The Possible Roles of Peroxiredoxins in Mediating Imatinib Resistance in CML cells and its Therapeutic Opportunities
The Possible Roles of Peroxiredoxins in Mediating Imatinib Resistance in CML cells and its Therapeutic Opportunities
Abstract
Purpose: Despite the impressive results with imatinib mesylate (IM) in treatment of chronic myeloid leukemia (CML), the clinical resistance to IM in patients leads to a still serious clinical problems. Clinical resistance was developed due to a heterogeneous array of mechanisms such as Bcr-Abl gene overexpression, point mutations in the kinase domain of BCR-ABL1, low intracellular drug levels caused by disordered expression of influx and efflux transporters, or activation of alternative signalling pathways by oncogenic enzymes. Bcr-Abl oncogene is known to induce high levels of intracellular ROS which may further induce genomic instability with malignant transformation and even imatinib (IM) resistance. In this study, to find possible targets for imatinib-resistant CML, we investigated the roles of ROS and antioxidants in mediating imatinib resistance in Philadelphia chromosome in CML cells. Methods: Three BCR-ABL1 positive cell lines with different resistance to TKI were compared with cell growth by MTT assay, BCR/ABL expression by western blot analysis according to different concentrations of IM between 0 to 10 μM in time dependent manner (24 hours/48 hours). At the same time, we evaluated changes of intracellular ROS level and antioxidant enzymes, peroxiredoxin ( Prx) 1, 2, 3 using immunoblot assay with or without ROS scavenger and NAD( P)H oxidase inhibitor. We also repeatedly investigated after generating IM-resistant sublines which showed profound declines of BCR-ABL levels and its TK activity from K562 cells by chronic exposure of increasing concentrations of IM. Results: Three BCR-ABL1 positive cell lines showed significant change in cell viability, Intracellular ROS level, eradication of BCR/ABL oncogene by western blot results and levels of Prx2 during IM treatment. But these cells were showed different response each other in degree and pattern by IM exposure, especially in levels of Prx2. The expression levels of Prx2 was significantly related to IM-resistant varients relative to K562 cells. Conclusions: Those results have been implicated the Prx2 might be able to control IM resistance of the BCR-ABL1 positive cells. Understanding the molecular mechanisms of changes on ROS and redox enzymes may be potential tools to develop more potent new drugs in Ph+ CML or Ph+ ALL patients especially for IM resistant.