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Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity

The expression of acid ceramidase (AC) – a cysteine amidase that hydrolyses the proapoptotic lipid ceramide – is abnormally high in several human tumors, which is suggestive of a role in chemoresistance. Available AC inhibitors lack, however, the potency and drug-likeness necessary to test this idea...

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Autores principales: Realini, Natalia, Solorzano, Carlos, Pagliuca, Chiara, Pizzirani, Daniela, Armirotti, Andrea, Luciani, Rosaria, Costi, Maria Paola, Bandiera, Tiziano, Piomelli, Daniele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539145/
https://www.ncbi.nlm.nih.gov/pubmed/23301156
http://dx.doi.org/10.1038/srep01035
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author Realini, Natalia
Solorzano, Carlos
Pagliuca, Chiara
Pizzirani, Daniela
Armirotti, Andrea
Luciani, Rosaria
Costi, Maria Paola
Bandiera, Tiziano
Piomelli, Daniele
author_facet Realini, Natalia
Solorzano, Carlos
Pagliuca, Chiara
Pizzirani, Daniela
Armirotti, Andrea
Luciani, Rosaria
Costi, Maria Paola
Bandiera, Tiziano
Piomelli, Daniele
author_sort Realini, Natalia
collection PubMed
description The expression of acid ceramidase (AC) – a cysteine amidase that hydrolyses the proapoptotic lipid ceramide – is abnormally high in several human tumors, which is suggestive of a role in chemoresistance. Available AC inhibitors lack, however, the potency and drug-likeness necessary to test this idea. Here we show that the antineoplastic drug carmofur, which is used in the clinic to treat colorectal cancers, is a potent AC inhibitor and that this property is essential to its anti-proliferative effects. Modifications in the chemical scaffold of carmofur yield new AC inhibitors that act synergistically with standard antitumoral drugs to prevent cancer cell proliferation. These findings identify AC as an unexpected target for carmofur, and suggest that this molecule can be used as starting point for the design of novel chemosensitizing agents.
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spelling pubmed-35391452013-01-08 Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity Realini, Natalia Solorzano, Carlos Pagliuca, Chiara Pizzirani, Daniela Armirotti, Andrea Luciani, Rosaria Costi, Maria Paola Bandiera, Tiziano Piomelli, Daniele Sci Rep Article The expression of acid ceramidase (AC) – a cysteine amidase that hydrolyses the proapoptotic lipid ceramide – is abnormally high in several human tumors, which is suggestive of a role in chemoresistance. Available AC inhibitors lack, however, the potency and drug-likeness necessary to test this idea. Here we show that the antineoplastic drug carmofur, which is used in the clinic to treat colorectal cancers, is a potent AC inhibitor and that this property is essential to its anti-proliferative effects. Modifications in the chemical scaffold of carmofur yield new AC inhibitors that act synergistically with standard antitumoral drugs to prevent cancer cell proliferation. These findings identify AC as an unexpected target for carmofur, and suggest that this molecule can be used as starting point for the design of novel chemosensitizing agents. Nature Publishing Group 2013-01-08 /pmc/articles/PMC3539145/ /pubmed/23301156 http://dx.doi.org/10.1038/srep01035 Text en Copyright © 2013, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Article
Realini, Natalia
Solorzano, Carlos
Pagliuca, Chiara
Pizzirani, Daniela
Armirotti, Andrea
Luciani, Rosaria
Costi, Maria Paola
Bandiera, Tiziano
Piomelli, Daniele
Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity
title Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity
title_full Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity
title_fullStr Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity
title_full_unstemmed Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity
title_short Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity
title_sort discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539145/
https://www.ncbi.nlm.nih.gov/pubmed/23301156
http://dx.doi.org/10.1038/srep01035
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