Effects of Src-kinase inhibition in cancer-induced bone pain.
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.
School of Clinical Dentistry, University of Sheffield, UK.
Milena
M
De Felice
School of Clinical Dentistry, University of Sheffield, UK.
Daniel
D
Lambert
Department of Oncology, University of Sheffield, UK.
Ingunn
I
Holen
Scientific Partnering and Alliances, AstraZeneca, Alderley Park, UK.
K Jane
KJ
Escott
School of Clinical Dentistry, University of Sheffield, UK d.andrew@sheffield.ac.uk.
David
D
Andrew
D000818:Animals; D001522:Behavior, Animal; D052117:Benzodioxoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D000072716:Cancer Pain / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D016194:Receptors, N-Methyl-D-Aspartate; C515233:saracatinib; D019061:src-Family Kinases
Bone cancer pain; hypersensitivity; phosphoGluN1; saracatinib