{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:02:40Z","timestamp":1793311360959,"version":"4.5.0"},"reference-count":46,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2019,1,1]],"date-time":"2019-01-01T00:00:00Z","timestamp":1546300800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000147","name":"Canadian Breast Cancer Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000147","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Mol Pain"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:p>\n                    Aggressive breast cancer subtypes utilize system x\n                    <jats:sub>c<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    , a membrane antiporter, to import cystine for glutathione synthesis and maintenance of redox homeostasis, in turn releasing glutamate as a metabolic pro-nociceptive by-product. Metastatic breast cancers establish themselves at distal sites including bone, where changes in extracellular glutamate levels contribute to cancer-induced bone pain. We previously established that stearically blocking system x\n                    <jats:sub>c<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    activity with sulfasalazine delays the onset of nociceptive behaviours and that xCT, the functional antiporter subunit, is positively regulated by signal transducer and activator of transcription 3 (STAT3). In the current investigation, a murine xenograft cancer-induced bone pain model was applied to examine whether pharmacological inhibition of phosphorylated STAT3 (pSTAT3) induces changes in nociception. A high glutamate-releasing, xCT\/pSTAT3 over-expressing human breast cancer cell line was selected for injection into the distal epiphysis of the right femur of female nude mice. A 14-day regimen of intraperitoneal injections with either vehicle or the novel STAT3 inhibitor DR-1\u201355 commenced three weeks after initial intrafemoral bone injection. Nociceptive behaviours were temporally monitored by automated von Frey, dynamic weight bearing and open-field testing for the duration of the study, beginning at the baseline. Prior to sacrifice and at ethical end point, tumour-induced osteolytic lesions were radiographically assessed. Treatment with DR-1\u201355 significantly delayed the onset and severity of spontaneous and induced nociceptive behaviours, also decreasing human SLC7A11 ( xCT) mRNA levels in tumour-bearing limbs without altering osteolysis. In addition, two pro-inflammatory cytokines released by this cell line, interleukin 6 and interleukin 1\u03b2, were also down-regulated at the mRNA level in response to DR-1\u201355 treatment in vivo, with lower human interleukin 6 levels detected in the host circulation. This study demonstrates that targeting pSTAT3 may be a viable therapeutic means to manage cancer-induced bone pain, alone or in combination with stearic system x\n                    <jats:sub>c<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    blockers.\n                  <\/jats:p>","DOI":"10.1177\/1744806918823477","type":"journal-article","created":{"date-parts":[[2019,1,9]],"date-time":"2019-01-09T14:57:11Z","timestamp":1547045831000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":9,"title":["Inhibiting STAT3 in a murine model of human breast cancer-induced bone pain delays the onset of nociception"],"prefix":"10.1177","volume":"15","author":[{"given":"Katja","family":"Linher-Melville","sequence":"first","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manu","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Nakhla","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Kum","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Ungard","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Rosa","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Gunning","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gurmit","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, 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