Trivalent methylated arsenic metabolites induce apoptosis in human myeloid leukemic HL-60 cells through generation of reactive oxygen species.
Trivalent methylated arsenic metabolites induce apoptosis in human myeloid leukemic HL-60 cells through generation of reactive oxygen species.
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DOI：
10.1039/c4mt00119b
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发表时间：
2014-07
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通讯作者：
K. Rehman;Yushi Fu;Yan Fang Zhang;Qian Qian Wang-Qian;Bin Wu;Yuan Wu;X. Zhou;Wu-hui Sun;Tianyu Sun;Hua Naranmandura
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文献类型：
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作者：
K. Rehman;Yushi Fu;Yan Fang Zhang;Qian Qian Wang-Qian;Bin Wu;Yuan Wu;X. Zhou;Wu-hui Sun;Tianyu Sun;Hua Naranmandura
三氧化二砷（As2O3）对白血病有显着的治疗作用。然而，As2O3生物转化后，砷代谢产物在抗白血病临床疗效中的作用仍需阐明。因此，为了探讨三价甲基化砷在治疗效果中的贡献，我们研究并比较了亚砷酸盐（iAs（III））、一甲基胂酸（MMA（III））和二甲基胂酸（DMA（III））对HL-60细胞的影响。甲基化砷物质 MMA(III) 和 DMA(III) 可能会降低细胞存活率，IC50 值分别为 3 和 2 μM。我们发现甲基化代谢物通过氧化应激和线粒体膜电位丧失引起细胞凋亡。此外，我们发现 caspase-9 和 -3 通过暴露于甲基化代谢物而显着激活，并裂解聚 ADP 核糖聚合酶 (PARP)。相反，用抗氧化剂 N-乙酰半胱氨酸 (NAC) 预处理可显着减弱细胞凋亡、ROS 的产生、caspase-3、-9 的激活以及 PARP 裂解。在暴露于 MMA(III) 或 DMA(III) 的 HL-60 细胞中也明显观察到 DNA 损伤，而 iAs(III) 在 HL-60 细胞中没有显示出任何相关影响。同样，组蛋白 H2A 变体 (γ-H2AX) 的磷酸化（DNA 损伤的生物标志物）在暴露于两种甲基化物质后在细胞核中显着发生，在 NAC 存在下磷酸化降低，表明 DNA 损伤的诱导主要是由两种代谢物通过氧化应激引起的。总之，我们建议砷中间代谢物； MMA(III) 和 DMA(III) 可能在未来被证明具有临床意义，因为这些方法可能有助于治疗白血病和其他类型的癌症。
Arsenic trioxide (As2O3) has remarkable therapeutic efficacy against leukemia. However, after As2O3 biotransformation, the role of arsenic metabolites in the clinical efficacy against leukemia still needs to be elucidated. Therefore, to explore the contribution of trivalent methylated arsenicals in the therapeutic effects, we investigated and compared the effects of arsenite (iAs(III)), monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) on HL-60 cells. Methylated arsenic species MMA(III) and DMA(III) showed potentially reduced cell survival with IC50 values of 3 and 2 μM, respectively. We found that methylated metabolites caused apoptosis through oxidative stress and loss of mitochondrial membrane potential. Furthermore, we found that the caspase-9 and -3 were markedly activated by exposure to methylated metabolites, with cleavage of poly-ADP ribose polymerase (PARP). Conversely, cellular apoptosis, generation of ROS, activation of caspase-3, -9 as well as PARP cleavage were significantly attenuated by pretreatment with an antioxidant, N-acetylcysteine (NAC). DNA damage was also markedly observed in HL-60 cells exposed to either MMA(III) or DMA(III), while iAs(III) did not show any relevant effects in HL-60 cells. Likewise, phosphorylation of the histone H2A variant (γ-H2AX), a biomarker of DNA damage, significantly occurred in cellular nuclei following exposure to two methylated species, which was reduced in the presence of NAC, suggesting that the induction of DNA damage was predominantly caused by the two metabolites via oxidative stress. In conclusion, we suggest that arsenic intermediate metabolites; MMA(III) and DMA(III) might prove to be of clinical relevance in future as such approaches may help in the treatment of leukemia and other types of cancers.