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Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells

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 t...

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Autores principales: Abate, Andrea, Rossini, Elisa, Bonini, Sara Anna, Fragni, Martina, Cosentini, Deborah, Tiberio, Guido Albero Massimo, Benetti, Diego, Hantel, Constanze, Laganà, Marta, Grisanti, Salvatore, Terzolo, Massimo, Memo, Maurizio, Berruti, Alfredo, Sigala, Sandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226156/
https://www.ncbi.nlm.nih.gov/pubmed/32283844
http://dx.doi.org/10.3390/cancers12040928
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author Abate, Andrea
Rossini, Elisa
Bonini, Sara Anna
Fragni, Martina
Cosentini, Deborah
Tiberio, Guido Albero Massimo
Benetti, Diego
Hantel, Constanze
Laganà, Marta
Grisanti, Salvatore
Terzolo, Massimo
Memo, Maurizio
Berruti, Alfredo
Sigala, Sandra
author_facet Abate, Andrea
Rossini, Elisa
Bonini, Sara Anna
Fragni, Martina
Cosentini, Deborah
Tiberio, Guido Albero Massimo
Benetti, Diego
Hantel, Constanze
Laganà, Marta
Grisanti, Salvatore
Terzolo, Massimo
Memo, Maurizio
Berruti, Alfredo
Sigala, Sandra
author_sort Abate, Andrea
collection PubMed
description 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.
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spelling pubmed-72261562020-05-18 Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells Abate, Andrea Rossini, Elisa Bonini, Sara Anna Fragni, Martina Cosentini, Deborah Tiberio, Guido Albero Massimo Benetti, Diego Hantel, Constanze Laganà, Marta Grisanti, Salvatore Terzolo, Massimo Memo, Maurizio Berruti, Alfredo Sigala, Sandra Cancers (Basel) Article 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. MDPI 2020-04-09 /pmc/articles/PMC7226156/ /pubmed/32283844 http://dx.doi.org/10.3390/cancers12040928 Text en © 2020 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
Abate, Andrea
Rossini, Elisa
Bonini, Sara Anna
Fragni, Martina
Cosentini, Deborah
Tiberio, Guido Albero Massimo
Benetti, Diego
Hantel, Constanze
Laganà, Marta
Grisanti, Salvatore
Terzolo, Massimo
Memo, Maurizio
Berruti, Alfredo
Sigala, Sandra
Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells
title Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells
title_full Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells
title_fullStr Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells
title_full_unstemmed Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells
title_short Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells
title_sort cytotoxic effect of trabectedin in human adrenocortical carcinoma cell lines and primary cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226156/
https://www.ncbi.nlm.nih.gov/pubmed/32283844
http://dx.doi.org/10.3390/cancers12040928
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