Vincristine potentiates the anti-proliferative effect of an aurora kinase inhibitor, VE-465, in myeloid leukemia cells.
Vincristine potentiates the anti-proliferative effect of an aurora kinase inhibitor, VE-465, in myeloid leukemia cells.
复制标题
DOI：
10.1016/j.bcp.2011.09.015
复制
发表时间：
2011-12
影响因子：
5.8
通讯作者：
Kozue Yoshida;T. Nagai;K. Ohmine;Mitsuyo Uesawa;Piyanuch Sripayap;Y. Ishida;K. Ozawa
中科院分区：
文献类型：
--
作者：
Kozue Yoshida;T. Nagai;K. Ohmine;Mitsuyo Uesawa;Piyanuch Sripayap;Y. Ishida;K. Ozawa
极光激酶在有丝分裂的调节中起重要作用。激酶在多种癌细胞中过表达，并参与肿瘤发生。虽然极光激酶抑制剂是治疗白血病的潜在药物，但建立有效的联合治疗是充分利用这些药物的有吸引力的方法。在这项研究中，我们研究了特异性极光激酶抑制剂VE-465与各种常规抗白血病药物（包括阿霉素、柔红霉素、伊达比星、米托蒽醌、阿糖胞苷、长春新碱和依托泊苷）联合对急性髓性白血病细胞系的作用（HL 60、U937、THP-1和KY 821）、慢性髓性白血病细胞系（KCL 22、K562和KU 812）和原代白血病细胞。我们发现VE-465和长春新碱的组合对白血病细胞的生长具有协同/相加抑制作用。VE-465最初增加G2/M期细胞，随后诱导亚G1期细胞。阿贝斯汀增强了VE-465的这种作用。VE-465和长春新碱的组合增加了裂解的半胱天冬酶3、裂解的半胱天冬酶7、裂解的半胱天冬酶9、裂解的PARP和磷酸化-Chk 2的水平，表明该组合引起Chk 2介导的G2/M检查点激活，导致细胞凋亡的顺序诱导。有趣的是，该组合显著降低了磷酸化ERK 1/2的水平，表明该组合改变了细胞信号传导途径的网络。相比之下，VE-465和其他药剂的组合没有显示出协同抑制作用，而是具有拮抗作用。总之，我们的研究结果表明VE-465和长春新碱的组合作为髓性白血病的潜在治疗的效用。
Aurora kinases play an essential role in the regulation of mitosis. The kinases are overexpressed in a variety of cancer cells and are involved in tumorgenesis. Although aurora kinase inhibitors are potential agents for treatment of leukemia, the establishment of efficacious combination therapies is an attractive approach for making good use of these agents. In this study, we examined the effects of a specific aurora kinase inhibitor, VE-465, in combination with various conventional anti-leukemia agents, including doxorubicin, daunorubicin, idarubicin, mitoxantron, cytosine arabinoside, vincristine and etoposide, on acute myeloid leukemia cell lines (HL60, U937, THP-1 and KY821), chronic myeloid leukemia cell lines (KCL22, K562 and KU812) and primary leukemia cells. We found that a combination of VE-465 and vincristine had a synergistic/additive inhibitory effect on the growth of leukemia cells. VE-465 initially increased G2/M-phase cells, followed by induction of sub-G1 cells. Vincristine enhanced this effect of VE-465. The combination of VE-465 and vincristine increased the levels of cleaved caspase 3, cleaved caspase 7, cleaved caspase 9, cleaved PARP and Phospho-Chk2, suggesting that the combination caused Chk2-mediated activation of the G2/M checkpoint, resulting in sequential induction of apoptosis. Interestingly, the combination markedly decreased the level of Phospho-ERK1/2, suggesting that the combination alters a network of cellular signaling pathways. In contrast, combinations of VE-465 and other agents showed no synergistic inhibitory effect but rather had an antagonistic effect. In conclusion, our results indicate the utility of the combination of VE-465 and vincristine as a potential therapy for myeloid leukemia.