Mitotane (also termed o,p'‑DDD) is the most effective
therapy for advanced adrenocortical carcinoma (ACC). Mitotane‑induced
dyslipidemia is treated with
statins.
Mitotane and
statins are known to exert anti‑proliferative effects in vitro; however, the effects of
statins have never been directly evaluated in patients with ACC and ACC cells, at least to the best of our knowledge. Thus, in this study, we aimed to examine the effects of the
rosuvastatin on ACC cells. It has been shown that the combined use of
mitotane and
statins significantly increases the
tumor control rate in patients with ACC; however, it would be of interest to elucidate the molecular mechanisms involved in this potentiation. In this study, we examined the effects of
mitotane,
rosuvastatin and their combination in NCI‑H295R human ACC cells using proliferation assays, gene expression analyses and free intracellular
cholesterol measurements. The results revealed that
mitotane dose‑dependently reduced cell viability, induced apoptosis and increased intracellular free
cholesterol levels, considered as one of the key features of
mitotane action, while
rosuvastatin alone reduced cell viability and increased apoptosis at high concentrations. We also demonstrated that
rosuvastatin potentiated the effects of
mitotane by reducing cell viability, inducing apoptosis, increasing intracellular free
cholesterol levels, and by decreasing the expression of 3‑hydroxy‑3‑methylglutaryl‑CoA
reductase (HMGCR) and
ATP binding cassette subfamily a member 1 (ABCA1), genes involved in
cholesterol metabolism, and inhibiting steroidogenesis. Collectively, potentiating the effects of
mitotane with the use of
rosuvastatin may provide novel therapeutic strategies for ACC, given that the combination of these drugs, pending clinical validation, may lead to the better management of ACC.