Abstract：
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.
摘要：
急性髓性白血病（AML）是一种异质性疾病，其特征是复杂的分子和细胞遗传学异常。促氧化剂细胞氧化还原状态是AML细胞的常见标志，为基于氧化还原的抗癌策略提供了理论基础。我们之前发现了金诺芬(AUF)，最初用于治疗类风湿性关节炎，并重新定位其抗癌活性，可以与药理学浓度的维生素C（VC）协同对抗乳腺癌细胞系模型。在这项研究中,我们观察到，这种药物组合协同有效地杀死了由不同骨髓亚型建立的白血病细胞系的细胞。除了诱导活性氧和ATP消耗的升高，4E-BP1和p70S6K的快速去磷酸化，对AUF/VC治疗的早期事件以及对蛋白质合成的强烈抑制，表明它们在AUF/VC诱导的细胞毒性中的意义。重要的是,一项对来自不同AML亚型的22个原发性AML样本的研究表明，在药理学上可达到的浓度下，AUF/VC组合可有效根除大多数样本中的原发性白血病CD34+细胞，同时对正常脐带血CD34+细胞毒性较小。我们的发现表明，针对AML的氧化还原脆弱性与AUF/VC组合可以提出一个潜在的抗AML治疗方法。
