TY - JOUR
T1 - Relationship between oxidative stress and imatinib resistance in model chronic myeloid leukemia cells
AU - Głowacki, Sylwester
AU - Synowiec, Ewelina
AU - Szwed, Marzena
AU - Toma, Monika
AU - Skorski, Tomasz
AU - Śliwiński, Tomasz
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/4
Y1 - 2021/4
N2 - 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. IMresistant 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.
AB - 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. IMresistant 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.
KW - Animals
KW - Antineoplastic Agents/toxicity
KW - Catalase/metabolism
KW - Cell Line, Tumor
KW - DNA Damage
KW - Drug Resistance, Neoplasm
KW - Fusion Proteins, bcr-abl/genetics
KW - Glutathione Peroxidase/metabolism
KW - Glutathione/metabolism
KW - Imatinib Mesylate/toxicity
KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
KW - Membrane Potential, Mitochondrial
KW - Mice
KW - Oxidative Stress
UR - http://www.scopus.com/inward/record.url?scp=85104402421&partnerID=8YFLogxK
U2 - 10.3390/biom11040610
DO - 10.3390/biom11040610
M3 - Article
C2 - 33924068
AN - SCOPUS:85104402421
SN - 2218-273X
VL - 11
JO - Biomolecules
JF - Biomolecules
IS - 4
M1 - 610
ER -