title: Inhibition of breast cancer-cell glutamate release with sulfasalazine limits cancer-induced bone pain.
abstract: Cancer in bone is frequently a result of metastases from distant sites, particularly from the breast, lung, and prostate. Pain is a common and often severe pathological feature of cancers in bone, and is a significant impediment to the maintenance of quality of life of patients living with bone metastases. Cancer cell lines have been demonstrated to release significant amounts of the neurotransmitter and cell-signalling molecule l-glutamate via the system xC(-) cystine/glutamate antiporter. We have developed a novel mouse model of breast cancer bone metastases to investigate the impact of inhibiting cancer cell glutamate transporters on nociceptive behaviour. Immunodeficient mice were inoculated intrafemorally with the human breast adenocarcinoma cell line MDA-MB-231, then treated 14days later via mini-osmotic pumps inserted intraperitoneally with sulfasalazine, (S)-4-carboxyphenylglycine, or vehicle. Both sulfasalazine and (S)-4-carboxyphenylglycine attenuated in vitro cancer cell glutamate release in a dose-dependent manner via the system xC(-) transporter. Animals treated with sulfasalazine displayed reduced nociceptive behaviours and an extended time until the onset of behavioural evidence of pain. Animals treated with a lower dose of (S)-4-carboxyphenylglycine did not display this reduction in nociceptive behaviour. These results suggest that a reduction in glutamate secretion from cancers in bone with the system xC(-) inhibitor sulfasalazine may provide some benefit for treating the often severe and intractable pain associated with bone metastases.
authors.affiliation: Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ungard
authors.forename: Eric P
authors.initials: EP
authors.lastname: Seidlitz
authors.forename: Gurmit
authors.initials: G
authors.lastname: Singh
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use; D001842:Bone and Bones / Q000503:physiopathology*; D001943:Breast Neoplasms / Q000150:complications / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D010147:Pain Measurement; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D012460:Sulfasalazine; C079693:4-carboxyphenylglycine; D005998:Glycine
keywords: Bone; Cancer; Cancer-induced bone pain; Glutamate; Nociception; Sulfasalazine; System x(C)(−)