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Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15

BACKGROUND: b-AP15/VLX1570 are small molecule inhibitors of the ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5) deubiquitinases (DUBs) of the 19S proteasome. b-AP15/VLX1570 have been shown to be cytotoxic to cells resistant to bortezomib, raising the possi...

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Autores principales: Mofers, Arjan, Perego, Paola, Selvaraju, Karthik, Gatti, Laura, Gullbo, Joachim, Linder, Stig, D'Arcy, Padraig
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804958/
https://www.ncbi.nlm.nih.gov/pubmed/31639138
http://dx.doi.org/10.1371/journal.pone.0223807
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author Mofers, Arjan
Perego, Paola
Selvaraju, Karthik
Gatti, Laura
Gullbo, Joachim
Linder, Stig
D'Arcy, Padraig
author_facet Mofers, Arjan
Perego, Paola
Selvaraju, Karthik
Gatti, Laura
Gullbo, Joachim
Linder, Stig
D'Arcy, Padraig
author_sort Mofers, Arjan
collection PubMed
description BACKGROUND: b-AP15/VLX1570 are small molecule inhibitors of the ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5) deubiquitinases (DUBs) of the 19S proteasome. b-AP15/VLX1570 have been shown to be cytotoxic to cells resistant to bortezomib, raising the possibility that this class of drugs can be used as a second-line therapy for treatment-resistant multiple myeloma. Limited information is available with regard to potential resistance mechanisms to b-AP15/VLX1570. RESULTS: We found that b-AP15-induced cell death is cell-cycle dependent and that non-cycling tumor cells may evade b-AP15-induced cell death. Such non-cycling cells may re-enter the proliferative state to form colonies of drug-sensitive cells. Long-term selection of cells with b-AP15 resulted in limited drug resistance (~2-fold) that could be reversed by buthionine sulphoximine, implying altered glutathione (GSH) metabolism as a resistance mechanism. In contrast, drug uptake and overexpression of drug efflux transporters were found not to be associated with b-AP15 resistance. CONCLUSIONS: The proteasome DUB inhibitors b-AP15/VLX1570 are cell cycle-active. The slow and incomplete development of resistance towards these compounds is an attractive feature in view of future clinical use.
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spelling pubmed-68049582019-11-02 Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15 Mofers, Arjan Perego, Paola Selvaraju, Karthik Gatti, Laura Gullbo, Joachim Linder, Stig D'Arcy, Padraig PLoS One Research Article BACKGROUND: b-AP15/VLX1570 are small molecule inhibitors of the ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5) deubiquitinases (DUBs) of the 19S proteasome. b-AP15/VLX1570 have been shown to be cytotoxic to cells resistant to bortezomib, raising the possibility that this class of drugs can be used as a second-line therapy for treatment-resistant multiple myeloma. Limited information is available with regard to potential resistance mechanisms to b-AP15/VLX1570. RESULTS: We found that b-AP15-induced cell death is cell-cycle dependent and that non-cycling tumor cells may evade b-AP15-induced cell death. Such non-cycling cells may re-enter the proliferative state to form colonies of drug-sensitive cells. Long-term selection of cells with b-AP15 resulted in limited drug resistance (~2-fold) that could be reversed by buthionine sulphoximine, implying altered glutathione (GSH) metabolism as a resistance mechanism. In contrast, drug uptake and overexpression of drug efflux transporters were found not to be associated with b-AP15 resistance. CONCLUSIONS: The proteasome DUB inhibitors b-AP15/VLX1570 are cell cycle-active. The slow and incomplete development of resistance towards these compounds is an attractive feature in view of future clinical use. Public Library of Science 2019-10-22 /pmc/articles/PMC6804958/ /pubmed/31639138 http://dx.doi.org/10.1371/journal.pone.0223807 Text en © 2019 Mofers et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Mofers, Arjan
Perego, Paola
Selvaraju, Karthik
Gatti, Laura
Gullbo, Joachim
Linder, Stig
D'Arcy, Padraig
Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15
title Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15
title_full Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15
title_fullStr Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15
title_full_unstemmed Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15
title_short Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15
title_sort analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-ap15
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804958/
https://www.ncbi.nlm.nih.gov/pubmed/31639138
http://dx.doi.org/10.1371/journal.pone.0223807
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