Azidothymidine hinders arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells by induction of p21 and attenuation of G2/M arrest
Azidothymidine hinders arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells by induction of p21 and attenuation of G2/M arrest
复制标题
DOI：
10.1007/s00277-013-1763-8
复制
发表时间：
2013-09-01
影响因子：
3.5
通讯作者：
Ghavamzadeh, Ardeshir
中科院分区：
文献类型：
--
作者：
Hassani, Saeed;Ghaffari, Seyed H.;Ghavamzadeh, Ardeshir
为了提高三氧化二砷（ATO）的抗癌效果，研究了ATO与叠氮胸苷（AZT）联合应用对急性早幼粒细胞白血病（APL）细胞株NB 4的端粒酶活性的影响。尽管这两种药物分别诱导细胞凋亡，并对hTERT下调和端粒酶抑制有协同作用，但当与AZT联合使用时，ATO诱导的细胞毒性降低。AZT减弱ATO对生存力、代谢活性、DNA合成和凋亡的影响。这些观察结果，尽管偏离本研究的主要目标，奉献了一个特殊的机会，阐明了一些已提出的ATO诱导细胞凋亡的机制的重要性。细胞周期分布、ROS水平和caspase-3激活分析表明，AZT可能通过相对诱导和减少（G1，S）和（G2/M）期细胞的积累，以及通过减少ROS的产生和随后的caspase-3抑制来降低ATO诱导的细胞毒性效应。QRT-PCR分析显示，与ATO单独相比，AZT/ATO联合诱导p21表达可能是G2/M期细胞积聚相对减少以及G1和S期细胞增加的原因。因此，G2/M期阻滞和ROS产生可能是ATO诱导的细胞凋亡的主要介质，并且可以用作指导设计涉及ATO和具有G2/M期阻滞或ROS产生能力的药物的合理组合策略以加强ATO诱导的细胞凋亡。
To enhance anticancer efficacy of the arsenic trioxide (ATO), the combination of ATO and azidothymidine (AZT), with convergence anti-telomerase activity, were examined on acute promyelocytic leukemia (APL) cell line, NB4. In spite of an induction of apoptosis by both drugs separately and a synergistic effect of them on hTERT down-regulation and telomerase inhibition, the ATO-induced cytotoxicity was reduced when it was used in combination with AZT. AZT attenuated the ATO effects on viability, metabolic activity, DNA synthesis, and apoptosis. These observations, despite the deflection from the main goal of this study, dedicate an especial opportunity to elucidate the importance of some of the mechanisms that have been suggested by which ATO induces apoptosis. Cell cycle distribution, ROS level, and caspase-3 activation analyses suggest that AZT reduced the ATO-induced cytotoxic effect possibly via relative induction and diminution of cells accumulated in (G1, S) and (G2/M) phase, respectively, as well as through attenuation of ROS generation and subsequent caspase-3 inhibition. QRT-PCR assay revealed that induction of p21expression by the combined AZT/ATO compared to ATO alone could be a reason for the relative decline of cells accumulation in G2/M and the increase of cells in G1 and S phases. Therefore, the G2/M arrest and ROS generation are likely principle mediators for the ATO-induced apoptosis and can be used as a guide to design rational combinatorial strategies involving ATO and agents with G2/M arrest or ROS generation capacity to intensify ATO-induced apoptosis.