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Induction of DNA breaks and apoptosis in crosslink-hypersensitive V79 cells by the cytostatic drug β-D-glucosyl-ifosfamide mustard
To study molecular aspects of cytotoxicity of the anticancer drug β-D-glucose-ifosfamide mustard we investigated the potential of the agent to induce apoptosis and DNA breakage. Since β-D-glucose-ifosfamide mustard generates DNA interstrand crosslinks, we used as an in vitro model system a pair of i...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2002
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746532/ https://www.ncbi.nlm.nih.gov/pubmed/11857024 http://dx.doi.org/10.1038/sj.bjc.6600027 |
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author | Becker, R Ritter, A Eichhorn, U Lips, J Bertram, B Wiessler, M Zdzienicka, M Z Kaina, B |
author_facet | Becker, R Ritter, A Eichhorn, U Lips, J Bertram, B Wiessler, M Zdzienicka, M Z Kaina, B |
author_sort | Becker, R |
collection | PubMed |
description | To study molecular aspects of cytotoxicity of the anticancer drug β-D-glucose-ifosfamide mustard we investigated the potential of the agent to induce apoptosis and DNA breakage. Since β-D-glucose-ifosfamide mustard generates DNA interstrand crosslinks, we used as an in vitro model system a pair of isogenic Chinese hamster V79 cells differing in their sensitivity to crosslinking agents. CL-V5B cells are dramatically more sensitive (30-fold based on D(10) values) to the cytotoxic effects of β-D-glucose-ifosfamide mustard as compared to parental V79B cells. After 48 h of pulse-treatment with the agent, sensitive cells but not the resistant parental line undergo apoptosis and necrosis, with apoptosis being the predominant form of cell death (70 and 20% of apoptosis and necrosis, respectively). Apoptosis increased as a function of dose and was accompanied by induction of DNA double-strand breaks in the hypersensitive cells. Furthermore, a strong decline in the level of Bcl-2 protein and activation of caspases-3, -8 and -9 were observed. The resistant parental cells were refractory to all these parameters. Bcl-2 decline in the sensitive cells preceded apoptosis, and transfection-mediated overexpression of Bcl-2 protected at least in part from apoptosis. From the data we hypothesize that non-repaired crosslinks induced by β-D-glucose-ifosfamide mustard are transformed into double-strand breaks which trigger apoptosis via a Bcl-2 dependent pathway. British Journal of Cancer (2002) 86, 130–135. DOI: 10.1038/sj/bjc/6600027 www.bjcancer.com © 2002 The Cancer Research Campaign |
format | Text |
id | pubmed-2746532 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2002 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-27465322009-09-18 Induction of DNA breaks and apoptosis in crosslink-hypersensitive V79 cells by the cytostatic drug β-D-glucosyl-ifosfamide mustard Becker, R Ritter, A Eichhorn, U Lips, J Bertram, B Wiessler, M Zdzienicka, M Z Kaina, B Br J Cancer Experimental Therapeutics To study molecular aspects of cytotoxicity of the anticancer drug β-D-glucose-ifosfamide mustard we investigated the potential of the agent to induce apoptosis and DNA breakage. Since β-D-glucose-ifosfamide mustard generates DNA interstrand crosslinks, we used as an in vitro model system a pair of isogenic Chinese hamster V79 cells differing in their sensitivity to crosslinking agents. CL-V5B cells are dramatically more sensitive (30-fold based on D(10) values) to the cytotoxic effects of β-D-glucose-ifosfamide mustard as compared to parental V79B cells. After 48 h of pulse-treatment with the agent, sensitive cells but not the resistant parental line undergo apoptosis and necrosis, with apoptosis being the predominant form of cell death (70 and 20% of apoptosis and necrosis, respectively). Apoptosis increased as a function of dose and was accompanied by induction of DNA double-strand breaks in the hypersensitive cells. Furthermore, a strong decline in the level of Bcl-2 protein and activation of caspases-3, -8 and -9 were observed. The resistant parental cells were refractory to all these parameters. Bcl-2 decline in the sensitive cells preceded apoptosis, and transfection-mediated overexpression of Bcl-2 protected at least in part from apoptosis. From the data we hypothesize that non-repaired crosslinks induced by β-D-glucose-ifosfamide mustard are transformed into double-strand breaks which trigger apoptosis via a Bcl-2 dependent pathway. British Journal of Cancer (2002) 86, 130–135. DOI: 10.1038/sj/bjc/6600027 www.bjcancer.com © 2002 The Cancer Research Campaign Nature Publishing Group 2002-01-07 /pmc/articles/PMC2746532/ /pubmed/11857024 http://dx.doi.org/10.1038/sj.bjc.6600027 Text en Copyright © 2002 The Cancer Research Campaign 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 Becker, R Ritter, A Eichhorn, U Lips, J Bertram, B Wiessler, M Zdzienicka, M Z Kaina, B Induction of DNA breaks and apoptosis in crosslink-hypersensitive V79 cells by the cytostatic drug β-D-glucosyl-ifosfamide mustard |
title | Induction of DNA breaks and apoptosis in crosslink-hypersensitive V79 cells by the cytostatic drug β-D-glucosyl-ifosfamide mustard |
title_full | Induction of DNA breaks and apoptosis in crosslink-hypersensitive V79 cells by the cytostatic drug β-D-glucosyl-ifosfamide mustard |
title_fullStr | Induction of DNA breaks and apoptosis in crosslink-hypersensitive V79 cells by the cytostatic drug β-D-glucosyl-ifosfamide mustard |
title_full_unstemmed | Induction of DNA breaks and apoptosis in crosslink-hypersensitive V79 cells by the cytostatic drug β-D-glucosyl-ifosfamide mustard |
title_short | Induction of DNA breaks and apoptosis in crosslink-hypersensitive V79 cells by the cytostatic drug β-D-glucosyl-ifosfamide mustard |
title_sort | induction of dna breaks and apoptosis in crosslink-hypersensitive v79 cells by the cytostatic drug β-d-glucosyl-ifosfamide mustard |
topic | Experimental Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746532/ https://www.ncbi.nlm.nih.gov/pubmed/11857024 http://dx.doi.org/10.1038/sj.bjc.6600027 |
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