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PARP inhibition in UV-associated angiosarcoma preclinical models
PURPOSE: Angiosarcoma (AS) is a rare vasoformative sarcoma, with poor overall survival and a high need for novel treatment options. Clinically, AS consists of different subtypes, including AS related to previous UV exposure (UV AS) which could indicate susceptibility to DNA damage repair inhibition....
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310857/ https://www.ncbi.nlm.nih.gov/pubmed/34085099 http://dx.doi.org/10.1007/s00432-021-03678-4 |
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author | Weidema, Marije E. Desar, Ingrid M. E. Hillebrandt-Roeffen, Melissa H. S. van Erp, Anke E. M. Masuzawa, Mikio Flucke, Uta E. van der Graaf, Winette T. A. Versleijen-Jonkers, Yvonne M. H. |
author_facet | Weidema, Marije E. Desar, Ingrid M. E. Hillebrandt-Roeffen, Melissa H. S. van Erp, Anke E. M. Masuzawa, Mikio Flucke, Uta E. van der Graaf, Winette T. A. Versleijen-Jonkers, Yvonne M. H. |
author_sort | Weidema, Marije E. |
collection | PubMed |
description | PURPOSE: Angiosarcoma (AS) is a rare vasoformative sarcoma, with poor overall survival and a high need for novel treatment options. Clinically, AS consists of different subtypes, including AS related to previous UV exposure (UV AS) which could indicate susceptibility to DNA damage repair inhibition. We, therefore, investigated the presence of biomarkers PARP1 (poly(ADP-ribose)polymerase-1) and Schlafen-11 (SLFN11) in UV AS. Based on experiences in other sarcomas, we examined (combination) treatment of PARP inhibitor (PARPi) olaparib and temozolomide (TMZ) in UV AS cell lines. METHODS: Previously collected UV AS (n = 47) and non-UV AS (n = 96) patient samples and two UV AS cell lines (MO-LAS and AS-M) were immunohistochemically assessed for PARP1 and SLFN11 expression. Both cell lines were treated with single agents PARPi olaparib and TMZ, and the combination treatment. Next, cell viability and treatment synergy were analyzed. In addition, effects on apoptosis and DNA damage were examined. RESULTS: In 46/47 UV AS samples (98%), PARP1 expression was present. SLFN11 was expressed in 80% (37/46) of cases. Olaparib and TMZ combination treatment was synergistic in both cell lines, with significantly increased apoptosis compared to single agent treatment. Furthermore, a significant increase in DNA damage marker γH2AX was present in both cell lines after combination therapy. CONCLUSION: We showed combination treatment of olaparib with TMZ was synergistic in UV AS cell lines. Expression of PARP1 and SLFN11 was present in the majority of UV AS tumor samples. Together, these results suggest combination treatment of olaparib and TMZ is a potential novel AS subtype-specific treatment option for UV AS patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00432-021-03678-4. |
format | Online Article Text |
id | pubmed-8310857 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-83108572021-08-12 PARP inhibition in UV-associated angiosarcoma preclinical models Weidema, Marije E. Desar, Ingrid M. E. Hillebrandt-Roeffen, Melissa H. S. van Erp, Anke E. M. Masuzawa, Mikio Flucke, Uta E. van der Graaf, Winette T. A. Versleijen-Jonkers, Yvonne M. H. J Cancer Res Clin Oncol Original Article – Cancer Research PURPOSE: Angiosarcoma (AS) is a rare vasoformative sarcoma, with poor overall survival and a high need for novel treatment options. Clinically, AS consists of different subtypes, including AS related to previous UV exposure (UV AS) which could indicate susceptibility to DNA damage repair inhibition. We, therefore, investigated the presence of biomarkers PARP1 (poly(ADP-ribose)polymerase-1) and Schlafen-11 (SLFN11) in UV AS. Based on experiences in other sarcomas, we examined (combination) treatment of PARP inhibitor (PARPi) olaparib and temozolomide (TMZ) in UV AS cell lines. METHODS: Previously collected UV AS (n = 47) and non-UV AS (n = 96) patient samples and two UV AS cell lines (MO-LAS and AS-M) were immunohistochemically assessed for PARP1 and SLFN11 expression. Both cell lines were treated with single agents PARPi olaparib and TMZ, and the combination treatment. Next, cell viability and treatment synergy were analyzed. In addition, effects on apoptosis and DNA damage were examined. RESULTS: In 46/47 UV AS samples (98%), PARP1 expression was present. SLFN11 was expressed in 80% (37/46) of cases. Olaparib and TMZ combination treatment was synergistic in both cell lines, with significantly increased apoptosis compared to single agent treatment. Furthermore, a significant increase in DNA damage marker γH2AX was present in both cell lines after combination therapy. CONCLUSION: We showed combination treatment of olaparib with TMZ was synergistic in UV AS cell lines. Expression of PARP1 and SLFN11 was present in the majority of UV AS tumor samples. Together, these results suggest combination treatment of olaparib and TMZ is a potential novel AS subtype-specific treatment option for UV AS patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00432-021-03678-4. Springer Berlin Heidelberg 2021-06-03 2021 /pmc/articles/PMC8310857/ /pubmed/34085099 http://dx.doi.org/10.1007/s00432-021-03678-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article – Cancer Research Weidema, Marije E. Desar, Ingrid M. E. Hillebrandt-Roeffen, Melissa H. S. van Erp, Anke E. M. Masuzawa, Mikio Flucke, Uta E. van der Graaf, Winette T. A. Versleijen-Jonkers, Yvonne M. H. PARP inhibition in UV-associated angiosarcoma preclinical models |
title | PARP inhibition in UV-associated angiosarcoma preclinical models |
title_full | PARP inhibition in UV-associated angiosarcoma preclinical models |
title_fullStr | PARP inhibition in UV-associated angiosarcoma preclinical models |
title_full_unstemmed | PARP inhibition in UV-associated angiosarcoma preclinical models |
title_short | PARP inhibition in UV-associated angiosarcoma preclinical models |
title_sort | parp inhibition in uv-associated angiosarcoma preclinical models |
topic | Original Article – Cancer Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310857/ https://www.ncbi.nlm.nih.gov/pubmed/34085099 http://dx.doi.org/10.1007/s00432-021-03678-4 |
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