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Auranofin is a potent suppressor of osteosarcoma metastasis
Osteosarcoma (OS) accounts for 56% of malignant bone cancers in children and adolescents. Patients with localized disease rarely develop metastasis; however, pulmonary metastasis occurs in approximately 50% of patients and leads to a 5-year survival rate of only 10–20%. Therefore, identifying the ge...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808036/ https://www.ncbi.nlm.nih.gov/pubmed/26573231 |
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author | Topkas, Eleni Cai, Na Cumming, Andrew Hazar-Rethinam, Mehlika Gannon, Orla Margaret Burgess, Melinda Saunders, Nicholas Andrew Endo-Munoz, Liliana |
author_facet | Topkas, Eleni Cai, Na Cumming, Andrew Hazar-Rethinam, Mehlika Gannon, Orla Margaret Burgess, Melinda Saunders, Nicholas Andrew Endo-Munoz, Liliana |
author_sort | Topkas, Eleni |
collection | PubMed |
description | Osteosarcoma (OS) accounts for 56% of malignant bone cancers in children and adolescents. Patients with localized disease rarely develop metastasis; however, pulmonary metastasis occurs in approximately 50% of patients and leads to a 5-year survival rate of only 10–20%. Therefore, identifying the genes and pathways involved in metastasis, as new therapeutic targets, is crucial to improve long-term survival of OS patients. Novel markers that define metastatic OS were identified using comparative transcriptomic analyses of two highly metastatic (C1 and C6) and two poorly metastatic clonal variants (C4 and C5) isolated from the metastatic OS cell line, KHOS. Using this approach, we determined that the metastatic phenotype correlated with overexpression of thioredoxin reductase 2 (TXNRD2) or vascular endothelial growth factor (VEGF). Validation in patient biopsies confirmed TXNRD2 and VEGF targets were highly expressed in 29–42% of metastatic OS patient biopsies, with no detectable expression in non-malignant bone or samples from OS patients with localised disease. Auranofin (AF) was used to selectively target and inhibit thioredoxin reductase (TrxR). At low doses, AF was able to inhibit TrxR activity without a significant effect on cell viability whereas at higher doses, AF could induce ROS-dependent apoptosis. AF treatment, in vivo, significantly reduced the development of pulmonary metastasis and we provide evidence that this effect may be due to an AF-dependent increase in cellular ROS. Thus, TXNRD2 may represent a novel druggable target that could be deployed to reduce the development of fatal pulmonary metastases in patients with OS. |
format | Online Article Text |
id | pubmed-4808036 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-48080362016-04-19 Auranofin is a potent suppressor of osteosarcoma metastasis Topkas, Eleni Cai, Na Cumming, Andrew Hazar-Rethinam, Mehlika Gannon, Orla Margaret Burgess, Melinda Saunders, Nicholas Andrew Endo-Munoz, Liliana Oncotarget Research Paper Osteosarcoma (OS) accounts for 56% of malignant bone cancers in children and adolescents. Patients with localized disease rarely develop metastasis; however, pulmonary metastasis occurs in approximately 50% of patients and leads to a 5-year survival rate of only 10–20%. Therefore, identifying the genes and pathways involved in metastasis, as new therapeutic targets, is crucial to improve long-term survival of OS patients. Novel markers that define metastatic OS were identified using comparative transcriptomic analyses of two highly metastatic (C1 and C6) and two poorly metastatic clonal variants (C4 and C5) isolated from the metastatic OS cell line, KHOS. Using this approach, we determined that the metastatic phenotype correlated with overexpression of thioredoxin reductase 2 (TXNRD2) or vascular endothelial growth factor (VEGF). Validation in patient biopsies confirmed TXNRD2 and VEGF targets were highly expressed in 29–42% of metastatic OS patient biopsies, with no detectable expression in non-malignant bone or samples from OS patients with localised disease. Auranofin (AF) was used to selectively target and inhibit thioredoxin reductase (TrxR). At low doses, AF was able to inhibit TrxR activity without a significant effect on cell viability whereas at higher doses, AF could induce ROS-dependent apoptosis. AF treatment, in vivo, significantly reduced the development of pulmonary metastasis and we provide evidence that this effect may be due to an AF-dependent increase in cellular ROS. Thus, TXNRD2 may represent a novel druggable target that could be deployed to reduce the development of fatal pulmonary metastases in patients with OS. Impact Journals LLC 2015-11-09 /pmc/articles/PMC4808036/ /pubmed/26573231 Text en Copyright: © 2016 Topkas et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Topkas, Eleni Cai, Na Cumming, Andrew Hazar-Rethinam, Mehlika Gannon, Orla Margaret Burgess, Melinda Saunders, Nicholas Andrew Endo-Munoz, Liliana Auranofin is a potent suppressor of osteosarcoma metastasis |
title | Auranofin is a potent suppressor of osteosarcoma metastasis |
title_full | Auranofin is a potent suppressor of osteosarcoma metastasis |
title_fullStr | Auranofin is a potent suppressor of osteosarcoma metastasis |
title_full_unstemmed | Auranofin is a potent suppressor of osteosarcoma metastasis |
title_short | Auranofin is a potent suppressor of osteosarcoma metastasis |
title_sort | auranofin is a potent suppressor of osteosarcoma metastasis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808036/ https://www.ncbi.nlm.nih.gov/pubmed/26573231 |
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