Relationship between Oxidative Stress and Imatinib Resistance in Model Chronic Myeloid Leukemia Cells

Abstract

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 (H2O2) as a model trigger of external oxidative stress, or with IM+H2O2. 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.

Antileukemic Activity of hsa-miR-203a-5p by Limiting Glutathione Metabolism in Imatinib-Resistant K562 Cells

“…The analysis revealed that GSH metabolism is the most enriched cellular metabolism in imatinib-sensitive (C) versus -resistant (R) K562 cells, and the same cellular metabolism may be responsible for resistance emergence in imatinib-resistant K562 cells ( Figure 2 ). The conclusion that GSH metabolism was possibly responsible for the emergence of resistance was supported by earlier research, which revealed that drug-sensitive CML cells had lower glutathione levels than resistant cells [ 44 , 45 ].…”

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

“…The BCR-ABL1 oncoprotein is responsible for the genomic instability observed in CML since its activity generates reactive oxygen species (ROS), disrupts the DDR pathways activating error-prone DNA repair, induces replication stress and centrosomal dysfunction, and inhibits apoptosis resulting from different DNA damage-induced lesions [ 50 , 55 , 56 ]. Although the activation of DNA damage repair pathways is increased to counteract DNA damage, unfaithful and error-prone pathways such as alternative non-homologous end joining (NHEJ), single-strand annealing (SSA), and unfaithful homologous recombination repair (HRR) are enhanced in Ph-positive cells [ 57 , 58 , 59 , 60 , 61 , 62 ].…”

Calcium influx, oxidative stress, and apoptosis induced by TRPV1 in chronic myeloid leukemia cells: Synergistic effects with imatinib

“…It is clear that leukemia progenitor cells are characterized by higher levels of ROS than normal hematopoietic cells. BCR-ABL1 oncoprotein is involved in the production of ROS that are then responsible for promoting genomic instability, a sort of “auto-mutagenesis” process that leads to malignancy ( Pascu VÎnturiŞ and GĂman, 2020 ; Głowacki et al, 2021 ). In addition, it has surprisingly been found that TKI treatment during time favors the control of the redox cell state by activating the repair enzyme human MutT homolog 1 which removes the oxidatively damaged cellular nucleotide pool and repairs the DNA breaks, leading to a strong reduction in therapy efficacy itself and chemoresistance ( Lee et al, 2022 ).…”