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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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Autores principales: Cerquetti, Lidia, Bucci, Barbara, Carpinelli, Giulia, Lardo, Pina, Proietti, Antonella, Saporito, Raffaele, Rindi, Guido, Petrangeli, Elisa, Toscano, Vincenzo, Stigliano, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895792/
https://www.ncbi.nlm.nih.gov/pubmed/31717612
http://dx.doi.org/10.3390/cancers11111768
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author Cerquetti, Lidia
Bucci, Barbara
Carpinelli, Giulia
Lardo, Pina
Proietti, Antonella
Saporito, Raffaele
Rindi, Guido
Petrangeli, Elisa
Toscano, Vincenzo
Stigliano, Antonio
author_facet Cerquetti, Lidia
Bucci, Barbara
Carpinelli, Giulia
Lardo, Pina
Proietti, Antonella
Saporito, Raffaele
Rindi, Guido
Petrangeli, Elisa
Toscano, Vincenzo
Stigliano, Antonio
author_sort Cerquetti, Lidia
collection PubMed
description 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.
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spelling pubmed-68957922019-12-24 Antineoplastic Effect of a Combined Mitotane Treatment/Ionizing Radiation in Adrenocortical Carcinoma: A Preclinical Study Cerquetti, Lidia Bucci, Barbara Carpinelli, Giulia Lardo, Pina Proietti, Antonella Saporito, Raffaele Rindi, Guido Petrangeli, Elisa Toscano, Vincenzo Stigliano, Antonio Cancers (Basel) Article 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. MDPI 2019-11-09 /pmc/articles/PMC6895792/ /pubmed/31717612 http://dx.doi.org/10.3390/cancers11111768 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cerquetti, Lidia
Bucci, Barbara
Carpinelli, Giulia
Lardo, Pina
Proietti, Antonella
Saporito, Raffaele
Rindi, Guido
Petrangeli, Elisa
Toscano, Vincenzo
Stigliano, Antonio
Antineoplastic Effect of a Combined Mitotane Treatment/Ionizing Radiation in Adrenocortical Carcinoma: A Preclinical Study
title Antineoplastic Effect of a Combined Mitotane Treatment/Ionizing Radiation in Adrenocortical Carcinoma: A Preclinical Study
title_full Antineoplastic Effect of a Combined Mitotane Treatment/Ionizing Radiation in Adrenocortical Carcinoma: A Preclinical Study
title_fullStr Antineoplastic Effect of a Combined Mitotane Treatment/Ionizing Radiation in Adrenocortical Carcinoma: A Preclinical Study
title_full_unstemmed Antineoplastic Effect of a Combined Mitotane Treatment/Ionizing Radiation in Adrenocortical Carcinoma: A Preclinical Study
title_short Antineoplastic Effect of a Combined Mitotane Treatment/Ionizing Radiation in Adrenocortical Carcinoma: A Preclinical Study
title_sort antineoplastic effect of a combined mitotane treatment/ionizing radiation in adrenocortical carcinoma: a preclinical study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895792/
https://www.ncbi.nlm.nih.gov/pubmed/31717612
http://dx.doi.org/10.3390/cancers11111768
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