Cross-talk between Bcr-abl and the Thioredoxin System in Chronic Myeloid Leukaemia: Implications for CML Treatment

Antioxidants
Erin ClapperKathryn F Tonissen

Abstract

Chronic myeloid leukaemia (CML) is currently treated with inhibitors of the CML specific oncoprotein, bcr-abl. While this strategy is initially successful, drug resistance can become a problem. Therefore, new targets need to be identified to ensure the disease can be appropriately managed. The thioredoxin (Trx) system, comprised of Trx, thioredoxin reductase (TrxR), and NADPH, is an antioxidant system previously identified as a target for therapies aimed at overcoming drug resistance in other cancers. We assessed the effectiveness of TrxR inhibitors on drug resistant CML cells and examined links between TrxR and the bcr-abl cell-signalling pathway. Two TrxR inhibitors, auranofin and [Au(d2pype)2]Cl, increased intracellular ROS levels and elicited apoptosis in both sensitive and imatinib resistant CML cells. Inhibition of TrxR activity by these pharmacological inhibitors, or by specific siRNA, also resulted in decreased bcr-abl mRNA and protein levels, and lower bcr-abl downstream signalling activity, potentially enhancing the effectiveness of TrxR inhibitors as CML therapies. In addition, imatinib resistant CML cell lines showed upregulated expression of the Trx system. Furthermore, analysis of datasets showed that CML patients...Continue Reading

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Citations

Dec 1, 2020·Leukemia & Lymphoma·Erin ClapperKathryn F Tonissen
Aug 30, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Geir BjørklundMassimiliano Peana

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Methods Mentioned

BETA
Assay
protein assay
PCR
transfection
RNAseq

Clinical Trials Mentioned

NCT01737502
NCT03456700

Software Mentioned

Graphpad Prism

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