Effect of glutaminase inhibition on cancer-induced bone pain
Authors Fazzari J, Singh G
Received 14 May 2019
Accepted for publication 23 July 2019
Published 11 September 2019 Volume 2019:11 Pages 273—282
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Nicola Ludin
Peer reviewer comments 2
Editor who approved publication: Professor Pranela Rameshwar
Jennifer Fazzari, Gurmit Singh
Department of Pathology and Molecular Medicine, Mcmaster University, Hamilton, ON, Canada
Correspondence: Gurmit Singh
McMaster University, 1280 Main St. W, 2102 Michael G DeGroote Centre for Learning and Discovery, Hamilton, Ontario L8S 4L8, Canada
Tel +1 905 525 9140 x28144
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.
Keywords: Cancer-induced bone pain, breast cancer, glutaminase, anaplerosis
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