Differential mechanistic investigation of protective effects from imperatorin and sec-O-glucosylhamaudol against arsenic trioxide-induced cytotoxicity in vitro
Differential mechanistic investigation of protective effects from imperatorin and sec-O-glucosylhamaudol against arsenic trioxide-induced cytotoxicity in vitro
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DOI：
10.1016/j.tiv.2016.09.002
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发表时间：
2016-12-01
影响因子：
3.2
通讯作者：
Tan, Yuqing
中科院分区：
文献类型：
--
作者：
Hu, Liufang;Sun, Jianhui;Tan, Yuqing
背景与目的：三氧化二砷（As2O3）治疗急性早幼粒细胞白血病（APL）的临床应用由于其严重的心脏毒性而受到限制。as2o3诱导心脏毒性的可能机制包括DNA断裂、活性氧（ROS）的产生、心脏离子通道的改变和细胞凋亡。本研究旨在探讨欧前胡素和硫- o -葡萄糖-哈马多酚的保护作用，并探讨其在as2o3诱导的细胞毒性中的机制参与。实验方法：分别用As2O3和欧前胡素或seco - o -葡萄糖基哈马多酚对H9c2细胞进行细胞活力测定、乳酸脱氢酶（LDH）释放、吖啶橙/溴化乙啶（AO/EB）双染、Caspase-3活性测定、ROS生成、细胞钙水平、qRT-PCR mRNA表达水平和Western blotting蛋白表达水平的检测。主要结果：我们观察到欧前胡素或硫- o -葡萄糖-哈马多尔处理的H9c2细胞更能抵抗as2o3诱导的细胞死亡。欧前胡素和欧前胡素均能降低H9c2细胞凋亡，但对Caspase-3活性和细胞内钙积累均无影响。此外，欧前胡素能够抑制ROS的产生，而秒- o -葡萄糖-哈马多尔则没有这种作用。此外，欧前胡素和seco -glucosylhamaudol触发Nrf2激活，导致下游II期代谢酶和抗氧化蛋白/酶上调，可能通过Nrf2信号通路对as2o3诱导的心脏毒性提供细胞保护。结论与意义：欧前胡素和硫- o -葡萄糖-哈马多酚可改善as2o3诱导的H9c2细胞毒性和凋亡，其机制可能与抗氧化作用有关。As2O3与欧前胡素或秒- o -葡萄糖-哈马多酚联用可作为扩大As2O3临床应用的新策略。(C) 2016 Elsevier Ltd.版权所有。
Background and purpose: The clinical use of arsenic trioxide (As2O3) for treating acute promyelocytic leukemia (APL) is limited due to its severe cardiotoxicity. The possible mechanisms of As2O3-induced cardiotoxicity include DNA fragmentation, reactive oxygen species (ROS) generation, cardiac ion channel changes and apoptosis. The present study is designed to investigate the protective effects of imperatorin and sec-O-glucosylhamaudol and to explore their mechanistic involvement in As2O3-induced cytotoxicity.Experimental methods: Cell viability assay, Lactate dehydrogenase (LDH) release, Acridine orange/ethidium bromide (AO/EB) double staining, Caspase-3 activity assay, ROS generation, cellular calcium levels, mRNA expression levels by qRT-PCR and protein expression levels by Western blotting were measured in H9c2 cells in combination with As2O3 and imperatorin or sec-O-glucosylhamaudol.Key results: We observed that H9c2 cells treated with imperatorin or sec-O-glucosylhamaudol were more resistant to As2O3-induced cell death. Both imperatorin and sec-O-glucosylhamaudol reduced H9c2 cell apoptosis, but both imperatorin and sec-O-glucosylhamaudol had no effects on Caspase-3 activity and intracellular calcium accumulation. Furthermore, imperatorin was capable of suppressing ROS generation, while sec-O-glucosylhamaudol did not show this effect. Moreover, imperatorin and sec-O-glucosylhamaudol triggered Nrf2 activation, which resulted in upregulation of downstream phase II metabolic enzymes and antioxidant protein/enzyme, probably offering cellular protection to As2O3-induced cardiotoxicity via the Nrf2 signal pathway.Conclusions and implications: Imperatorin and sec-O-glucosylhamaudol can ameliorate As2O3-induced cytotoxicity and apoptosis in H9c2 cells, the mechanisms probably related to antioxidation. As2O3 in combination with imperatorin or sec-O-glucosylhamaudol could be considered as a novel strategy to expand the clinical application of As2O3. (C) 2016 Elsevier Ltd. All rights reserved.