Abstract
Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regimen to be added to mitotane is a chemotherapy including etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Evidence indicates that ACC seems to be sensitive to alkylating agents. Trabectedin is an anti-tumor drug that acts as an alkylating agent with a complex mechanism of action. Here, we investigated whether trabectedin could exert a cytotoxic activity in in vitro cell models of ACC. Cell viability was evaluated by MTT assay on ACC cell lines and primary cell cultures. The gene expression was evaluated by q-RT-PCR, while protein expression and localization were studied by Western blot and immunocytochemistry. Combination experiments were performed to evaluate their interaction on ACC cell line viability. Trabectedin demonstrated high cytotoxicity at sub-nanomolar concentrations in ACC cell lines and patient-derived primary cell cultures. The drug was able to reduce /β catenin nuclear localization, although it is unclear whether this effect is involved in the observed cytotoxicity. Trabectedin/mitotane combination exerted a synergic cytotoxic effect in NCI-H295R cells. Trabectedin has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of trabectedin with mitotane provides the rationale for testing this combination in a clinical study.
Highlights
Adrenocortical carcinoma (ACC) is a rare and aggressive tumor characterized by an estimated incidence of 0.7–2.0 cases/million people per year and an overall 5 year survival rate less than 15% in patients with metastatic disease [1]
Cell viability was assessed at four days of treatment, the drug was withdrawn, and cells were kept in a drug-naive complete medium to evaluate whether the trabectedin cytotoxic insult was a long-lasting effect
Results show that trabectedin treatment induced cell damage that progressed in the absence of the drug (Figure 1B)
Summary
Adrenocortical carcinoma (ACC) is a rare and aggressive tumor characterized by an estimated incidence of 0.7–2.0 cases/million people per year and an overall 5 year survival rate less than 15% in patients with metastatic disease [1]. Radical surgery at experienced centers still remains the only potential curative treatment for patients with early disease stage and those with locally advanced. 30–70% of radically operated patients recur within two years, often with metastatic disease [1]. Standard systemic therapies for patients with advanced ACC are mitotane and chemotherapy [2]. The dichlorodiphenyl trichloroethane derivative mitotane represents the only drug that has been approved for the treatment of ACC for many decades, its mechanism of antineoplastic activity is not fully understood [3]
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