Nitrogen-containing bisphosphonate, YM529/ONO-5920, inhibits macrophage inflammatory protein 1α expression and secretion in mouse myeloma cells
Nitrogen-containing bisphosphonate, YM529/ONO-5920, inhibits macrophage inflammatory protein 1α expression and secretion in mouse myeloma cells
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DOI：
10.1111/j.1349-7006.2007.00651.x
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发表时间：
2008-01-01
期刊：
影响因子：
5.7
通讯作者：
Nishida, Shozo
中科院分区：
文献类型：
--
作者：
Tsubaki, Masanobu;Kato, Chisato;Nishida, Shozo
巨噬细胞炎症蛋白 1 α (MIP-1 α) 在多发性骨髓瘤患者中检测到高浓度，被认为在多发性骨髓瘤和骨溶解的病因学中发挥重要作用。因此，我们研究了新型双膦酸盐 YM529/ONO-5920 是否抑制小鼠骨髓瘤细胞中 MIP-1 α mRNA 的表达以及 MIP-1 α 的分泌。当细胞受到脂多糖刺激时，观察到MIP-1α mRNA表达和MIP-1α分泌增加。 YM529/ONO-5920 以浓度依赖性方式抑制 MIP-1 α mRNA 表达和 MIP-1 α 分泌。脂多糖刺激后观察到细胞外调节激酶 1/2 (ERK1/2) 和 Akt 的磷酸化短暂增加。给予YM529/ONO-5920后，ERK1/2或Akt的磷酸化没有短暂增加。这些结果表明，YM529/ONO-5920通过阻断Ras/丝裂原激活蛋白激酶激酶/ERK和Ras/磷脂酰肌醇-3激酶/Akt的信号通路来抑制MIP-1α的表达和分泌。因此，YM529/ONO-5920 似乎有望在未来有效治疗依赖于 MIP-1 α 的骨质溶解和骨髓瘤细胞生长。
Macrophage inflammatory protein 1 alpha (MIP-1 alpha) is detected at high concentrations in patients with multiple myeloma, and it is thought to play an important role in the etiology of multiple myeloma and osteolysis. Thus, we investigated whether or not YM529/ONO-5920, a new bisphosphonate, inhibited MIP-1 alpha mRNA expression in, and MIP-1 alpha secretion from, mouse myeloma cells. When the cells were stimulated by lipopolysaccharide, increased MIP-1 alpha mRNA expression and MIP-1 alpha secretion were observed. YM529/ONO-5920 inhibited MIP-1 alpha mRNA expression and MIP-1 alpha secretion in a concentration-dependent manner. A transient increase in the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) and Akt was observed after lipopolysaccharide stimulation. After YM529/ONO-5920 was given, there was no transient increase in the phosphorylation of ERK1/2 or Akt. These results indicated that YM529/ONO-5920 inhibited the expression and secretion of MIP-1 alpha through blocking the signaling pathway of the Ras/mitogen-activated protein kinase kinase/ERK and Ras/phosphatidylinositol-3 kinase/Akt. Accordingly, YM529/ONO-5920 appears to have promise for use in effective future therapy for osteolysis and myeloma cell growth that depends on MIP-1 alpha.