Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació i Institut de Biomedicina, University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain.
Institut Curie, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
Chemistry. 2020 Jun 10;26(33):7369-7373. doi: 10.1002/chem.202000159. Epub 2020 May 26.
Cancer stem cells (CSC) constitute a cell subpopulation in solid tumors that is responsible for resistance to conventional chemotherapy, metastasis and cancer relapse. The natural product Salinomycin can selectively target this cell niche by directly interacting with lysosomal iron, taking advantage of upregulated iron homeostasis in CSC. Here, inhibitors of the divalent metal transporter 1 (DMT1) have been identified that selectively target CSC by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death with features of ferroptosis. DMT1 inhibitors selectively target CSC in primary cancer cells and circulating tumor cells, demonstrating the physiological relevance of this strategy. Taken together, this opens up opportunities to tackle unmet needs in anti-cancer therapy.
癌症干细胞（CSC）构成实体瘤中的细胞亚群，其负责对常规化疗、转移和癌症复发产生抵抗。天然产物萨利霉素可以通过直接与溶酶体铁相互作用，利用 CSC 中上调的铁稳态，选择性地靶向这个细胞生态位。在这里，已经鉴定出二价金属转运蛋白 1（DMT1）的抑制剂，通过阻断溶酶体铁转运来选择性地靶向 CSC。这导致溶酶体铁积累、活性氧的产生和具有铁死亡特征的细胞死亡。DMT1 抑制剂在原发性癌细胞和循环肿瘤细胞中选择性地靶向 CSC，证明了这种策略的生理相关性。总之，这为解决癌症治疗中的未满足需求提供了机会。
