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Understanding mitotane mode of action.

Adrenocortical carcinoma is a rare disease with poor prognosis. Mitotane is the most effective agent in post-operative treatment (or when inoperable). It selectively limits growth and bioactivity of adrenal tissue. Despite 60 years of use, the basis for its action has yet to be convincingly established. This review summarizes current knowledge of mitotane effects, based on studies on adrenal tissue and primary cell cultures, with emphasis on more recent studies of cell lines. We consider features of the adrenal cortex that might explain mitotane selectivity, and review effects on non-adrenal cells. Since the most clear-cut mitotane effects have been observed for mitochondria, this topic is the core of the review. Mitochondria present unique characteristics in steroidogenic tissue and are known to be important in malignancy development and apoptosis. We look at the evidence for mitotane activation within mitochondria, its impact on mitochondrial energy metabolism and other cellular processes as well as on downstream effects in the cell, such as apoptosis initiation. Further genomic and proteomic investigative studies are likely to yield useful results.