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

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.

Investigating the Thioredoxin and Glutathione Systems’ Response in Lymphoma Cells after Treatment with [Au(d2pype)2]Cl

“…Our laboratory has previously shown that proliferation of both myeloma and chronic myeloid leukemia cells were inhibited by gold-based compounds such as auranofin and [Au(d2pype)2]Cl [ 30 , 31 ]. Although auranofin is considered to be primarily a TrxR inhibitor [ 53 , 54 ], studies have shown that it also targets other proteins, including bcr/abl, NFkB2, or CHORDC1, directly or indirectly [ 55 , 56 ].…”

“…A gold(I) phosphine TrxR inhibitor, bis-chelated tetrahedral gold(I) phosphine complex [Au(d2pype)2]Cl was designed to target TrxR [ 24 , 29 ]. Studies have indicated that [Au(d2pype)2]Cl has a higher selectivity towards TrxR than auranofin [ 29 ], and recently has been shown to exhibit anticancer effects against multiple myeloma (MM) and chronic myeloid leukaemia (CML) [ 30 , 31 ]. However, it has not yet been tested against lymphoma.…”

ND‑09 inhibits chronic myeloid leukemia K562 cell growth by regulating BCR‑ABL signaling

“…CML, a myeloproliferative malignancy driven by the constitutively active BCR-ABL1 tyrosine kinase, is currently treated with TKIs that have proven to be clinically effective (17). However, while TKI treatment was initially successful, the emerging development of TKI resistance presents a considerable challenge (18,19). In this study, we developed ND-09, which exhibited potent anticancer activity against CML by targeting BCR-ABL.…”

Involvement of Blnk and Foxo1 in tumor suppression in BCR‑ABL1‑transformed pro‑B cells

“…Consistent with this argument, Blnk- or Foxo1-deficient BCR-ABL1 -transformed pro-B cells revealed enhanced Bcr-Abl kinase activity, accompanied by marked cell survival and increased genomic instability mediated by enhanced Aid expression. It has been reported that the aberrant expression of Aid initiating SHM on Ig and non-Ig genes is driven by carcinogenic Bcr-Abl kinase and is related to the poor prognosis of BCR-ABL1 + leukemia ( 43 ) Continuous upregulation of BCR-ABL1 not only induces the survival advantage of leukemic cells, but also provides a target for Aid ( 58 , 59 ). Numerous studies have suggested that Aid promotes the mutations of BCR-ABL1 to cause imatinib-resistance and leads to the rapid progression of CML-blast crisis progression ( 13 , 60 , 61 ).…”