Journal Article

Effects of Src-kinase inhibition in cancer-induced bone pain

Lambert, Daniel, Andrew, David, Escott, K Jane, Holen, Ingunn, De Felice, Milena

2016

Overview

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.

• Publisher: SAGE Publications,Sage Publications Ltd
• Subject: Analgesics / Animals / Behavior, Animal / Benzodioxoles - pharmacokinetics / Benzodioxoles - pharmacology / Benzodioxoles - therapeutic use / Bone cancer / Bone Neoplasms - complications / Bone Neoplasms - drug therapy / Bone Neoplasms - physiopathology / Bone Remodeling - drug effects / Bone resorption / Bone Resorption - complications / Bone Resorption - drug therapy / Bone Resorption - physiopathology / Breast cancer / Cancer / Cancer Pain - complications / Cancer Pain - drug therapy / Cancer Pain - physiopathology / Disease Models, Animal / Glutamic acid receptors / Hyperalgesia / Hyperalgesia - complications / Hyperalgesia - drug therapy / Hypersensitivity / Immunoblotting / Inflammation / Injection / Lung cancer / Male / Mechanical stimuli / Metastases / Metastasis / N-Methyl-D-aspartic acid receptors / Nervous system / Neurons - drug effects / Neurons - metabolism / Neurons - pathology / Osteoclasts / Pain / Pain perception / Phosphorylation / Phosphorylation - drug effects / Prostate cancer / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Protein-tyrosine kinase receptors / Quinazolines - pharmacokinetics / Quinazolines - pharmacology / Quinazolines - therapeutic use / Rats, Sprague-Dawley / Receptor mechanisms / Receptors, N-Methyl-D-Aspartate - metabolism / Spinal Cord - pathology / src-Family Kinases - antagonists & inhibitors / src-Family Kinases - metabolism / Tumor cells