Cancer Res：科学家开发新策略摧毁多发性骨髓瘤

弗吉尼亚联邦大学梅西癌症中心研究人员报告称他们在实验室动物实验中多发性骨髓瘤的新的组合疗法取得了可喜的突破，多发性骨髓瘤是血液癌症的第二个最常见的形式。

这项研究在线发表在Cancer Research杂志上，其详细介绍了药物小分子Bcl-2克制剂（Obatoclax）和Flavopiridol（夫拉平度）联合使用导致多发性骨髓瘤细胞死亡的急剧增加。研究人员指出，发现这两种药物通过不同的机制一起发挥作用，以促进细胞自杀，这一过程被称为细胞凋亡。

Obatoclax是一个处于实验性阶段的药物，目前在在测试其对各种形式的血液癌症的作用。它通过禁用抑制防止癌细胞凋亡的蛋白质发挥作用。夫拉平度除了能降低抗凋亡蛋白的水平，它也是一类称为周期蛋白依赖性激酶（CDK）抑制剂，能阻止癌细胞增长。
 
在实验室实验研究中，一种新的药物组合大大促进了多发性骨髓瘤细胞的死亡。这些结果证实了药物组合能显著改善多发性骨髓瘤小鼠免疫功能低下动物模型的生存。

结果证实了这两个类药物之间具有协同作用，目前研究人员计划测试obatoclax结合其他临床相关的CDK抑制剂来之考察对多发性骨髓瘤的作用。

编译自：Scientists Devise New Strategy to Destroy Multiple Myeloma

doi:10.1158/0008-5472.CAN-12-1118
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CDK Inhibitors Upregulate BH3-Only Proteins to Sensitize Human Myeloma Cells to BH3 Mimetic Therapies

Shuang Chen1, Yun Dai1, Xin-Yan Pei1, Jennifer Myers1, Li Wang1, Lora B. Kramer1,et al.

BH3 mimetic drugs induce cell death by antagonizing the activity of antiapoptotic Bcl-2 family proteins. Cyclin-dependent kinase (CDK) inhibitors that function as transcriptional repressors downregulate the Bcl-2 family member Mcl-1 and increase the activity of selective BH3 mimetics that fail to target this protein. In this study, we determined whether CDK inhibitors potentiate the activity of pan-BH3 mimetics directly neutralizing Mcl-1. Specifically, we evaluated interactions between the prototypical pan-CDK inhibitor flavopiridol and the pan-BH3 mimetic obatoclax in multiple myeloma (MM) cells in which Mcl-1 is critical for survival. Coadministration of flavopiridol and obatoclax synergistically triggered apoptosis in both drug-naïve and drug-resistant MM cells. Mechanistic investigations revealed that flavopiridol inhibited Mcl-1 transcription but increased transcription of Bim and its binding to Bcl-2/Bcl-xL. Obatoclax prevented Mcl-1 recovery and caused release of Bim from Bcl-2/Bcl-xL and Mcl-1, accompanied by activation of Bax/Bak. Whether administered singly or in combination with obatoclax, flavopiridol also induced upregulation of multiple BH3-only proteins, including BimEL, BimL, Noxa, and Bik/NBK. Notably, short hairpin RNA knockdown of Bim or Noxa abrogated lethality triggered by the flavopiridol/obatoclax combination in vitro and in vivo. Together, our findings show that CDK inhibition potentiates pan-BH3 mimetic activity through a cooperative mechanism involving upregulation of BH3-only proteins with coordinate downregulation of their antiapoptotic counterparts. These findings have immediate implications for the clinical trial design of BH3 mimetic-based therapies that are presently being studied intensively for the treatment of diverse hematopoietic malignancies, including lethal multiple myeloma.