First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan.
Ann Hematol. 2010 Nov;89(11):1081-7. doi: 10.1007/s00277-010-0998-x. Epub 2010 Jun 20.
Aurora kinases play a pivotal role in the regulator of mitotic processes during cell division and Aurora kinases are overexpressed in a number of human cancers. In this study, we examined the intracellular signaling of Aurora kinases inhibitor, MK-0457 (VX-680), in BCR-ABL positive cell lines and in primary samples. MK-0457 induced apoptosis. Caspase 3 and poly (ADP-ribose) polymerase (PARP) were activated and heat shock proteins were reduced. A combination of MK-0457 and histone deacetylase inhibitor, vorinostat, increased apoptosis. Caspase 3 and PARP were activated and phosphorylation of BCR-ABL, Lyn, and Crk-L were reduced. BCR-ABL and Aurora A and B were reduced after vorinostat treatment. Moreover, combination of vorinostat and MK-0457 synergistically increased the extent of apoptosis in primary acute lymphoblastic leukemia cells with T315I mutation. Our study increases insight into how MK-0457 may mediate its effects on BCR-ABL positive leukemia cells with T315I mutation, and information of potential therapeutic relevance.
极光激酶在细胞分裂过程中对有丝分裂过程的调节中起着关键作用，并且在许多人类癌症中过度表达。在这项研究中，我们研究了 Aurora 激酶抑制剂 MK-0457（VX-680）在 BCR-ABL 阳性细胞系和原代样本中的细胞内信号转导。MK-0457 诱导细胞凋亡。Caspase 3 和多聚（ADP-核糖）聚合酶（PARP）被激活，热休克蛋白减少。MK-0457 与组蛋白去乙酰化酶抑制剂伏立诺他联合使用可增加细胞凋亡。Caspase 3 和 PARP 被激活，BCR-ABL、Lyn 和 Crk-L 的磷酸化减少。伏立诺他处理后 BCR-ABL 和 Aurora A 和 B 减少。此外，伏立诺他和 MK-0457 的联合使用可协同增加 T315I 突变的原发性急性淋巴细胞白血病细胞的凋亡程度。我们的研究增加了对 MK-0457 如何介导其对 T315I 突变的 BCR-ABL 阳性白血病细胞的作用的深入了解，并提供了潜在治疗相关性的信息。
Zotero 插件