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

Erin Clapper,Giovanna Di Trapani,Kathryn F. Tonissen,Sicong Wang,Prahlad V. Raninga

doi:10.3390/antiox9030207

Erin Clapper, Giovanna Di Trapani + Show 3 more

Open Access

https://doi.org/10.3390/antiox9030207

Copy DOI

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 who did not respond to imatinib had higher Trx mRNA levels than patients who responded to treatment. Our study demonstrates a link between the Trx system and the bcr-abl protein and highlights the therapeutic potential of targeting the Trx system to improve CML patients’ outcomes.

Highlights

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder caused by a fusion oncoprotein known as bcr-abl
This study aims to investigate thioredoxin reductase (TrxR) as a possible therapeutic target by assessing the effectiveness of TrxR inhibitors on CML cells and on overcoming tyrosine kinase inhibitors (TKIs) resistance, as well as studying a potential cross talk between bcr-abl and the Trx system
This study aimed to examine the effectiveness of two TrxR1 inhibitors, auranofin and [Au(d2pype)2]Cl, on overcoming intrinsic imatinib resistance in CML and degree of resistance towards auranofin compared to the parental cell line (Figure C,D)

Summary

Introduction

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder caused by a fusion oncoprotein known as bcr-abl. The bcr-abl fusion arises from a reciprocal chromosomal translocation between chromosomes 9 and 22, which results in a truncated chromosome 22 known as the Philadelphia chromosome. There is evidence that the transcription of the bcr-abl gene is controlled via the MYC pathway [2,3]. The vast majority of CML therapies are tyrosine kinase inhibitors (TKIs) that target bcr-abl. While these therapies are effective in the chronic phase of the disease, the final and most severe stage of this disease, blast crisis, is still untreatable with chemotherapy [6,7].

Objectives

Methods

Results

Discussion

Conclusion