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.
Highlights
Pain is a severe and debilitating complication of metastatic bone cancer
Despite improvement in treatment options, many patients with advanced- or metastatic cancer experience unsatisfactory pain relief which severely compromises their quality of life[2, 14]
Our original hypothesis was that inhibition of Src family tyrosine kinases by dasatinib would reduce pain-related behaviour through a decrease in NMDAR mediated central sensitization, tumour burden and bone degradation
Summary
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. Liu and colleagues reported in 2008 that blocking the interaction between Src and the NMDA receptor complex with a peptide mimicking the amino acid sequence of the unique domain of Src ameliorates inflammatory and neuropathic pain[32, 33] and recently Felice et al reported that the multi-kinase inhibitor saracatinib inhibits thermal hyperalgesia in cancer-induced bone pain[34]. Using a rat model of cancer-induced bone pain, we sought to determine whether inhibition of Src family tyrosine kinases by dasatinib would decrease tumour burden, decrease bone degradation, and reduce pain-related behaviours. Using a combination of behavioural, imaging, and immunoblotting assays we show that dasatinib acts as a disease modifier that delays onset of cancer-induced bone pain by preserving bone mass
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
