De Felice Milena, Lambert Daniel, Holen Ingunn, Escott K Jane, Andrew David
School of Clinical Dentistry, University of Sheffield, UK.
Department of Oncology, University of Sheffield, UK.
Mol Pain. 2016 Apr 18;12. doi: 10.1177/1744806916643725. Print 2016.
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.
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.
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.
骨转移在晚期乳腺癌、肺癌和前列腺癌中频繁发生，约70%的患者会受到影响。疼痛是骨转移的主要症状，而目前的治疗方法可能效果不佳或有不可接受的副作用。导致癌症诱导性骨痛的机制尚未完全明确；然而，已知外周骨传入神经和中枢脊髓回路均存在敏化现象。众所周知，N-甲基-D-天冬氨酸受体在疼痛超敏反应的病理生理学中起主要作用。抑制非受体酪氨酸激酶Src可控制N-甲基-D-天冬氨酸受体的活性，抑制Src可减轻与神经性和炎性疼痛相关的超敏反应。由于Src也与破骨细胞性骨吸收有关，我们研究了抑制Src是否能改善癌症诱导性骨痛。我们在癌症诱导性骨痛的大鼠模型中使用口服生物可利用的Src抑制剂（萨拉卡替尼）对这一假设进行了测试。
在大鼠胫骨内注射大鼠乳腺癌细胞（乳腺大鼠转移瘤细胞-1）而非赋形剂，会使后爪对热刺激和机械刺激产生超敏反应，在注射后第6天达到峰值，并在注射后至少持续13天。在胫骨内注射7天后开始每日口服萨拉卡替尼（20 mg/kg）可逆转热痛觉过敏，但不能逆转机械性异常性疼痛。萨拉卡替尼的镇痛机制似乎是由于对神经系统的作用，因为对L2-5脊髓节段进行免疫印迹分析显示，注射乳腺大鼠转移瘤细胞-1会诱导N-甲基-D-天冬氨酸受体的GluN1亚基磷酸化，表明受体被激活，而萨拉卡替尼可使其降低。此外，组织学检查显示，萨拉卡替尼在任何剂量下均无抗肿瘤作用，对骨保留也无显著影响。
这是首次证明Src在癌症诱导性骨痛的发生中起作用，并且抑制Src代表了一种可能用于骨转移患者的新镇痛策略。
