A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6
A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6
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DOI：
10.1158/0008-5472.can-06-1098
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Chen-Kiang, Selina
中科院分区：
文献类型：
--
作者：
Baughn, Linda B.;Di Liberto, Maurizio;Chen-Kiang, Selina
细胞周期失调是多发性骨髓瘤（第二种最常见的造血系统癌症）发生和死亡的核心，尽管受损的细胞凋亡在骨髓瘤细胞在骨髓中的积累中起着关键作用。骨髓瘤细胞的间歇性、无限制增殖的机制尚不清楚，但在体内骨髓瘤细胞增殖之前，细胞周期蛋白依赖性激酶4（Cdk 4）-细胞周期蛋白D1或Cdk 6-细胞周期蛋白D2的相互排斥激活。在这里，我们表明，通过特异性抑制Cdk 4/6，口服活性小分子PD 0332991有效地诱导体外原代骨髓瘤细胞中的G1阻滞，并防止播散性人骨髓瘤异种移植物中的肿瘤生长。PD 0332991抑制Cdk 4/6，与细胞的循环状态成比例，不依赖于细胞转化，并与生理Cdk 4/6抑制剂p18（INK 4c）协同作用。PD 0332991对Cdk 4/6的抑制不伴有细胞凋亡的诱导。然而，当与第二种药物（如地塞米松）联合使用时，PD 0332991可显著增强地塞米松对骨髓瘤细胞的杀伤作用。因此，PD 0332991代表了第一个有希望的和特异性的抑制剂，用于多发性骨髓瘤和可能的其他B细胞癌症中的Cdk 4/6的治疗靶向。
Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6, the orally active small-molecule PD 0332991 potently induces G, arrest in primary bone marrow myeloma cells ex vivo and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation and acts in concert with the physiologic Cdk4/6 inhibitor p18(INK4c). Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent, such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B-cell cancers.