Targeting non-oncogene ROS pathway by alantolactone in B cell acute lymphoblastic leukemia cells.
Targeting non-oncogene ROS pathway by alantolactone in B cell acute lymphoblastic leukemia cells.
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DOI：
10.1016/j.lfs.2019.04.034
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发表时间：
2019-06
期刊：
影响因子：
6.1
通讯作者：
Xiaoguang Xu;Lei Huang;Zilu Zhang;Jia Tong;J. Mi;Yingli Wu;Chen-li Zhang;Hua Yan
中科院分区：
文献类型：
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作者：
Xiaoguang Xu;Lei Huang;Zilu Zhang;Jia Tong;J. Mi;Yingli Wu;Chen-li Zhang;Hua Yan
目的土木香内酯(ALT)是天然产物土木香的活性成分，具有多种药理作用，其中包括抗肿瘤作用。本工作旨在探讨ALT在B细胞急性淋巴细胞白血病(B-ALL)中的抗肿瘤作用。主要方法用不同浓度的ALT处理B-ALL细胞，然后采用台盼蓝法、Annexin V/PI染色法、PI染色法、western blot分析法测定ALT对B-ALL细胞活力、凋亡和细胞周期的影响。此外，利用综合生物信息学方法预测 ALT 抗肿瘤作用的潜在机制。然后使用活性氧（ROS）探针二氢乙锭（DHE）和2',7'-二氯二氢荧光素二乙酸酯（DCFH-DA）检测细胞ROS的积累。同时，通过8-oxoG、p-ATM1987、γ-H2AX和彗星实验鉴定DNA损伤。此外，还测量了谷胱甘肽还原酶（GR）、硫氧还蛋白还原酶（TrxR）和过氧化氢酶的活性，并在SEM和RS4;11细胞中过表达，以研究对这些酶的抑制作用。最后，使用 B-ALL NOD-SCID 小鼠模型测试其体内性能。 主要发现 ALT 通过诱导 ROS 过载，导致 DNA 损伤，在体内和体外对 B-ALL 表现出良好的抗肿瘤作用。此外，我们发现ALT引起的ROS过载是由于其对还原酶的直接抑制。意义我们发现ALT作为一种天然产物，在靶向ROS途径治疗B-ALL中显示出一种有前途的策略。
AimsAlantolactone (ALT) is active component of natural productInulaheleniumwith a lot of pharmacological effects, including anti-tumor effect. The present work aimed to explore the antitumor effect of ALT in B cell acute lymphoblastic leukemia (B-ALL).Main methodsB-ALL cells were treated with various concentrations of ALT, and then trypan blue assay, Annexin V/PI staining assay, PI staining assay, western blot analysis were employed to measure the effect of ALT on viability, apoptosis and cell cycle in B-ALL cells. In addition, a synthetic bioinformatics method was used to predict the underlying mechanism of antitumor effect of ALT. Then Reactive Oxygen Species (ROS) probe Dihydroethidium (DHE) and 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) were used to detect accumulation of cellular ROS. Meanwhile, DNA damage was identified by 8-oxoG, p-ATM1987, γ-H2AX and comet assay. In addition, activity of glutathione reductase (GR), thioredoxin reductase (TrxR) and catalase were measured and overexpressed in SEM and RS4;11 cells to study the inhibition on these enzymes. Finally, B-ALL NOD-SCID mouse model was used to test its performance in vivo.Key findingsALT showed good antitumor effect in B-ALL in vivo and in vitro through inducing ROS overload, which led to DNA damage. In addition, we found ROS overload caused by ALT was due to its direct inhibition on reductase.SignificanceWe found that ALT, a natural product, showing a promising tactic in the therapy of B-ALL by targeting ROS pathway.