Adrenocortical carcinoma (ACC), a rare tumor, with incidence of 12 per million population annually, has a bimodal distribution by age, with cases clustering in children under 6, and in adults 3040 years old. ACC has a dismal prognosis. The only curative treatment is complete surgical excision of the tumor, but late diagnosis prevents surgical cure, since ACC frequently recurs and metastasize. Chemotherapy is frequently ineffective, due to the overexpression of the MDR-1 gene, encoding for detoxifying pump P-gp, which confers chemoresistance to ACC. Mitotane, an adrenolitic drug, is being used as adjuvant therapy to prevent recurrence, despite several and important side effects appearing at therapeutic concentrations (1420 mg/l; 4060 μM).
We aimed at identifying therapeutic strategies to overcome adrenocortical carcinoma chemoresistance by using mitotane.
Human adrenocortical cells, NCI-H295R, expressing high P-gp levels, were treated with mitotane (2.580 μM) and doxorubicin (1100 nM), identifying minimal cytotoxic concentrations. Cell viability and caspase 3/7 activity under 25 and 50 nM doxorubicin without or with 5 μM mitotane were tested. These drug concentrations are much lower than those reached in vivo. Combination treatments significantly and more potently reduced cell viability (4060%) by inducing caspase-3/7 activity. In addition, we found that mitotane significantly reduced P-gp activity, promoting the intracellular accumulation of fluorescent compounds.
Our results indicate that mitotane enhances the cytotoxic effects of doxorubicin in a chemoresistant adrenocortical carcinoma cell line, likely inhibiting P-gp activity.
30 Apr - 04 May 2011
European Society of Endocrinology