Introduction: In case of inoperable disease or tumor recurrence, therapy with mitotane (MIT), sometimes in combination with doxorubicin (DOX), etoposide (ETO), cisplatin (CIS) or streptozocin (STREP), is frequently applied in patients with adrenocortical carcinoma (ACC). The multidrug resistance pump MDR1 is responsible for resistance of tumor cells to cytostatic drugs. The activity of MDR1 is inhibited by the calcium-channel blocker verapamil. There are equivocal data in the literature regarding the efficacy of cytostatic compounds in the treatment of ACC.
Aim of the study: To evaluate the effects of MIT and verapamil, in combination with cytostatic drugs, on the growth of human ACC.
Methods: The human ACC cell lines H295, HAC-15 and SW13 were treated with increasing concentrations of cytostatic drugs (range: 10 nM100 μM), with or without MIT (IC50) or verapamil (10 μM). After 144 h, cells were harvested for determination of cell number. MDR1 mRNA expression was measured in a series of adrenal tissues by qPCR.
Results: H295, HAC-15 and SW13 cell lines showed a dose-dependent inhibitory response to DOX (EC50 range: 0.010.09 μM), ETO (EC50 range: 0.620.79 μM), CIS (EC50 range: 0.060.53 μM) and MIT (EC50 range: 5.8110.00 μM), but not to STREP. The effects of the cytostatic drugs and MIT were only partially additive. MDR1 expression was detected in H295 and HAC-15, but not in SW13 cells. MDR1 mRNA was detected in normal adrenal, adrenal hyperplasia, adrenal adenoma, and at a significantly lower level in ACC (P<0.005). Verapamil increased the sensitivity of H295 and HAC-15 to DOX (10- and 13-fold respectively) and ETO (3- and 3.5-fold respectively).
Conclusions: The cytostatic drugs, except STREP, used for treatment of patients with ACC have an inhibitory effect on growth of human ACC cell lines. The effects of the cytostatic drugs are only partially additive with the effects of MIT. Inhibition of MDR1 by verapamil increases sensitivity to DOX and ETO, suggesting that MDR1 plays a role in the sensitivity of ACC to these cytostatic drugs.
30 Apr - 04 May 2011
European Society of Endocrinology