Endocrine Abstracts

Background: Actually mitotane is an adrenal-specific agent employed in the treatment of adrenocortical carcinoma (ACC), and although it has been used for several decades, its exact mechanism of action, remain to be fully elucidated. Some authors reported that mitotane affected in vitro the multidrug resistance gene mdr-1/P-glycoprotein. MRP1, belonging a multidrug resistance protein family, exerts a chemo-resistance activity in many type of cancer leading to the failure of chemotherapy. Interestingly many aggressive tumours are often associated to MRP1 over-expression.

Aim: In this study we investigated the effect of mitotane in different human cancer cell lines. The aim of the present study was to investigate the hypothetical link between MRP1 protein expression level and response to mitotane treatment.

Materials and methods: Adrenocortical cancer, glioblastoma, medulloblastoma, ovarian cancer and breast cancer cell lines were grown in appropriate culture medium and treated with mitotane at different concentration. Cell cycle analysis was analyzed by flow cytometry (FCM). Cell cycle related protein and apoptotic molecules expression levels were detected by Western Blot analysis. Instead MRP1 protein was evaluated by immunofluorescence flow cytometric analysis.

Results: Mitotane treatment induced in all cell lines examined a cell growth inhibition characterized by an alteration of cell cycle. The expression level of MRP1 protein was modulated after mitotane exposure, indicating its possible role in response to treatment. In addition, we also observed a different expression of cell cycle molecules (cyclin B1 and E, cdk1) and apoptotic cell death protein (caspase 3) affected by mitotane treatment in human cancer cell lines examined.

Conclusions: Mitotane exposure shows an antiproliferative effect in several cancer cell lines, interfering with MRP1 expression. It could explain the pharmacological effect of the drug. These findings support the hypothetical role of mitotane in therapeutic approach in different type of human cancers.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.