Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143 Street, 90-236 Lodz, Poland.
Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143 Street, 90-236 Lodz, Poland.
Biomolecules. 2021 Apr 20;11(4):610. doi: 10.3390/biom11040610.
Chronic myeloid leukemia (CML) develops due to the presence of the BCR-ABL1 protein, a target of tyrosine kinase inhibitors (TKIs), such as imatinib (IM), used in a CML therapy. CML eradication is a challenge due to developing resistance to TKIs. BCR-ABL1 induces endogenous oxidative stress leading to genomic instability and development of TKI resistance. Model CML cells susceptible or resistant to IM, as well as wild-type, non-cancer cells without the BCR-ABL1 protein were treated with IM, hydrogen peroxide (HO) as a model trigger of external oxidative stress, or with IM+HO. Accumulation of reactive oxygen species (ROS), DNA damage, activity of selected antioxidant enzymes and glutathione (GSH), and mitochondrial potential (MMP) were assessed. We observed increase in ROS accumulation in BCR-ABL1 positive cells and distinct levels of ROS accumulation in IM-susceptible cells when compared to IM-resistant ones, as well as increased DNA damage caused by IM action in sensitive cells. Depletion of GSH levels and a decreased activity of glutathione peroxidase (GPx) in the presence of IM was higher in the cells susceptible to IM. IM-resistant cells showed an increase of catalase activity and a depletion of MMP. BCR-ABL1 kinase alters ROS metabolism, and IM resistance is accompanied by the changes in activity of GPx, catalase, and alterations in MMP.
慢性髓性白血病 (CML) 的发生是由于存在 BCR-ABL1 蛋白，这是酪氨酸激酶抑制剂 (TKI) 的靶点，如伊马替尼 (IM)，用于 CML 治疗。由于对 TKI 的耐药性的发展，CML 的根除是一个挑战。BCR-ABL1 诱导内源性氧化应激，导致基因组不稳定和 TKI 耐药性的发展。对 IM 敏感或耐药的 CML 模型细胞，以及野生型、不含 BCR-ABL1 蛋白的非癌细胞，用 IM、过氧化氢 (HO)（作为外部氧化应激模型触发物）或 IM+HO 处理。评估活性氧 (ROS) 积累、DNA 损伤、选定抗氧化酶和谷胱甘肽 (GSH) 的活性以及线粒体电位 (MMP)。我们观察到 BCR-ABL1 阳性细胞中 ROS 积累增加，与 IM 耐药细胞相比，IM 敏感细胞中 ROS 积累水平明显增加，以及 IM 作用引起的敏感细胞中 DNA 损伤增加。在存在 IM 的情况下，GSH 水平的耗竭和谷胱甘肽过氧化物酶 (GPx) 活性的降低在对 IM 敏感的细胞中更高。IM 耐药细胞显示过氧化氢酶活性增加和 MMP 耗竭。BCR-ABL1 激酶改变 ROS 代谢，IM 耐药性伴随着 GPx、过氧化氢酶活性的变化和 MMP 的改变。
