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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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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. |
format | Online Article Text |
id | pubmed-6804958 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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