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

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...

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Bibliographic Details
Published in:Cancers 2019-11, Vol.11 (11), p.1768
Main Authors: Cerquetti, Lidia, Bucci, Barbara, Carpinelli, Giulia, Lardo, Pina, Proietti, Antonella, Saporito, Raffaele, Rindi, Guido, Petrangeli, Elisa, Toscano, Vincenzo, Stigliano, Antonio
Format: Article
Language:English
Subjects:
Apoptosis
Cell cycle
Cell death
Cell size
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Flow cytometry
Gene expression
Ionizing radiation
Kinases
Medical prognosis
Mismatch repair
MSH2 protein
Radiation therapy
Tumors
Xenografts
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Summary: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 ( < 0.0001) compared to MTT and IR given alone ( < 0.05). The MTT results confirm its antisteroidogenic activity ( < 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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11111768