The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain.
The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain.
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DOI：
10.1038/s41598-017-05029-1
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发表时间：
2017-07-06
影响因子：
4.6
通讯作者：
Heegaard AM
中科院分区：
文献类型：
--
作者：
Appel CK;Gallego-Pedersen S;Andersen L;Blancheflor Kristensen S;Ding M;Falk S;Sayilekshmy M;Gabel-Jensen C;Heegaard AM
疼痛是转移性骨癌的严重并发症。目前的镇痛药不能为所有患者提供足够的疼痛缓解，因此需要新的治疗方案。Src激酶是一种非受体蛋白酪氨酸激酶，参与癌症诱导的骨痛过程，包括癌症生长、破骨细胞骨降解和伤害性信号传导。在这里，我们研究了达沙替尼（一种口服Src激酶家族和Bcr-Abl酪氨酸激酶抑制剂）在癌症性骨痛动物模型中的作用。从接种MRMT-1乳腺癌细胞后第7天开始，每天给药达沙替尼（15 mg/kg, p.o）可显著减轻癌变大鼠的运动诱发和非诱发性疼痛行为。x线摄影和显微计算机断层扫描分析显示，达沙替尼治疗组的相对骨密度显著提高，骨微结构得到相当程度的保存，表明达沙替尼具有保骨作用。用15mg /kg达沙替尼治疗的患癌大鼠血清TRACP 5b水平显著降低支持了这一点。此外，腰椎节段免疫印迹显示Src激活增加，但NMDA受体亚基2B未见增加。这些发现支持达沙替尼作为一种疾病调节药物在以破骨细胞活性增加为特征的疼痛病理中的作用，如骨转移。
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.
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影响因子：
3.7
作者：
Garcia-Gomez A;Ocio EM;Crusoe E;Santamaria C;Hernández-Campo P;Blanco JF;Sanchez-Guijo FM;Hernández-Iglesias T;Briñón JG;Fisac-Herrero RM;Lee FY;Pandiella A;San Miguel JF;Garayoa M
通讯作者：
Garayoa M
SRC抑制剂dasatinib加速了人骨骨髓衍生的间充质基质细胞分化成成骨细胞。
影响因子：
3.8
作者：
Id Boufker H;Lagneaux L;Najar M;Piccart M;Ghanem G;Body JJ;Journé F
通讯作者：
Journé F
影响因子：
7.4
作者：
Grond, S;Zech, D;Lehmann, KA
通讯作者：
Lehmann, KA
DOI：
10.1097/spc.0b013e328133f5e9
发表时间：
2007-04-01
影响因子：
2.1
作者：
Gordon-Williams, Richard M;Dickenson, Anthony H
通讯作者：
Dickenson, Anthony H
影响因子：
5.3
作者：
Furusho, Miki;Dupree, Jeffrey L.;Bansal, Rashmi
通讯作者：
Bansal, Rashmi