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首页> 外文期刊>BioResearch open access. >Reactive Oxygen Species and Mitochondrial DNA Damage and Repair in BCR-ABL1 Cells Resistant to Imatinib
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Reactive Oxygen Species and Mitochondrial DNA Damage and Repair in BCR-ABL1 Cells Resistant to Imatinib

机译：伊马替尼耐药的BCR-ABL1细胞中的活性氧和线粒体DNA损伤和修复

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Imatinib revolutionized the therapy of chronic myeloid leukemia (CML), but the resistance to it became an emerging problem. We reported previously that CML cells expressing the BCR/ABL1 fusion gene, accumulated a high level of reactive oxygen species (ROS) due to deregulated mitochondrial electron transport chain, which in turn led to genomic instability, resulting in imatinib resistance. In the present work, we hypothesize that imatinib-resistant cells may show higher instability of mitochondrial DNA (mtDNA) than their sensitive counterparts. To verify this hypothesis, we checked the ROS level and mtDNA damage and repair in model CML cells sensitive and resistant to imatinib and exposed to doxorubicin (DOX), a DNA-damaging agent. The extent of endogenous ROS in imatinib-resistant cells was higher than in their sensitive counterparts and DOX potentiated this relationship. ROS level in cells with primary resistance, which resulted from the T315I mutation in BCR/ABL1 , was higher than in cells with acquired resistance. DOX-induced mtDNA damage in T315I imatinib-resistant cells was more pronounced than in imatinib-sensitive cells. All kinds of cells were repairing mtDNA damage with similar kinetics. In conclusion, imatinib-resistant cells can show increased instability of mtDNA, which can result from increased ROS production.
机译：伊马替尼彻底改变了慢性粒细胞白血病（CML）的治疗方法，但对它的耐药性成为一个新出现的问题。我们以前曾报道过，表达BCR / ABL1融合基因的CML细胞由于线粒体电子传输链失控而积聚了高水平的活性氧（ROS），进而导致基因组不稳定，从而导致伊马替尼耐药。在目前的工作中，我们假设对伊马替尼耐药的细胞可能比敏感的细胞显示更高的线粒体DNA（mtDNA）不稳定性。为了验证这一假设，我们检查了对伊马替尼敏感并具有抗性并暴露于DNA损伤剂阿霉素（DOX）的模型CML细胞中的ROS水平以及mtDNA的损伤和修复。伊马替尼耐药细胞中内源性ROS的程度高于其敏感对应物，DOX增强了这种关系。由BCR / ABL1中的T315I突变引起的具有主要耐药性的细胞中的ROS水平高于具有获得性耐药性的细胞中的ROS水平。 T315I伊马替尼耐药细胞中DOX诱导的mtDNA损伤比伊马替尼敏感细胞中更明显。各种细胞都以相似的动力学修复mtDNA损伤。总之，伊马替尼耐药细胞可能显示出mtDNA的不稳定性增加，这可能是由于ROS产生增加所致。

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