Desferrioxamine-caffeine shows improved efficacy in chelating iron and depleting cancer stem cells

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^+/high/CD24^-/low and ALDH^+/high 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.