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Effect of glutaminase inhibition on cancer-induced bone pain
PURPOSE: The complex nature of cancer-induced bone pain (CIBP) has led to investigation into cancer-targeted therapies. This has involved targeting glutamate release from the tumor, secreted as a byproduct of antioxidant responses and metabolic disruption. Cancer cells undergo many metabolic changes...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750878/ https://www.ncbi.nlm.nih.gov/pubmed/31571981 http://dx.doi.org/10.2147/BCTT.S215655 |
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author | Fazzari, Jennifer Singh, Gurmit |
author_facet | Fazzari, Jennifer Singh, Gurmit |
author_sort | Fazzari, Jennifer |
collection | PubMed |
description | PURPOSE: The complex nature of cancer-induced bone pain (CIBP) has led to investigation into cancer-targeted therapies. This has involved targeting glutamate release from the tumor, secreted as a byproduct of antioxidant responses and metabolic disruption. Cancer cells undergo many metabolic changes that result in increased glutamine metabolism and subsequently the production of glutamate. Glutaminase (GLS) is the enzyme that mediates the conversion of glutamine to glutamate and has been shown to be upregulated in many cancer types including malignancies of the breast. This enzyme, therefore, represents another potential therapeutic target for CIBP, one that lies upstream of glutamate secretion. METHODS: A recently developed inhibitor of GLS, CB-839, was tested in an animal model of CIBP induced by intrafemoral MDA-MB-231 xenografts. CIBP behaviors were assessed using Dynamic Weight Bearing and Dynamic Plantar Aesthesiometer readings of mechanical hyperalgesia and allodynia. RESULTS: CB-839 failed to modulate any of the associated nociceptive behaviors induced by intrafemoral MDA-MB-231 tumor growth. Further investigation in vitro revealed the sensitivity of the drug is dependent on the metabolic flexibility of the cell line being tested which can be modulated by cell culture environment. CONCLUSION: Adaptation to metabolic disturbances may explain the failure of CB-839 to exhibit any significant effects in vivo and the metabolic flexibility of the cell line tested should be considered for future investigations studying the metabolic effects of glutaminase inhibition. |
format | Online Article Text |
id | pubmed-6750878 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-67508782019-09-30 Effect of glutaminase inhibition on cancer-induced bone pain Fazzari, Jennifer Singh, Gurmit Breast Cancer (Dove Med Press) Original Research PURPOSE: The complex nature of cancer-induced bone pain (CIBP) has led to investigation into cancer-targeted therapies. This has involved targeting glutamate release from the tumor, secreted as a byproduct of antioxidant responses and metabolic disruption. Cancer cells undergo many metabolic changes that result in increased glutamine metabolism and subsequently the production of glutamate. Glutaminase (GLS) is the enzyme that mediates the conversion of glutamine to glutamate and has been shown to be upregulated in many cancer types including malignancies of the breast. This enzyme, therefore, represents another potential therapeutic target for CIBP, one that lies upstream of glutamate secretion. METHODS: A recently developed inhibitor of GLS, CB-839, was tested in an animal model of CIBP induced by intrafemoral MDA-MB-231 xenografts. CIBP behaviors were assessed using Dynamic Weight Bearing and Dynamic Plantar Aesthesiometer readings of mechanical hyperalgesia and allodynia. RESULTS: CB-839 failed to modulate any of the associated nociceptive behaviors induced by intrafemoral MDA-MB-231 tumor growth. Further investigation in vitro revealed the sensitivity of the drug is dependent on the metabolic flexibility of the cell line being tested which can be modulated by cell culture environment. CONCLUSION: Adaptation to metabolic disturbances may explain the failure of CB-839 to exhibit any significant effects in vivo and the metabolic flexibility of the cell line tested should be considered for future investigations studying the metabolic effects of glutaminase inhibition. Dove 2019-09-11 /pmc/articles/PMC6750878/ /pubmed/31571981 http://dx.doi.org/10.2147/BCTT.S215655 Text en © 2019 Fazzari and Singh. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Fazzari, Jennifer Singh, Gurmit Effect of glutaminase inhibition on cancer-induced bone pain |
title | Effect of glutaminase inhibition on cancer-induced bone pain |
title_full | Effect of glutaminase inhibition on cancer-induced bone pain |
title_fullStr | Effect of glutaminase inhibition on cancer-induced bone pain |
title_full_unstemmed | Effect of glutaminase inhibition on cancer-induced bone pain |
title_short | Effect of glutaminase inhibition on cancer-induced bone pain |
title_sort | effect of glutaminase inhibition on cancer-induced bone pain |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750878/ https://www.ncbi.nlm.nih.gov/pubmed/31571981 http://dx.doi.org/10.2147/BCTT.S215655 |
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