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 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.

Cancer-induced Bone Pain Impairs Burrowing Behaviour in Mouse and Rat

“…von Frey and Randall Selitto, and non-stimulus-evoked tests, e.g. weight bearing and grid climbing (28,29,41,42). In accordance with this, our data showed a decrease in burrowing performance in cancer-bearing mice parallel to the development of limb-use impairment and a shift in weight distribution.…”

Neuropeptide Y is Up-regulated and Induces Antinociception in Cancer-induced Bone Pain

“…Rats were allowed to walk freely in a transparent plastic cage with no bedding (500 mm x 300 mm x 500 mm). After 15 min acclimation to the cage in groups of five, the animals were observed individually for 3 min, and their gait was scored as follows: 3=normal use of the cancer-bearing limb, 2=mild or insignificant limping and normal bodyweight distribution, 1=significant limping accompanied by a shift in bodyweight distribution towards the healthy limb, 0=partial or total lack of use of the cancer-bearing limb (shown as momentarily holding the limb aloft while in locomotion and/or sitting), as previously described (Appel et al, 2017). A humane endpoint was established for a limb use score of 0.…”

Nuclear factor kappa B regulated monocyte chemoattractant protein-1/chemokine CC motif receptor-2 expressing in spinal cord contributes to the maintenance of cancer-induced bone pain in rats

“… 2 , 3 Surgery, radiotherapy, chemotherapy, nerve block technique, adoptive tumor immunotherapy, and drugs have been used to treat cancer-induced bone pain (CIBP). 4 However, current clinical therapies for persistent CIBP are limited, and some often cause serious side effects. 5 Therefore, new analgesic treatments are urgently needed.…”