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Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin™
Aplidin™ (APL) is a new antitumoral drug from marine origin currently in phase II clinical trials against a wide multiplicity of cancers. As resistance may be, as with other drugs, an important obstacle to the APL therapeutic efficacy, we have established an acquired resistance cellular model by con...
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2004
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409906/ https://www.ncbi.nlm.nih.gov/pubmed/15365569 http://dx.doi.org/10.1038/sj.bjc.6602166 |
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author | Losada, A López-Oliva, J M Sánchez-Puelles, J M García-Fernández, L F |
author_facet | Losada, A López-Oliva, J M Sánchez-Puelles, J M García-Fernández, L F |
author_sort | Losada, A |
collection | PubMed |
description | Aplidin™ (APL) is a new antitumoral drug from marine origin currently in phase II clinical trials against a wide multiplicity of cancers. As resistance may be, as with other drugs, an important obstacle to the APL therapeutic efficacy, we have established an acquired resistance cellular model by continuous exposure of HeLa cells to the drug. The stably resistant subline generated (HeLa-APL), possessing more than 1000-fold relative resistance to APL than parental cells, did not show crossresistance to a subset of clinically relevant antitumoral agents. In addition, resistance was not related to overexpression of P-glycoprotein or differences in overall drug accumulation. Comparing to parental cells, HeLa-APL cells did not present either significant differences in the growth rate or apparent alterations in the cell cycle distribution. Aplidin™ induced rapid and persistent phosphorylation of both JNK and p38 MAPKs, resulting in activation of the mitochondrial apoptotic pathway in parental cells, but, notably, in HeLa-APL-resistant cells MAPKs activation only occurred in a slight and transiently manner, failing to activate the above-mentioned apoptotic machinery. These results suggest that sustained activation of JNK and p38 is essential for triggering the apoptotic programme induced by APL and that HeLa-APL cells bypass this apoptotic response by preventing the specific mechanisms that prime and sustain the long-term activation of these signalling cascades. Although far from human tumour physiology in vivo, HeLa-APL cells represent a potentially useful tool in gaining insights into the mode of action of APL, in selecting non-crossresistant APL structural analogues, as well as in investigating and developing methods to prevent resistance to this drug. |
format | Text |
id | pubmed-2409906 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2004 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-24099062009-09-10 Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin™ Losada, A López-Oliva, J M Sánchez-Puelles, J M García-Fernández, L F Br J Cancer Experimental Therapeutics Aplidin™ (APL) is a new antitumoral drug from marine origin currently in phase II clinical trials against a wide multiplicity of cancers. As resistance may be, as with other drugs, an important obstacle to the APL therapeutic efficacy, we have established an acquired resistance cellular model by continuous exposure of HeLa cells to the drug. The stably resistant subline generated (HeLa-APL), possessing more than 1000-fold relative resistance to APL than parental cells, did not show crossresistance to a subset of clinically relevant antitumoral agents. In addition, resistance was not related to overexpression of P-glycoprotein or differences in overall drug accumulation. Comparing to parental cells, HeLa-APL cells did not present either significant differences in the growth rate or apparent alterations in the cell cycle distribution. Aplidin™ induced rapid and persistent phosphorylation of both JNK and p38 MAPKs, resulting in activation of the mitochondrial apoptotic pathway in parental cells, but, notably, in HeLa-APL-resistant cells MAPKs activation only occurred in a slight and transiently manner, failing to activate the above-mentioned apoptotic machinery. These results suggest that sustained activation of JNK and p38 is essential for triggering the apoptotic programme induced by APL and that HeLa-APL cells bypass this apoptotic response by preventing the specific mechanisms that prime and sustain the long-term activation of these signalling cascades. Although far from human tumour physiology in vivo, HeLa-APL cells represent a potentially useful tool in gaining insights into the mode of action of APL, in selecting non-crossresistant APL structural analogues, as well as in investigating and developing methods to prevent resistance to this drug. Nature Publishing Group 2004-10-04 2004-09-14 /pmc/articles/PMC2409906/ /pubmed/15365569 http://dx.doi.org/10.1038/sj.bjc.6602166 Text en Copyright © 2004 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Experimental Therapeutics Losada, A López-Oliva, J M Sánchez-Puelles, J M García-Fernández, L F Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin™ |
title | Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin™ |
title_full | Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin™ |
title_fullStr | Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin™ |
title_full_unstemmed | Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin™ |
title_short | Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin™ |
title_sort | establishment and characterisation of a human carcinoma cell line with acquired resistance to aplidin™ |
topic | Experimental Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409906/ https://www.ncbi.nlm.nih.gov/pubmed/15365569 http://dx.doi.org/10.1038/sj.bjc.6602166 |
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