Targeting the redox vulnerability of acute myeloid leukaemia cells with a combination of auranofin and vitamin C

Summary Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by complex molecular and cytogenetic abnormalities. Pro‐oxidant cellular redox status is a common hallmark of AML cells, providing a rationale for redox‐based anticancer strategy. We previously discovered that auranofin (AUF), initially used for the treatment of rheumatoid arthritis and repositioned for its anticancer activity, can synergize with a pharmacological concentration of vitamin C (VC) against breast cancer cell line models. In this study, we observed that this drug combination synergistically and efficiently killed cells of leukaemic cell lines established from different myeloid subtypes. In addition to an induced elevation of reactive oxygen species and ATP depletion, a rapid dephosphorylation of 4E‐BP1 and p70S6K, together with a strong inhibition of protein synthesis were early events in response to AUF/VC treatment, suggesting their implication in AUF/VC‐induced cytotoxicity. Importantly, a study on 22 primary AML specimens from various AML subtypes showed that AUF/VC combinations at pharmacologically achievable concentrations were effective to eradicate primary leukaemic CD34+ cells from the majority of these samples, while being less toxic to normal cord blood CD34+ cells. Our findings indicate that targeting the redox vulnerability of AML with AUF/VC combinations could present a potential anti‐AML therapeutic approach. Pro‐oxidant cellular redox status is a common hallmark of acute myeloid leukaemia (AML) cells, providing a rationale for redox‐based anti‐AML strategy. Auranofin and vitamin C are promising redox‐modulating anticancer molecules. Auranofin/vitamin C combinations at pharmacologically relevant concentrations are able to synergistically kill myeloid leukaemia cell lines and to efficiently eliminate most primary leukaemic CD34+ cells from several types of AML, while being less toxic to normal cord blood CD34+ cells. Mechanistically, a rapid dephosphorylation of 4E‐BP1 and a consequent strong inhibition of protein synthesis could implicate in auranofin/vitamin C‐induced cytotoxicity. Targeting the redox vulnerability of AML with auranofin/vitamin C combinations may provide a new anti‐AML therapeutic approach.