The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain

Abstract Pain is a severe and debilitating complication of metastatic bone cancer. Current analgesics do not provide sufficient pain relief for all patients, creating a great need for new treatment options. The Src kinase, a non-receptor protein tyrosine kinase, is implicated in processes involved i...

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Autores principales:	Camilla Kristine Appel, Simone Gallego-Pedersen, Line Andersen, Sophie Blancheflor Kristensen, Ming Ding, Sarah Falk, Manasi Sayilekshmy, Charlotte Gabel-Jensen, Anne-Marie Heegaard
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8a2be61aace84981bb8033b783094820
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spelling	oai:doaj.org-article:8a2be61aace84981bb8033b7830948202021-12-02T12:31:50ZThe Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain10.1038/s41598-017-05029-12045-2322https://doaj.org/article/8a2be61aace84981bb8033b7830948202017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05029-1https://doaj.org/toc/2045-2322Abstract Pain is a severe and debilitating complication of metastatic bone cancer. Current analgesics do not provide sufficient pain relief for all patients, creating a great need for new treatment options. The Src kinase, a non-receptor protein tyrosine kinase, is implicated in processes involved in cancer-induced bone pain, including cancer growth, osteoclastic bone degradation and nociceptive signalling. Here we investigate the role of dasatinib, an oral Src kinase family and Bcr-Abl tyrosine kinase inhibitor, in an animal model of cancer-induced bone pain. Daily administration of dasatinib (15 mg/kg, p.o.) from day 7 after inoculation of MRMT-1 mammary carcinoma cells significantly attenuated movement-evoked and non-evoked pain behaviour in cancer-bearing rats. Radiographic - and microcomputed tomographic analyses showed significantly higher relative bone density and considerably preserved bone micro-architecture in the dasatinib treated groups, suggesting a bone-preserving effect. This was supported by a significant reduction of serum TRACP 5b levels in cancer-bearing rats treated with 15 mg/kg dasatinib. Furthermore, immunoblotting of lumbar spinal segments showed an increased activation of Src but not the NMDA receptor subunit 2B. These findings support a role of dasatinib as a disease modifying drug in pain pathologies characterized by increased osteoclast activity, such as bone metastases.Camilla Kristine AppelSimone Gallego-PedersenLine AndersenSophie Blancheflor KristensenMing DingSarah FalkManasi SayilekshmyCharlotte Gabel-JensenAnne-Marie HeegaardNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Camilla Kristine Appel Simone Gallego-Pedersen Line Andersen Sophie Blancheflor Kristensen Ming Ding Sarah Falk Manasi Sayilekshmy Charlotte Gabel-Jensen Anne-Marie Heegaard The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain
description	Abstract Pain is a severe and debilitating complication of metastatic bone cancer. Current analgesics do not provide sufficient pain relief for all patients, creating a great need for new treatment options. The Src kinase, a non-receptor protein tyrosine kinase, is implicated in processes involved in cancer-induced bone pain, including cancer growth, osteoclastic bone degradation and nociceptive signalling. Here we investigate the role of dasatinib, an oral Src kinase family and Bcr-Abl tyrosine kinase inhibitor, in an animal model of cancer-induced bone pain. Daily administration of dasatinib (15 mg/kg, p.o.) from day 7 after inoculation of MRMT-1 mammary carcinoma cells significantly attenuated movement-evoked and non-evoked pain behaviour in cancer-bearing rats. Radiographic - and microcomputed tomographic analyses showed significantly higher relative bone density and considerably preserved bone micro-architecture in the dasatinib treated groups, suggesting a bone-preserving effect. This was supported by a significant reduction of serum TRACP 5b levels in cancer-bearing rats treated with 15 mg/kg dasatinib. Furthermore, immunoblotting of lumbar spinal segments showed an increased activation of Src but not the NMDA receptor subunit 2B. These findings support a role of dasatinib as a disease modifying drug in pain pathologies characterized by increased osteoclast activity, such as bone metastases.
format	article
author	Camilla Kristine Appel Simone Gallego-Pedersen Line Andersen Sophie Blancheflor Kristensen Ming Ding Sarah Falk Manasi Sayilekshmy Charlotte Gabel-Jensen Anne-Marie Heegaard
author_facet	Camilla Kristine Appel Simone Gallego-Pedersen Line Andersen Sophie Blancheflor Kristensen Ming Ding Sarah Falk Manasi Sayilekshmy Charlotte Gabel-Jensen Anne-Marie Heegaard
author_sort	Camilla Kristine Appel
title	The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain
title_short	The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain
title_full	The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain
title_fullStr	The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain
title_full_unstemmed	The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain
title_sort	src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8a2be61aace84981bb8033b783094820
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The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain

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