Synergistic mitosis-arresting effects of arsenic trioxide and paclitaxel on human malignant lymphocytes
Synergistic mitosis-arresting effects of arsenic trioxide and paclitaxel on human malignant lymphocytes
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三氧化二砷和紫杉醇对人恶性淋巴细胞的协同有丝分裂抑制作用。
DOI：
10.1016/j.cbi.2009.09.012
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发表时间：
2010-01-05
影响因子：
5.1
通讯作者：
Chen, Guo-Qiang
中科院分区：
文献类型：
--
作者：
Duan, Xu-Fang;Wu, Ying-Li;Chen, Guo-Qiang
急性淋巴细胞白血病（ALL）的治疗结果在过去50年中稳步改善。然而，目前的治疗方法不太可能进一步提高治愈率。由于增加化疗药物的剂量也可能增加毒性，因此如何以最小剂量实现最大治疗效果的解决方案迫在眉睫。一种可能性是采用联合药物疗法。三氧化二砷（ATO）是一种广泛应用于治疗急性早幼粒细胞白血病（APL）的药物。考虑到ATO在诱导细胞凋亡之前诱导有丝分裂阻滞的事实，我们试图以恶性淋巴细胞为体外模型，研究ATO与微管稳定剂紫杉醇（PTX）联合使用的潜在抗癌作用。用ATO和/或PTX处理三种恶性淋巴细胞细胞系和原代细胞。用Chou-Talalay分析评价ATO和PTX的联合作用，我们发现两种药物在抑制细胞生长方面具有协同作用。我们还发现，ATO和PTX在低浓度下的组合协同诱导恶性淋巴细胞的有丝分裂阻滞，随后凋亡，这增加了Thr（161）上的磷酸化细胞周期蛋白依赖性激酶1（Cdk 1），并促进Cdkt的失调激活。ATO/PTX组合还通过诱导抑制性检查点复合物BubR 1/Cdc 20的形成而显著增强纺锤体检查点的激活。我们的研究提供了第一个在体外证明，低浓度的ATO和PTX协同诱导恶性淋巴细胞有丝分裂阻滞。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
The treatment outcome of acute lymphoblastic leukemia (ALL) has improved steadily over the last 50 years. However, the cure rates are unlikely to be raised further with current therapies. Since increasing the dosage of chemotherapeutic agents could also elevate toxicity, a solution to how one could achieve maximum therapeutic effect with the minimum dosage possible is imminent. One possibility is the employment of combination drug therapies. Arsenic trioxide (ATO) is a widely used drug for acute promyelocytic leukemia (APL). Its combination with other drugs presented therapeutic activities in malignant cancers other than APL Considering the fact that ATO induces mitotic arrest prior to apoptosis induction, we attempted to investigate the potential anti-cancer effects of ATO in combination with the microtubule-stabilizing agent, paclitaxel (PTX), using malignant lymphocytes as in vitro models. Three malignant lymphocytic cell lines and primary cells were treated with ATO and/or PTX. Using the Chou-Talalay analysis for evaluation of combined effect of ATO and PTX, we found a synergistic effect of the two drugs in the inhibition of cell growth. We also found that the combination of ATO and PTX at low concentrations synergistically induced mitotic arrest followed by apoptosis in malignant lymphocytes, which increased phosphorylated cyclin-dependent kinase 1 (Cdk1) on Thr(161) and promoted the dysregulated activation of Cdkt. The ATO/PTX combination also significantly enhanced the activation of spindle checkpoint by inducing the formation of the inhibitory checkpoint complex BubR1/Cdc20. Our study provided the first in vitro demonstration that low concentrations of ATO and PTX synergistically induce mitotic arrest in malignant lymphocytes. (C) 2009 Elsevier Ireland Ltd. All rights reserved.