RRC ID 65753
Author De Felice M, Lambert D, Holen I, Escott KJ, Andrew D.
Title Effects of Src-kinase inhibition in cancer-induced bone pain.
Journal Mol Pain
Abstract BACKGROUND:Bone metastases occur frequently in advanced breast, lung, and prostate cancer, with approximately 70% of patients affected. Pain is a major symptom of bone metastases, and current treatments may be inadequate or have unacceptable side effects. The mechanisms that drive cancer-induced bone pain are not fully understood; however, it is known that there is sensitization of both peripheral bone afferents and central spinal circuits. It is well established that the N-methyl-D-aspartate receptor plays a major role in the pathophysiology of pain hypersensitivity. Inhibition of the non-receptor tyrosine kinase Src controls N-methyl-D-aspartate receptor activity and inhibiting Src reduces the hypersensitivity associated with neuropathic and inflammatory pains. As Src is also implicated in osteoclastic bone resorption, we have investigated if inhibiting Src ameliorates cancer-induced bone pain. We have tested this hypothesis using an orally bioavailable Src inhibitor (saracatinib) in a rat model of cancer-induced bone pain.
RESULTS:Intra-tibial injection of rat mammary cancer cells (Mammary rat metastasis tumor cells -1), but not vehicle, in rats produced hindpaw hypersensitivity to thermal and mechanical stimuli that was maximal after six days and persisted for at least 13 days postinjection. Daily oral gavage with saracatinib (20 mg/kg) beginning seven days after intra-tibial injection reversed the thermal hyperalgesia but not the mechanical allodynia. The analgesic mechanisms of saracatinib appear to be due to an effect on the nervous system as immunoblotting of L2-5 spinal segments showed that mammary rat metastasis tumor cells-1 injection induced phosphorylation of the GluN1 subunit of the N-methyl-D-aspartate receptor, indicative of receptor activation, and this was reduced by saracatinib. Additionally, histology showed no anti-tumor effect of saracatinib at any dose and no significant effect on bone preservation.
CONCLUSIONS:This is the first demonstration that Src plays a role in the development of cancer-induced bone pain and that Src inhibition represents a possible new analgesic strategy for patients with bone metastases.
Volume 12
Published 2016-1-1
DOI 10.1177/1744806916643725
PII 12/0/1744806916643725
PMID 27094550
PMC PMC4956174
MeSH Animals Behavior, Animal Benzodioxoles / pharmacokinetics Benzodioxoles / pharmacology Benzodioxoles / therapeutic use Bone Neoplasms / complications* Bone Neoplasms / drug therapy* Bone Neoplasms / physiopathology Bone Remodeling / drug effects Bone Resorption / complications Bone Resorption / drug therapy Bone Resorption / physiopathology Cancer Pain / complications* Cancer Pain / drug therapy* Cancer Pain / physiopathology Disease Models, Animal Hyperalgesia / complications Hyperalgesia / drug therapy Male Neurons / drug effects Neurons / metabolism Neurons / pathology Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use* Quinazolines / pharmacokinetics Quinazolines / pharmacology Quinazolines / therapeutic use Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate / metabolism Spinal Cord / pathology src-Family Kinases / antagonists & inhibitors* src-Family Kinases / metabolism
IF 2.696
Human and Animal Cells MRMT-1(RCB2860)