Antineoplastic Effect of a Combined Mitotane Treatment/Ionizing Radiation in Adrenocortical Carcinoma: A Preclinical Study.

Cerquetti Cerquetti,Proietti Proietti,Toscano Toscano,Saporito Saporito,Lardo Lardo,Petrangeli Petrangeli,Rindi Rindi,Bucci Bucci,Carpinelli Carpinelli,Stigliano Stigliano

doi:10.3390/cancers11111768

Abstract

Mitotane (MTT) is an adrenolytic drug used in adjuvant and advanced treatments of adrenocortical carcinoma (ACC). Ionizing radiation (IR) is also used in adrenal cancer treatment, even though its biological action remains unknown. To provide a reliable in vivo preclinical model of ACC, we used mouse xenografts bearing human ACC to test the effects of MTT and IR alone and in combination. We evaluated tumor growth inhibition by the RECIST criteria and analyzed the cell cycle by flow cytometry (FCM). In the xenograft ACC model treated with MTT/IR in combination, we observed a marked inhibition of tumor growth, with strong tumor regression (p < 0.0001) compared to MTT and IR given alone (p < 0.05). The MTT results confirm its antisteroidogenic activity (p < 0.05) in the xenograft ACC model, revealing its ability to render cancer cells more prone to radiotherapy treatment. In addition, to explain the biological effect of these treatments on the Mismatch Repair System (MMR), we interfered with the MSH2 gene expression in untreated and MTT/IR-treated H295R and SW13 cell lines. Moreover, we observed that upon treatment with MTT/IR to induce DNA damage, MSH2 gene inhibition in both the H295R and SW13 cell lines did not allow DNA damage repair, thus inducing cell death. In conclusion, MTT seems to have a radiosensitizing property and, when given in combination with IR, is able to promote neoplastic growth inhibition, leading to a significant reduction in tumor size due to cell death.

Highlights

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis.In ACC patients, the overall 5-year survival rates range from 16% to 44% in different series, with prognosis being largely dependent on the disease stage at diagnosis and success of surgery [1].Cancers 2019, 11, 1768; doi:10.3390/cancers11111768 www.mdpi.com/journal/cancersAdrenalectomy represents the treatment of choice [2], though local recurrence and metastatic disease are common during follow-up [3], supporting the need for adjuvant therapy [4]
We have demonstrated that G2 arrest was characterized by the ability of MTT to enhance the cytotoxic effects of Ionizing radiation (IR) by attenuating DNA repair and interfering with the activation of the mitosis promoting factor (MPF), which is mainly regulated by the degradation of cyclin B1 in the mitotic process [17]
In our previous in vitro study, we reported that MTT interferes with the modulation of both MSH1 and MSH2 enzymes belonging to Mismatch Repair Systems (MMRs), which could explain the radiosensitizing properties of MTT [17]

Summary

Introduction

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis.In ACC patients, the overall 5-year survival rates range from 16% to 44% in different series, with prognosis being largely dependent on the disease stage at diagnosis and success of surgery [1].Cancers 2019, 11, 1768; doi:10.3390/cancers11111768 www.mdpi.com/journal/cancersAdrenalectomy represents the treatment of choice [2], though local recurrence and metastatic disease are common during follow-up [3], supporting the need for adjuvant therapy [4]. In ACC patients, the overall 5-year survival rates range from 16% to 44% in different series, with prognosis being largely dependent on the disease stage at diagnosis and success of surgery [1]. Mitotane (MTT) is the only adrenal-specific drug approved in Europe and the United States with an ascertained efficacy in ACC [5], but its use in adjuvant therapy remains a matter of debate [6]. Published series suggest a benefit of postoperative MTT administration in prolonging recurrence-free survival in patients with macroscopic radical ACC resection [7]. Important data derived from a multicenter study based on a retrospective analysis have reported an increase in disease-free and overall survival in MTT-treated patients compared with those from two independent untreated control groups [8].

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