{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T10:41:50Z","timestamp":1789123310659,"version":"build-2803163510"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2012,12,13]],"date-time":"2012-12-13T00:00:00Z","timestamp":1355356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Insulin-like growth factor 1 (IGF-1) plays an important role in both bone metabolism and breast cancer. In this study, we investigated the effects of the novel IGF-1 receptor tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) on osteolytic bone disease associated with breast cancer. Human MDA-MB-231 and mouse 4T1 breast cancer cells enhanced osteoclast formation in receptor activator of NF-\u03baB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) stimulated bone marrow cultures, and these effects were significantly inhibited by PQIP. Functional studies in osteoclasts showed that PQIP inhibited both IGF-1 and conditioned medium\u2013induced osteoclast formation by preventing phosphatidylinositol 3-kinase (PI3K)\/protein kinase B (Akt) activation without interfering with RANKL or M-CSF signaling. Treatment of osteoblasts with PQIP significantly inhibited the increase in RANKL\/osteoprotegerin (OPG) ratio by IGF-1 and conditioned medium and totally prevented conditioned medium\u2013induced osteoclast formation in osteoblast\u2013bone marrow (BM) cell cocultures, thereby suggesting an inhibitory effect on osteoblast\u2013osteoclast coupling. PQIP also inhibited IGF-1\u2013induced osteoblast differentiation, spreading, migration, and bone nodule formation. Treatment with PQIP significantly reduced MDA-MB-231 conditioned medium\u2013induced osteolytic bone loss in a mouse calvarial organ culture system ex vivo and in adult mice in vivo. Moreover, once daily oral administration of PQIP significantly decreased trabecular bone loss and reduced the size of osteolytic bone lesions following 4T1 intratibial injection in mice. Quantitative histomorphometry showed a significant reduction in bone resorption and formation indices, indicative of a reduced rate of cancer-associated bone turnover. We conclude that inhibition of IGF-1 receptor tyrosine kinase activity by PQIP suppresses breast cancer\u2013induced bone turnover and osteolysis. Therefore, PQIP, and its novel derivatives that are currently in advanced clinical development for the treatment of a number of solid tumors, may be of value in the treatment of osteolytic bone disease associated with breast cancer. \u00a9 2013 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.1847","type":"journal-article","created":{"date-parts":[[2012,12,13]],"date-time":"2012-12-13T15:01:58Z","timestamp":1355410918000},"page":"1229-1242","source":"Crossref","is-referenced-by-count":17,"title":["Selective tyrosine kinase inhibition of insulin-like growth factor-1 receptor inhibits human and mouse breast cancer\u2013induced bone cell activity, bone remodeling, and osteolysis"],"prefix":"10.1093","volume":"28","author":[{"given":"John G","family":"Logan","sequence":"first","affiliation":[{"name":"Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK"},{"name":"Bone and Cancer Group, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Sophocleous","sequence":"additional","affiliation":[{"name":"The Centre for Molecular Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Marino","sequence":"additional","affiliation":[{"name":"Bone and Cancer Group, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morwenna","family":"Muir","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie G","family":"Brunton","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aymen I","family":"Idris","sequence":"additional","affiliation":[{"name":"Bone and Cancer Group, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,12,13]]},"reference":[{"key":"2024020318400045200_bib1","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/nrc867","article-title":"Metastasis to bone: causes, consequences and therapeutic opportunities","volume":"2","author":"Mundy","year":"2002","journal-title":"Nat Rev Cancer."},{"key":"2024020318400045200_bib2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.1600-0714.2006.00360.x","article-title":"Pathogenesis of bone metastasis: a review","volume":"35","author":"Raubenheimer","year":"2006","journal-title":"J Oral Pathol Med."},{"key":"2024020318400045200_bib3"},{"key":"2024020318400045200_bib4","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1002\/1097-0142(20000615)88:12+<2892::AID-CNCR2>3.0.CO;2-Y","article-title":"Molecular mechanisms of osteolytic bone metastases","volume":"88","author":"Guise","year":"2000","journal-title":"Cancer."},{"key":"2024020318400045200_bib5","doi-asserted-by":"crossref","first-page":"6309s","DOI":"10.1158\/1078-0432.CCR-06-0652","article-title":"Skeletal complications of breast cancer therapies","volume":"12","author":"Hirbe","year":"2006","journal-title":"Clin Cancer Res."},{"key":"2024020318400045200_bib6","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1002\/j.1460-2075.1986.tb04528.x","article-title":"Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity","volume":"5","author":"Ullrich","year":"1986","journal-title":"EMBO.J."},{"issue":"(Suppl 2","key":"2024020318400045200_bib7","doi-asserted-by":"crossref","first-page":"S54","DOI":"10.1007\/s001250051402","article-title":"Modifications in the B10 and B. 26\u201330 regions of the B chain of human insulin alter affinity for the human IGF-I receptor more than for the insulin receptor","author":"Slieker","year":"1997","journal-title":"Diabetologia."},{"key":"2024020318400045200_bib8","doi-asserted-by":"crossref","first-page":"18650","DOI":"10.1074\/jbc.272.30.18650","article-title":"Identification of common ligand binding determinants of the insulin and insulin-like growth factor 1 receptors. 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