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Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL
TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo-2L) is a promising novel anticancer agent that selectively induces apoptosis in tumour cells and the activity of which can be enhanced by combined treatment with chemo- or radiotherapy. For therapeutic purposes, the use of full-length T...
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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/PMC2364740/ https://www.ncbi.nlm.nih.gov/pubmed/15173860 http://dx.doi.org/10.1038/sj.bjc.6601910 |
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author | Abou El Hassan, M A I Mastenbroek, D C J Gerritsen, W R Giaccone, G Kruyt, F A E |
author_facet | Abou El Hassan, M A I Mastenbroek, D C J Gerritsen, W R Giaccone, G Kruyt, F A E |
author_sort | Abou El Hassan, M A I |
collection | PubMed |
description | TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo-2L) is a promising novel anticancer agent that selectively induces apoptosis in tumour cells and the activity of which can be enhanced by combined treatment with chemo- or radiotherapy. For therapeutic purposes, the use of full-length TRAIL may be favourable to recombinant TRAIL based on its increased tumour cell killing potential, and the delivery of TRAIL at the tumour site by adenovirus vectors may provide an approach to overcome the short half-life of recombinant TRAIL and hepatocyte toxicity in vivo. Here, we constructed an adenoviral vector expressing full-length TRAIL (AdTRAIL) and studied the potential of chemo- and radiotherapy in enhancing AdTRAIL-induced apoptosis in non-small cell lung cancer (NSCLC) H460 cells and normal cells and, in addition, investigated the mechanism of AdTRAIL-induced apoptosis. AdTRAIL effectively killed H460 cells, which we previously showed to have a deficiency in mitochondria-dependent apoptosis by downstream activation of caspase-8 rather than caspase-9. Further analyses revealed that AdTRAIL induces death receptor- and mitochondria-dependent apoptosis that could be partially suppressed by Bcl2 overexpression. Combined treatment with doxorubicin (DOX), cisplatin (CDDP), paclitaxel (PTX) and radiation strongly enhanced AdTRAIL-induced cytotoxicity in a synergistic way. Synergy was accompanied by the cleavage of Bid and an increase in caspase-8 processing that was abolished by Bcl2 overexpression, indicating that the Bid-mitochondrial amplification loop is functional in H460 cells. Moreover, combination treatment did not alter the tumour selectivity of AdTRAIL since normal human fibroblasts (NHFs) remained resistant under these conditions. These findings further indicate that the combined use of chemo/radiotherapy and adenovirus-produced full-length TRAIL may provide a valuable treatment option for NSCLC. |
format | Text |
id | pubmed-2364740 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2004 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-23647402009-09-10 Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL Abou El Hassan, M A I Mastenbroek, D C J Gerritsen, W R Giaccone, G Kruyt, F A E Br J Cancer Experimental Therapeutics TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo-2L) is a promising novel anticancer agent that selectively induces apoptosis in tumour cells and the activity of which can be enhanced by combined treatment with chemo- or radiotherapy. For therapeutic purposes, the use of full-length TRAIL may be favourable to recombinant TRAIL based on its increased tumour cell killing potential, and the delivery of TRAIL at the tumour site by adenovirus vectors may provide an approach to overcome the short half-life of recombinant TRAIL and hepatocyte toxicity in vivo. Here, we constructed an adenoviral vector expressing full-length TRAIL (AdTRAIL) and studied the potential of chemo- and radiotherapy in enhancing AdTRAIL-induced apoptosis in non-small cell lung cancer (NSCLC) H460 cells and normal cells and, in addition, investigated the mechanism of AdTRAIL-induced apoptosis. AdTRAIL effectively killed H460 cells, which we previously showed to have a deficiency in mitochondria-dependent apoptosis by downstream activation of caspase-8 rather than caspase-9. Further analyses revealed that AdTRAIL induces death receptor- and mitochondria-dependent apoptosis that could be partially suppressed by Bcl2 overexpression. Combined treatment with doxorubicin (DOX), cisplatin (CDDP), paclitaxel (PTX) and radiation strongly enhanced AdTRAIL-induced cytotoxicity in a synergistic way. Synergy was accompanied by the cleavage of Bid and an increase in caspase-8 processing that was abolished by Bcl2 overexpression, indicating that the Bid-mitochondrial amplification loop is functional in H460 cells. Moreover, combination treatment did not alter the tumour selectivity of AdTRAIL since normal human fibroblasts (NHFs) remained resistant under these conditions. These findings further indicate that the combined use of chemo/radiotherapy and adenovirus-produced full-length TRAIL may provide a valuable treatment option for NSCLC. Nature Publishing Group 2004-07-05 2004-06-01 /pmc/articles/PMC2364740/ /pubmed/15173860 http://dx.doi.org/10.1038/sj.bjc.6601910 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 Abou El Hassan, M A I Mastenbroek, D C J Gerritsen, W R Giaccone, G Kruyt, F A E Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL |
title | Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL |
title_full | Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL |
title_fullStr | Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL |
title_full_unstemmed | Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL |
title_short | Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL |
title_sort | overexpression of bcl2 abrogates chemo- and radiotherapy-induced sensitisation of nci-h460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length trail |
topic | Experimental Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364740/ https://www.ncbi.nlm.nih.gov/pubmed/15173860 http://dx.doi.org/10.1038/sj.bjc.6601910 |
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