiproliferative effects of such drug.
30 Apr - 04 May 2011
European Society of Endocrinology