Iron-Sensitive Prodrugs That Trigger Active Ferroptosis in Drug- Tolerant Pancreatic Cancer Cells
Iron-Sensitive Prodrugs That Trigger Active Ferroptosis in Drug- Tolerant Pancreatic Cancer Cells
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DOI：
10.1021/jacs.2c03973
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发表时间：
2022-06-13
影响因子：
15
通讯作者：
Rodriguez, Raphael
中科院分区：
文献类型：
--
作者：
Antoszczak, Michal;Muller, Sebastian;Rodriguez, Raphael
持久癌细胞代表对治疗有抗性的罕见细胞群体。癌细胞可以利用上皮-间充质可塑性来采取不依赖于遗传改变的耐药状态。可以干扰细胞可塑性或以细胞状态依赖性方式杀死细胞的小分子受到高度追捧。盐霉素已被证明可以通过将铁螯合在溶酶体中来杀死间充质状态的癌细胞，利用这种细胞状态的铁成瘾性。在这里，我们报告的化学和立体选择性合成一系列结构复杂的小分子嵌合体盐霉素衍生物和铁反应性双氢青蒿素。我们发现，这些嵌合体在溶酶体中积累，可以与铁反应释放生物活性物质，从而诱导耐药胰腺癌细胞和胰腺导管腺癌活检衍生的类器官中的铁凋亡。这项工作为开发通过活性铁凋亡发挥作用的新癌症药物铺平了道路。
Persister cancer cells represent rare populations of cells resistant to therapy. Cancer cells can exploit epithelial-mesenchymal plasticity to adopt a drug-tolerant state that does not depend on genetic alterations. Small molecules that can interfere with cell plasticity or kill cells in a cell state-dependent manner are highly sought after. Salinomycin has been shown to kill cancer cells in the mesenchymal state by sequestering iron in lysosomes, taking advantage of the iron addiction of this cell state. Here, we report the chemo-and stereoselective synthesis of a series of structurally complex small molecule chimeras of salinomycin derivatives and the iron-reactive dihydroartemisinin. We show that these chimeras accumulate in lysosomes and can react with iron to release bioactive species, thereby inducing ferroptosis in drug-tolerant pancreatic cancer cells and biopsy-derived organoids of pancreatic ductal adenocarcinoma. This work paves the way toward the development of new cancer medicines acting through active ferroptosis.