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Cross-talk between Bcr-abl and the Thioredoxin System in Chronic Myeloid Leukaemia: Implications for CML Treatment.
Antioxidants (Basel). 2020 Mar 03; 9(3)A

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.

Authors+Show Affiliations

School of Environment and Science, Griffith University, Nathan, Brisbane, QLD 4111, Australia. Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia.School of Environment and Science, Griffith University, Nathan, Brisbane, QLD 4111, Australia. Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia.Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia.School of Environment and Science, Griffith University, Nathan, Brisbane, QLD 4111, Australia.School of Environment and Science, Griffith University, Nathan, Brisbane, QLD 4111, Australia. Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32138149

Citation

Clapper, Erin, et al. "Cross-talk Between Bcr-abl and the Thioredoxin System in Chronic Myeloid Leukaemia: Implications for CML Treatment." Antioxidants (Basel, Switzerland), vol. 9, no. 3, 2020.
Clapper E, Wang S, Raninga PV, et al. Cross-talk between Bcr-abl and the Thioredoxin System in Chronic Myeloid Leukaemia: Implications for CML Treatment. Antioxidants (Basel). 2020;9(3).
Clapper, E., Wang, S., Raninga, P. V., Di Trapani, G., & Tonissen, K. F. (2020). Cross-talk between Bcr-abl and the Thioredoxin System in Chronic Myeloid Leukaemia: Implications for CML Treatment. Antioxidants (Basel, Switzerland), 9(3). https://doi.org/10.3390/antiox9030207
Clapper E, et al. Cross-talk Between Bcr-abl and the Thioredoxin System in Chronic Myeloid Leukaemia: Implications for CML Treatment. Antioxidants (Basel). 2020 Mar 3;9(3) PubMed PMID: 32138149.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cross-talk between Bcr-abl and the Thioredoxin System in Chronic Myeloid Leukaemia: Implications for CML Treatment. AU - Clapper,Erin, AU - Wang,Sicong, AU - Raninga,Prahlad V, AU - Di Trapani,Giovanna, AU - Tonissen,Kathryn F, Y1 - 2020/03/03/ PY - 2020/01/28/received PY - 2020/02/24/revised PY - 2020/03/01/accepted PY - 2020/3/7/entrez PY - 2020/3/7/pubmed PY - 2020/3/7/medline KW - CML KW - ROS KW - apoptosis KW - bcr-abl KW - drug resistance KW - imatinib KW - thioredoxin JF - Antioxidants (Basel, Switzerland) JO - Antioxidants (Basel) VL - 9 IS - 3 N2 - 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. SN - 2076-3921 UR - https://www.unboundmedicine.com/medline/citation/32138149/Cross-talk_between_Bcr-abl_and_the_Thioredoxin_System_in_Chronic_Myeloid_Leukaemia:_Implications_for_CML_Treatment L2 - http://www.mdpi.com/resolver?pii=antiox9030207 DB - PRIME DP - Unbound Medicine ER -
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