Relative importance of apoptosis and cell cycle blockage in the synergistic effect of combined R115777 and imatinib treatment in BCR/ABL-positive cell lines
Relative importance of apoptosis and cell cycle blockage in the synergistic effect of combined R115777 and imatinib treatment in BCR/ABL-positive cell lines
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DOI：
10.1016/j.bcp.2005.02.021
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发表时间：
2005-06-01
影响因子：
5.8
通讯作者：
Ozawa, K
中科院分区：
文献类型：
--
作者：
Miyoshi, T;Nagai, T;Ozawa, K
伊马替尼和法呢基转移酶抑制剂的组合可能有效地减少BCR/ABL阳性白血病细胞的数量。在这项研究中，我们研究了伊马替尼和R115777（Zarriestra（TM））组合在BCR/ABL阳性细胞系中的生长抑制作用机制的差异。Steel和Peckham等效线图分析表明，该组合对所有伊马替尼耐药细胞系及其亲本细胞系的生长具有强烈的协同抑制作用。在所有细胞系中，通过组合处理增加了裂解的半胱天冬酶3的水平。然而，在KCL 22和KCL 22/SR细胞中，裂解的PARP水平和膜联蛋白V阳性细胞的数量的增加均远低于K562、KU 812、K562/SR和KU 812/SR细胞。联合处理促进了p27（KIP 1）的积累，并诱导G 0/G1期KCL 22和KCL 22/SR细胞的百分比显著增加。在其他细胞系中，G 0/G1细胞的百分比没有增加，而是减少。结果表明，诱导细胞凋亡和阻断细胞周期是联合治疗协同抑制作用的主要机制。但这些机制的相对重要性在细胞类型中不同。可能需要额外的治疗来覆盖G1检查点以根除白血病细胞，其中该组合诱导细胞周期停滞。(c)2005年爱思唯尔公司All rights reserved.
The combination of imatinib and a famesyltransferase inhibitor might be effective for reducing the number of BCR/ABL-positive leukemia cells. In this study, we examined the differences in the mechanisms of the growth inhibitory effect of the combination of imatinib and R115777 (Zarriestra (TM)) among BCR/ABL-positive cell lines. Steel and Peckham isobologram analysis indicated that this combination had a strong synergistic inhibitory effect on growth in all imatinib-resistant cell lines and their parental cell lines. Levels of cleaved caspase 3 were increased by the combination treatment in all cell lines. However, both the level of cleaved PARP and the number of annexin-V-positive cells were much less increased in KCL22 and KCL22/SR cells than in K562, KU812, K562/SR and KU812/SR cells. The combination treatment promoted p27(KIP1) accumulation and induced a significant increase in the percentage of G0/G1 KCL22 and KCL22/SR cells. In other cell lines, the percentage of G0/G1 cells was not increased but rather decreased. The results indicate that induction of apoptosis and blockage of the cell cycle were major mechanisms of the synergistic inhibitory effect of the combination treatment. but the relative importance of these mechanisms differed among cell types. Additional treatment for overriding the G1 checkpoint may be required to eradicate leukemia cells, in which the combination induces cell cycle arrest. (c) 2005 Elsevier Inc. All rights reserved.