Department of Urology, Tianjin Institute of Urology, The Second Hospital, Tianjin Medical University, Tianjin 300211, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, São Paulo 05508-000, Brazil.
J Trace Elem Med Biol. 2019 Mar;52:232-238. doi: 10.1016/j.jtemb.2019.01.004. Epub 2019 Jan 9.
Iron chelation has already been proposed to be a feasible strategy for cancer therapeutics in that reinforced iron demand is demonstrated in cancer cells, and quite a few iron chelators have been developed for this purpose. Desferrioxamine (DFO), an iron chelator approved by the U.S. Food and Drug Administration (FDA), has been extensively examined to remove extra iron. However, DFO has been found to harbor limited efficacies in combating cancer cells due to poor cellular permeability. In the current study, we synthesized the DFO derivative, named as desferrioxamine-caffeine dimer (DFCAF) by linking DFO to caffeine with high purity and excellent stability. Our data showed that DFCAF displayed greater cellular permeability to chelate intracellular iron in 4T1 breast cancer cells than DFO, posing more inhibition on cell growth and cellular motility/invasion. Importantly, DFCAF was uncovered to remarkably deplete cancer stem cells (CSCs), as characterized by the remarkable decrease of the CD44/CD24 and ALDH subpopulation. In parallel, DFCAF was also found to greatly reverse epithelial-mesenchymal transition (EMT), suggesting the potential application to restrain tumor progression and metastasis. Collectively, these data unveiled the improved efficacy to target cancer cells and to deplete CSCs, thus opening a new path for better cancer therapeutics through iron chelation.
铁螯合已被提议作为癌症治疗的一种可行策略，因为癌细胞中表现出强化的铁需求，并且已经开发了相当多的铁螯合剂用于此目的。去铁胺（DFO），一种获得美国食品和药物管理局（FDA）批准的铁螯合剂，已被广泛研究用于去除多余的铁。然而，由于细胞通透性差，DFO 被发现对对抗癌细胞的疗效有限。在本研究中，我们通过用咖啡因将 DFO 连接起来合成了 DFO 的衍生物，命名为去铁胺-咖啡因二聚体（DFCAF），其具有高纯度和优异的稳定性。我们的数据表明，DFCAF 在乳腺癌 4T1 细胞中螯合细胞内铁的细胞通透性大于 DFO，对细胞生长和细胞迁移/侵袭的抑制作用更大。重要的是，DFCAF 被发现可显著耗尽癌症干细胞（CSC），表现为 CD44/CD24 和 ALDH 亚群的显著减少。同时，DFCAF 也被发现可极大地逆转上皮-间充质转化（EMT），表明其具有抑制肿瘤进展和转移的潜在应用。总之，这些数据揭示了靶向癌细胞和耗尽 CSC 的疗效得到了改善，从而为通过铁螯合更好地治疗癌症开辟了新途径。
