Biological response of adrenal carcinoma and melanoma cells to mitotane treatment.

A previous case report described an adrenal incidentaloma initially misdiagnosed as adrenocortical carcinoma (ACC), which was treated with mitotane. The final diagnosis was metastatic melanoma of unknown primary origin. However, the patient developed rapid disease progression after mitotane withdrawal, suggesting a protective role for mitotane in a non-adrenal-derived tumor. The aim of the present study was to determine the biological response of primary melanoma cells obtained from that patient, and that of other established melanoma and ACC cell lines, to mitotane treatment using a proliferation assay, flow cytometry, quantitative PCR and microarrays. Although mitotane inhibited the proliferation of both ACC and melanoma cells, its role in melanoma treatment appears to be limited. Flow cytometry analysis and transcriptomic studies indicated that the ACC cell line was highly responsive to mitotane treatment, while the primary melanoma cells showed a moderate response in vitro. Mitotane modified the activity of several key biological processes, including 'mitotic nuclear division', 'DNA repair', 'angiogenesis' and 'negative regulation of ERK1 and ERK2 cascade'. Mitotane administration led to elevated levels of DNA double-strand breaks, necrosis and apoptosis. The present study provides a comprehensive insight into the biological response of mitotane-treated cells at the molecular level. Notably, the present findings offer new knowledge on the effects of mitotane on ACC and melanoma cells.

Immunohistochemical analysis of ghrelin expression in various types of adrenal tumors.

INTRODUCTION: Ghrelin, originally isolated from the endocrine cells of the gastric mucosa, is also expressed in many peripheral tissues, including normal adrenals and adrenocortical tumors. It was shown that ghrelin stimulates proliferation and inhibits apoptosis of adrenocortical cells. In the current study, we compared ghrelin expression at the protein level in various adrenal tumors. We analyzed whether immunoreactive ghrelin could be considered as a potential marker for different types of adrenal tumors. MATERIAL AND METHODS: Study was carried out on 200 adrenal specimens arranged on microscope slide in tissue microarray format. We performed standardized immunohistochemical reactions with semiquantitative reaction intensity measurements. RESULTS: At the protein level, the expression of ghrelin was significantly reduced in adrenocortical adenocarcinoma in relation to the control group and pheochromocytoma as well as cancer-adjacent normal adrenal tissue. In contrast, a relatively high ghrelin expression was found in pheochromocytoma compared to all analyzed groups, with the exception of cancer-adjacent normal adrenal tissue. CONCLUSIONS: The ghrelin expression profile at the protein level may be associated with the type of adrenal tumor. In this context, our results suggest that adrenal immunoreactive ghrelin may be considered as a sensitive and specific marker for differentiating adrenocortical carcinoma from adrenocortical adenoma and pheochromocytoma.