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

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 610
Author(s):  
Sylwester Głowacki ◽  
Ewelina Synowiec ◽  
Marzena Szwed ◽  
Monika Toma ◽  
Tomasz Skorski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Protein A ◽  
Mitochondrial Potential ◽  
Imatinib Resistance ◽  
Ros Accumulation ◽  
Ros Metabolism

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.

scholarly journals Serum concentrations of nitrite and malondialdehyde as markers of oxidative stress in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

2012 ◽  
Vol 34 (5) ◽  
pp. 352-355 ◽  
Author(s):  
Maria Juracy Petrola ◽  
Alana Joselina Montenegro de Castro ◽  
Maria Helena da Silva Pitombeira ◽  
Maritza Cavalcante Barbosa ◽  
Acy Telles de Souza Quixadá ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Serum Concentrations ◽  
Markers Of Oxidative Stress

High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3409-3420 ◽  
Author(s):  
Wolfgang Warsch ◽  
Karoline Kollmann ◽  
Eva Eckelhart ◽  
Sabine Fajmann ◽  
Sabine Cerny-Reiterer ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Clonal Selection ◽  
Imatinib Treatment ◽  
Imatinib Resistance ◽  
Protein Levels

Abstract In BCR-ABL1+ leukemia, drug resistance is often associated with up-regulation of BCR-ABL1 or multidrug transporters as well as BCR-ABL1 mutations. Here we show that the expression level of the transcription factor STAT5 is another parameter that determines the sensitivity of BCR-ABL1+ cells against tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, or dasatinib. Abelson-transformed cells, expressing high levels of STAT5, were found to be significantly less sensitive to TKI-induced apoptosis in vitro and in vivo but not to other cytotoxic drugs, such as hydroxyurea, interferon-β, or Aca-dC. The STAT5-mediated protection requires tyrosine phosphorylation of STAT5 independent of JAK2 and transcriptional activity. In support of this concept, under imatinib treatment and with disease progression, STAT5 mRNA and protein levels increased in patients with Ph+ chronic myeloid leukemia. Based on our data, we propose a model in which disease progression in BCR-ABL1+ leukemia leads to up-regulated STAT5 expression. This may be in part the result of clonal selection of cells with high STAT5 levels. STAT5 then accounts for the resistance against TKIs, thereby explaining the dose escalation frequently required in patients reaching accelerated phase. It also suggests that STAT5 may serve as an attractive target to overcome imatinib resistance in BCR-ABL1+ leukemia.

scholarly journals LncRNA OIP5-AS1 Promotes the Autophagy-Related Imatinib Resistance in Chronic Myeloid Leukemia Cells by Regulating miR-30e-5p/ATG12 Axis

2021 ◽  
Vol 20 ◽  
pp. 153303382110521
Author(s):  
Hongdan Dai ◽  
Jianming Wang ◽  
Zhenglan Huang ◽  
Hui Zhang ◽  
Xin Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Myeloid Leukemia ◽  
Western Blot ◽  
Cell Line ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Resistance Mechanism ◽  
Luciferase Reporter ◽  
Parental Cell Line ◽  
Imatinib Resistance

Background: Resistance to tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML) remains a problem in clinical treatment, and the mechanism has not been fully clarified. Autophagy can protect cancer cells under chemotherapeutic stimulation. Long noncoding RNAs (lncRNAs) are critical in drug resistance of CML. The role of lncRNAs in autophagy and drug resistance of CML needs to be further explored. Methods: Western blot and immunofluorescence were used to evaluate the autophagy activity in the drug-resistant CML cell line K562/G01 and its parental cell line K562. Then the sensitivity of K562/G01 cells to the first generation TKI imatinib (IM) after autophagy inhibition was determined by CCK-8 assays. The lncRNA OIP5-AS1 related to the drug resistance of CML cells was determined by Gene Expression Omnibus database analysis. Western blot and drug-sensitivity assays were used to detect changes in autophagy and sensitivity to the IM in resistant CML cells after OIP5-AS1 knockdown. The interactions of OIP5-AS1, miR-30e-5p, and ATG12 were explored by RNA immunoprecipitation and dual-luciferase reporter assays. Results: In this study, we found that autophagy was associated with drug resistance in CML cells. Moreover, the upregulation of OIP5-AS1 in K562/G01 cells was related to the enhancement of autophagy. Knockdown of OIP5-AS1 suppressed autophagy and enhanced the sensitivity of K562/G01 cells to IM. Furthermore, OIP5-AS1 regulated ATG12 by competitively binding miR-30e-5p, thereby affecting autophagy-related drug resistance. Conclusion: Our study reveals that OIP5-AS1 promotes the autophagy-related IM resistance in CML cells by regulating miR-30e-5p/ATG12 axis, providing new insights into the drug resistance mechanism of CML.

scholarly journals The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Gabriela Nestal de Moraes ◽  
Paloma Silva Souza ◽  
Fernanda Casal de Faria Costas ◽  
Flavia Cunha Vasconcelos ◽  
Flaviana Ruade Souza Reis ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Resistance Mechanisms ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase ◽  
Alternative Drug

Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML.

Oxidative Stress and BCR-ABL1 Transcript Levels in Chronic Myeloid Leukemia: an Intricate Relationship

2019 ◽  
Vol 70 (9) ◽  
pp. 3193-3196 ◽  
Author(s):  
Emilia Georgiana Pascu ◽  
Mihnea Alexandru Gaman ◽  
Cornel Moisa ◽  
Amelia Maria Gaman
Keyword(s):  
Oxidative Stress ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Compensatory Mechanism ◽  
Stress Levels ◽  
Tki Treatment

Chronic myeloid leukemia (CML) is a chronic myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome. Oxidative stress is involved in CML etiopathogenesis and disease progression, as well as the response to tyrosine kinase inhibitors (TKI) treatment. We evaluated oxidative stress levels in 47 CML patients vs. controls. The total antioxidant capacity (TAC) was measured using a FLUOstar Omega microplate reader (reagents from Sigma-Aldrich). Cellular reactive oxygen species (ROS) were evaluated using a CyFlow SPACE Sysmex flow-cytometer (reagents from Abcam). Oxidative stress levels were higher in CML patients vs. controls. The maximum TAC value and the minimum ROS value were recorded in CML patients with a BCR-ABL1 transcript value of 0.1-1%, suggesting that the production of plasma antioxidants progressively increases as a compensatory mechanism in CML patients undergoing TKI treatment in order to annihilate ROS. The pseudonormalization of the cell redox status observed in these patients could be an alarm signal prior to the development of resistance to TKI treatment or disease progression.

Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 461-476 ◽  
Author(s):  
Dale Bixby ◽  
Moshe Talpaz
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Enzyme Inhibitors ◽  
Chronic Phase ◽  
Imatinib Resistance ◽  
Durable Response ◽  
Secondary Resistance ◽  
Cellular Processes

AbstractGiven its relative rarity, it may at first seem surprising that chronic myeloid leukemia (CML) has garnered so much attention over the last decade. Yet, the advances in molecular pathogenesis that have been derived from studying this leukemia have clearly benefited all of oncology. Moreover, the strides in drug design and development that have also ensued around CML have given rise to what others have called a molecular revolution in cancer therapy. While a majority of patients with chronic phase CML (CP-CML) have an excellent durable response to imatinib (Gleevec, Novartis, Basel, Switzerland), a clear minority will unfortunately have signs of primary or secondary resistance to therapy. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the biology of drug trafficking into and out of cells, epigenetic control of cellular processes, alterations in enzymatic structures, and the rational structural-based design of small molecule enzyme inhibitors. This review will describe the efforts at understanding the pathogenesis of imatinib resistance and the molecular rationale for the development of second- and now third-generation therapies for patients with CML.

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