Effect of glutaminase inhibition on cancer-induced bone pain

Jennifer Fazzari, Gurmit Singh Department of Pathology and Molecular Medicine, Mcmaster University, Hamilton, ON, CanadaCorrespondence: Gurmit SinghMcMaster University, 1280 Main St. W, 2102 Michael G DeGroote Centre for Learning and Discovery, Hamilton, Ontario L8S 4L8, CanadaTel +1 905 525 9140 x2...

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Autores principales:	Fazzari J, Singh G
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	Cancer-induced bone pain breast cancer glutaminase anaplerosis. Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/758e641b17694fcd940e3c54c158f3d2
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spelling	oai:doaj.org-article:758e641b17694fcd940e3c54c158f3d22021-12-02T07:38:36ZEffect of glutaminase inhibition on cancer-induced bone pain1179-1314https://doaj.org/article/758e641b17694fcd940e3c54c158f3d22019-09-01T00:00:00Zhttps://www.dovepress.com/effect-of-glutaminase-inhibition-on-cancer-induced-bone-pain-peer-reviewed-article-BCTThttps://doaj.org/toc/1179-1314Jennifer Fazzari, Gurmit Singh Department of Pathology and Molecular Medicine, Mcmaster University, Hamilton, ON, CanadaCorrespondence: Gurmit SinghMcMaster University, 1280 Main St. W, 2102 Michael G DeGroote Centre for Learning and Discovery, Hamilton, Ontario L8S 4L8, CanadaTel +1 905 525 9140 x28144Email singhg@mcmaster.caPurpose: 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.Keywords: Cancer-induced bone pain, breast cancer, glutaminase, anaplerosisFazzari JSingh GDove Medical PressarticleCancer-induced bone painbreast cancerglutaminaseanaplerosis.Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBreast Cancer: Targets and Therapy, Vol Volume 11, Pp 273-282 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cancer-induced bone pain breast cancer glutaminase anaplerosis. Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Cancer-induced bone pain breast cancer glutaminase anaplerosis. Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Fazzari J Singh G Effect of glutaminase inhibition on cancer-induced bone pain
description	Jennifer Fazzari, Gurmit Singh Department of Pathology and Molecular Medicine, Mcmaster University, Hamilton, ON, CanadaCorrespondence: Gurmit SinghMcMaster University, 1280 Main St. W, 2102 Michael G DeGroote Centre for Learning and Discovery, Hamilton, Ontario L8S 4L8, CanadaTel +1 905 525 9140 x28144Email singhg@mcmaster.caPurpose: 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.Keywords: Cancer-induced bone pain, breast cancer, glutaminase, anaplerosis
format	article
author	Fazzari J Singh G
author_facet	Fazzari J Singh G
author_sort	Fazzari J
title	Effect of glutaminase inhibition on cancer-induced bone pain
title_short	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_sort	effect of glutaminase inhibition on cancer-induced bone pain
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/758e641b17694fcd940e3c54c158f3d2
work_keys_str_mv	AT fazzarij effectofglutaminaseinhibitiononcancerinducedbonepain AT singhg effectofglutaminaseinhibitiononcancerinducedbonepain
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Effect of glutaminase inhibition on cancer-induced bone pain

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