SRC kinase inhibition with saracatinib limits the development of osteolytic bone disease in multiple myeloma.
SRC kinase inhibition with saracatinib limits the development of osteolytic bone disease in multiple myeloma.
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DOI：
10.18632/oncotarget.8750
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Caers J
中科院分区：
文献类型：
--
作者：
Heusschen R;Muller J;Binsfeld M;Marty C;Plougonven E;Dubois S;Mahli N;Moermans K;Carmeliet G;Léonard A;Baron F;Beguin Y;Menu E;Cohen-Solal M;Caers J
多发性骨髓瘤（MM）相关的溶骨性骨病是MM患者发病和死亡的主要原因，新的治疗策略的开发引起了极大的兴趣。原癌基因SRC是这种策略的一个有吸引力的靶标。在本研究中，我们研究了SRC抑制剂saracatinib（AZD 0530）治疗对破骨细胞和成骨细胞分化和功能的影响，以及对5TGM.1和5T2MM小鼠MM模型中MM及其相关骨病的发展的影响。体外数据显示，saracatinib对破骨细胞分化、极化和吸收功能具有抑制作用。在成骨细胞中，胶原沉积和基质矿化受到saracatinib的影响。在saracatinib治疗后，MM细胞增殖和肿瘤负荷保持不变，我们无法检测到作为MM标准治疗一部分的药物的任何协同作用。我们观察到用saracatinib治疗MM荷瘤小鼠后骨丢失显著减少，这反映在小梁骨参数恢复到未处理对照小鼠中观察到的水平。组织形态学分析支持这是通过抑制骨吸收而发生的。总之，这些数据进一步确立了SRC抑制作为治疗MM相关溶骨性疾病的有前景的治疗方法。
Multiple myeloma (MM)-associated osteolytic bone disease is a major cause of morbidity and mortality in MM patients and the development of new therapeutic strategies is of great interest. The proto-oncogene SRC is an attractive target for such a strategy. In the current study, we investigated the effect of treatment with the SRC inhibitor saracatinib (AZD0530) on osteoclast and osteoblast differentiation and function, and on the development of MM and its associated bone disease in the 5TGM.1 and 5T2MM murine MM models. In vitro data showed an inhibitory effect of saracatinib on osteoclast differentiation, polarization and resorptive function. In osteoblasts, collagen deposition and matrix mineralization were affected by saracatinib. MM cell proliferation and tumor burden remained unaltered following saracatinib treatment and we could not detect any synergistic effects with drugs that are part of standard care in MM. We observed a marked reduction of bone loss after treatment of MM-bearing mice with saracatinib as reflected by a restoration of trabecular bone parameters to levels observed in naive control mice. Histomorphometric analyses support that this occurs through an inhibition of bone resorption. In conclusion, these data further establish SRC inhibition as a promising therapeutic approach for the treatment of MM-associated osteolytic bone disease.
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影响因子：
5.6
作者：
Chellaiah MA;Schaller MD
通讯作者：
Schaller MD
影响因子：
15.9
作者：
Ersek, Adel;Xu, Ke;Karadimitris, Anastasios
通讯作者：
Karadimitris, Anastasios
影响因子：
20.3
作者：
Asosingh, K;De Raeve, H;Vanderkerken, K
通讯作者：
Vanderkerken, K
DOI：
10.1038/sj.thj.6200052
发表时间：
2000-01-01
期刊：
The hematology journal : the official journal of the European Haematology Association
影响因子：
--
作者：
Asosingh, K;Radl, J;Vanderkerken, K
通讯作者：
Vanderkerken, K
影响因子：
20.3
作者：
Coluccia, Addolorata Maria Luce;Cirulli, Teresa;Vacca, Angelo
通讯作者：
Vacca, Angelo