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

Area of Science:

• Biochemistry
• Oncology
• Molecular Biology

Background:

• Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 protein, a target for tyrosine kinase inhibitors (TKIs) like imatinib (IM).
• Therapeutic resistance to TKIs, a major challenge in CML treatment, is associated with BCR-ABL1-induced oxidative stress and genomic instability.

Purpose of the Study:

• To investigate the role of oxidative stress and antioxidant mechanisms in mediating imatinib (IM) resistance in chronic myeloid leukemia (CML).
• To compare reactive oxygen species (ROS) levels, DNA damage, antioxidant enzyme activity, glutathione (GSH) levels, and mitochondrial membrane potential (MMP) in IM-susceptible and IM-resistant CML cells.

Main Methods:

• Treatment of BCR-ABL1 positive CML cells (susceptible and resistant) and wild-type non-cancer cells with imatinib (IM), hydrogen peroxide (H2O2), or both.
• Assessment of reactive oxygen species (ROS) accumulation, DNA damage, glutathione (GSH) levels, glutathione peroxidase (GPx) and catalase activity, and mitochondrial membrane potential (MMP).

Main Results:

• BCR-ABL1 positive cells exhibited increased ROS accumulation, with distinct levels observed in IM-susceptible versus IM-resistant cells.
• IM treatment caused greater DNA damage in susceptible cells, along with significant GSH depletion and decreased GPx activity.
• IM-resistant cells displayed elevated catalase activity and a diminished MMP, indicating altered cellular responses to oxidative stress and treatment.

Conclusions:

• The BCR-ABL1 kinase critically influences ROS metabolism, and its alteration is central to the development of IM resistance in CML.
• Changes in GPx and catalase activity, alongside alterations in MMP, are significant biomarkers associated with imatinib resistance in CML.