The pan-caspase inhibitor Q-VD-OPh has anti-leukemia effects and can interact with vitamin D analogs to increase HPK1 signaling in AML cells.
The pan-caspase inhibitor Q-VD-OPh has anti-leukemia effects and can interact with vitamin D analogs to increase HPK1 signaling in AML cells.
复制标题
DOI：
10.1016/j.leukres.2012.03.023
复制
发表时间：
2012-07
影响因子：
2.7
通讯作者：
Studzinski GP
中科院分区：
文献类型：
--
作者：
Chen-Deutsch X;Kutner A;Harrison JS;Studzinski GP
半胱氨酸天冬氨酸氨基转移酶功能在细胞凋亡中起重要作用，但现在越来越多的人认识到，这些蛋白水解酶在其他细胞事件中也发挥着重要作用。在这里，我们首次报道了抑制细胞caspase活性可以诱导AML原始细胞分化，并可以增强维生素D诱导的这些细胞的分化。这是在9名AML患者和1名CML患者的体外培养中，在含有PAN caspase抑制剂Q-VD-Oph(QVD)的情况下进行的研究。单核细胞分化标志物CD11b和CD14的表达是细胞分化的标志。QVD可不同程度地促进1-α、25-二羟基维生素D(1，25D)及其类似物PRI1906和PRI2191诱导分化，其作用因白血病亚型而异。在QVD和1，25D诱导分化的同时，造血祖细胞激酶1(HPK1)信号增强，参与单核细胞分化的转录因子表达增加。尽管这些变化的大小和性质并不是一成不变的，但很明显，caspase抑制剂作为白血病分化治疗的组成部分值得注意，可能与维生素D的衍生物结合使用。
Caspase function is known to be essential for cell death by apoptosis, but it is now increasingly recognized that these proteases also play important roles in other cellular events. Here we report for the first time that inhibition of cellular caspase activity can induce differentiation of AML blasts, and can enhance vitamin D-induced cell differentiation of these cells. This was studied in blasts obtained from nine patients with AML and one patient with CML by ex vivo culture in the presence of Q-VD-OPh (QVD), a pan caspase inhibitor. Cell differentiation was manifested by the expression of markers of monocytic differentiation CD11b and CD14. Differentiation induced by 1α,25-dihydroxyvitamin D (1,25D) or its analogs PRI-1906 and PRI-2191 was enhanced by QVD to a varying degree, depending on the subtype of the leukemia. QVD and 1,25D-induced differentiation was accompanied by increased signaling by Hematopoietic Progenitor Kinase 1(HPK1), and the expression of transcription factors known to be involved in monocytic differentiation was increased. Although the magnitude and nature of these changes were not invariable, it is clear that caspase inhibitors warrant attention as components of differentiation therapy of leukemia, perhaps in combination with derivatives of vitamin D.
登录
查看更多内容
影响因子：
4.3
作者：
Ji, Yan;Kutner, Andrzej;Studzinski, George P.
通讯作者：
Studzinski, George P.
影响因子：
12.4
作者：
Arnold, R.;Frey, C. R.;Kiefer, F.
通讯作者：
Kiefer, F.
影响因子：
7.2
作者：
Caserta, TM;Smith, AN;Brown, TL
通讯作者：
Brown, TL
影响因子：
4.3
作者：
Chen-Deutsch, Xiangwen;Studzinski, George P.
通讯作者：
Studzinski, George P.
影响因子：
20.3
作者：
Brenner, Dirk;Golks, Alexander;Arnold, Ruediger
通讯作者：
Arnold, Ruediger