Bose Prithviraj, Grant Steven
Massey Cancer Center, Virginia Commonwealth University, Richmond, VA ; Departments of Internal Medicine, Virginia Commonwealth University, Richmond, VA.
Leuk Res Rep. 2013 Jan 1;2(1):12-14. doi: 10.1016/j.lrr.2012.11.006.
The B-cell lymphoma-2 (Bcl-2) family of proteins regulates the intrinsic, or mitochondrial pathway of apoptosis, the final common mechanism of cell death in response to a variety of physiologic and pharmacologic signals, and plays a central role in AML pathogenesis, prognosis and responsiveness to chemotherapy. Traditionally thought to be an important survival factor for multiple myeloma cells, the anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) has recently been shown in preclinical studies to be critical to the development and maintenance of AML, making it an attractive therapeutic target in this disease. Several characteristics, such as its very short half-life, distinguish Mcl-1 from other anti-apoptotic Bcl-2 family members. Additionally, Mcl-1 levels are regulated by a large number of pathways affecting its transcription, translation and degradation. A variety of approaches exploiting these features has been developed to inhibit directly or indirectly the anti-apoptotic function of Mcl-1. Many of these lend themselves well to combination therapies, leading to striking synergism, at least in preclinical models. In this brief review, we highlight some of the more promising strategies targeting Mcl-1 in AML, with a particular emphasis on rational combinations of novel agents.
B细胞淋巴瘤-2（Bcl-2）家族蛋白调节细胞凋亡的内在途径，即线粒体途径，这是细胞对多种生理和药理信号作出反应时最终的共同细胞死亡机制，并且在急性髓系白血病（AML）的发病机制、预后及化疗反应中发挥核心作用。抗凋亡Bcl-2家族蛋白髓系细胞白血病-1（Mcl-1）传统上被认为是多发性骨髓瘤细胞的重要生存因子，最近临床前研究表明它对AML的发生和维持至关重要，使其成为这种疾病有吸引力的治疗靶点。Mcl-1具有一些特征，如半衰期非常短，这使其有别于其他抗凋亡Bcl-2家族成员。此外，Mcl-1水平受大量影响其转录、翻译和降解的途径调控。已经开发出多种利用这些特性的方法来直接或间接抑制Mcl-1的抗凋亡功能。其中许多方法很适合联合治疗，至少在临床前模型中能产生显著的协同作用。在这篇简短的综述中，我们重点介绍一些在AML中靶向Mcl-1的更有前景的策略，特别强调新型药物的合理联合。
