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

Abstract

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-α (ER-α) 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-α receptor and the induced conformational changes. The ER-α 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-α silencing was performed using two ER-α 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 17β-estradiol and bisphenol A (BPA) and a significant binding affinity to ER-α. MD simulations showed that mitotane preserves the active conformation of ER-α 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-α knock-down. Integrating bioinformatics approaches with cell biology and pharmacological methods, we demonstrated that mitotane directly binds and activates ER-α.

Evaluation of the Therapeutic Effect of the Traditional Herbal Medicine Atrifil and Oshagh Gum on Testosterone-Induced Benign Prostatic Hyperplasia in Wistar Rats

“…Studies showed that if a special substance tends to affect Er α and Er β as an agonist or relative agonist it should be placed at the interaction distance of the active site of amino acids Glu353, Arg394, and His524, but for an antagonist, it differs and just one missing interaction can have the opposite effect [ 70 ]. To evaluate the physiological behavior of ligands in the vicinity of enzymes, the binding affinity (binding energy) of ligands to receptors is important (Figures 6 – 9 ).…”

Precocious puberty and other endocrine disorders during mitotane treatment for paediatric adrenocortical carcinoma – case series and literature review

“…The research conducted by Rossini et al . demonstrated that mitotane also directly binds ER-α as an agonist and suggested that selective oestrogen receptor modulators (SERM) or selective oestrogen receptor degrader (SERD) could be clinically useful to antagonize the oestrogen-like mitotane-induced effects [ 51 ]. Mitotane also has oestrogenic action, possibly impacting bone age advancement [ 30 ].…”

The effect of adjuvant mitotane therapy of the adrenocortical carcinoma on the endometrium and its clinical consequences in menstruating women. Literature review and authors’ own experiences

“…Most likely, mitotane also affects the peripheral metabolism of steroids, affecting CBG and SHBG, increasing their concentration in the blood, and thereby reducing the level of free hormones [22,41,57]. Additionally, the substance directly binds to the oestrogen receptor (α) as an agonist, causing the oestrogen-like mitotane-induced effects [58].…”