Cotargeting of thioredoxin 1 and glutamate-cysteine ligase in both imatinib-sensitive and imatinib-resistant CML cells.

Chronic myeloid leukemia (CML) is a type of malignancy characterized by harboring the oncogene Bcr-Abl, which encodes the constitutively activated tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors targeting BCR-ABL have revolutionized CML therapy, native and acquired drug resistance commonly remains a great challenge. Thioredoxin 1 (Trx1) and glutamate-cysteine ligase (GCL), which are two major antioxidants that maintain cellular redox homeostasis, are potential targets for cancer therapy and overcoming drug resistance. However, how their inhibition is implicated in CML is still unclear. Here, our results revealed that Trx1 was overexpressed in patients with CML compared with healthy donors. Trx1 expression was greater in imatinib-resistant CML cells than in imatinib-sensitive cells. Pharmacological inhibitors of Trx1 attenuated cell growth and reduced colony formation in both imatinib-sensitive and imatinib-resistant CML cells. Furthermore, decreased Trx1 expression enhanced the cytotoxicity of the GCL inhibitor buthionine sulfoximine (BSO). We surmise that the combined inhibition of Trx1 and GCL promotes the induction of hydrogen peroxide and depletes GPX4 expression in CML cells, resulting in ferroptosis in cancerous cells. Finally, the combined inhibition of Trx1 and GCL had a synergistic effect on CML cells in murine xenograft models. These findings offer crucial informationregarding the combined roles ofTrx1 and GCL in triggering ferroptosis in CML and suggestefficacioustherapeutic uses for these systems in this disease.