Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells
Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells
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DOI：
10.1182/blood-2009-03-209965
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发表时间：
2009-10-01
期刊：
影响因子：
20.3
通讯作者：
Schimmer, Aaron D.
中科院分区：
文献类型：
--
作者：
Eberhard, Yanina;McDermott, Sean P.;Schimmer, Aaron D.
具有以前未被识别的抗癌活性的非专利药物可以迅速重新用于这一新的适应症。为了鉴定这些化合物，我们进行了2次独立的基于细胞的化学筛选，并在两次筛选中鉴定了抗微生物环吡酮胺（CPX）。CPX在似乎难以实现的低微摩尔浓度下降低恶性白血病、骨髓瘤和实体瘤细胞系以及原发性AML患者样品的细胞生长和活力。此外，与对照组相比，口服CPX使3种白血病小鼠模型中的肿瘤重量和体积降低高达65%，而没有体重减轻或大体器官毒性的证据。此外，口服CPX可防止原代AML细胞在非肥胖糖尿病/严重联合免疫缺陷小鼠模型中的植入，从而建立其靶向白血病干细胞的能力。从机制上讲，CPX结合细胞内铁，这种细胞内铁螯合作用对其细胞毒性具有重要的功能。通过电子顺磁共振，CPX在与细胞死亡相关的浓度下抑制铁依赖性酶核糖核苷酸还原酶。因此，总之，CPX在可实现的浓度下具有先前未被认识到的抗癌活性。因此，CPX可以迅速用于治疗恶性肿瘤，包括白血病和骨髓瘤。（血。2009; 114：3064 - 3073）
Off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication. To identify such compounds, we conducted 2 independent cell-based chemical screens and identified the antimicrobial ciclopirox olamine (CPX) in both screens. CPX decreased cell growth and viability of malignant leukemia, myeloma, and solid tumor cell lines as well as primary AML patient samples at low-micromolar concentrations that appear pharmacologically achievable. Furthermore, oral CPX decreased tumor weight and volume in 3 mouse models of leukemia by up to 65% compared with control without evidence of weight loss or gross organ toxicity. In addition, oral CPX prevented the engraftment of primary AML cells in nonobese diabetic/severe combined immunodeficiency mouse models, thereby establishing its ability to target leukemia stem cells. Mechanistically, CPX bound intracellular iron, and this intracellular iron chelation was functionally important for its cytotoxicity. By electron paramagnetic resonance, CPX inhibited the iron-dependent enzyme ribonucleotide reductase at concentrations associated with cell death. Thus, in summary, CPX has previously unrecognized anticancer activity at concentrations that are pharmacologically achievable. Therefore, CPX could be rapidly repurposed for the treatment of malignancies, including leukemia and myeloma. (Blood. 2009; 114: 3064-3073)