Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α

Mitotane is the cornerstone of medical treatment of adrenocortical carcinoma. Estrogenic-like side effects frequently occur in patients, and previous studies explored the chemical nature of the interaction between estrogen receptor-alpha (ER-alpha) and toxic compounds, including the DDD derivatives. We used molecular docking and molecular dynamics (MD) simulations to explore the possible interaction between mitotane and the ER-alpha receptor and the induced conformational changes. The ER-alpha expressing MCF-7 cells were exposed to mitotane with/without tamoxifen, and the cell viability/proliferation was evaluated by MTT assay and direct count. The transient ER-alpha silencing was performed using two ER-alpha siRNA (50 nM) and verified by Western blot. MDA-MB-231 cells were used as a negative control. Mitotane showed a similar docking configuration to 17 beta-estradiol and bisphenol A (BPA) and a significant binding affinity to ER-alpha. MD simulations showed that mitotane preserves the active conformation of ER-alpha more than both BPA and Bisphenol C, classifying it as an agonist. Exposure of MCF-7 cells to mitotane led to the concentration-dependent increase of cell viability and proliferation, which was reduced in the presence of tamoxifen and nullified by the transient ER-alpha knock-down. Integrating bioinformatics approaches with cell biology and pharmacological methods, we demonstrated that mitotane directly binds and activates ER-alpha.

Automated summary

Mitotane is found to have estrogenic-like effects on the ER-alpha receptor. Through cell experiments and molecular simulations, it was demonstrated that mitotane binds directly to and activates ER-alpha.