Cancer stem cells are bad actors. They enable cancers to metastasize, or spread, and help revive cancers after the malignancies go dormant. One of the few agents that can effectively attack them is a small molecule called salinomycin. But scientists haven’t understood how the compound kills the cells.
Now, researchers have discovered salinomycin’s mechanism (Nat. Chem. 2017, DOI: 10.1038/nchem.2778). The findings reveal a key weakness of cancer stem cells that could lead to the design of other drugs to help fight the cells.
To discover the mechanism, Raphaël Rodriguez of Institut Curie and France’s National Center for Scientific Research, Maryam Mehrpour of Institut Necker Enfants Malades and INSERM, and coworkers first tried to create a more potent version of salinomycin by modifying it with groups of varying polarity and charge. The most potent was ironomycin, in which one of salinomycin’s hydroxyl groups was replaced by a short amine-alkyne chain. Ironomycin has an order of magnitude greater potency than salinomycin at killing breast cancer stem cells, both in culture and in mice.
They then used in vivo click chemistry on ironomycin’s alkyne group to label the compound with a fluorescent dye, enabling them to track where the compound goes when in cancer stem cells. They had expected it to distribute evenly throughout the cells and were surprised when it instead localized in lysosomes, which are cellular compartments with enzymes that break down certain molecules.
This led them to the mechanism: Salinomycin, or ironomycin, binds cellular iron and sequesters it in lysosomes. The high concentration of lysosomal iron then triggers a process called ferroptosis—in which iron catalyzes the so-called Fenton reaction, producing reactive oxygen species that break lysosomal membranes, oxidize cell lipids, and cause cell death. The mechanism is not specific to cancer stem cells, Rodriguez says, but these cells are more susceptible to salinomycin’s or ironomycin’s activity because they are more dependent on iron and may be less efficient at scavenging free radicals than conventional cells.
The study “is the first to characterize salinomycin’s mechanism of action at a molecular level, which is in itself a major step forward and an impressive feat, given the structural complexity of this compound,” says Piyush Gupta of the Whitehead Institute and MIT, who discovered salinomycin’s activity against cancer stem cells. “It is also the first to convincingly show that iron plays an unusually important role in regulating the malignant properties of cancer stem cells. These are both important contributions that will guide the development of new therapies targeting the most malignant of cancer cells.”
“Selective mechanisms for killing cancer stem cells have been a long-standing goal of cancer drug discovery, but few mechanisms have been identified,” says Brent R. Stockwell of Columbia University, who discovered ferroptosis. “This paper suggests that iron sequestration in lysosomes could be one such effective mechanism for targeting cancer stem cells.”
One possible drawback to a cancer-stem-cell-targeting compound is that other cells in the tumor might still survive, he adds. “So you would likely need a combination of drugs targeting cancer stem cells and non-stem-cell tumor cells. And there might be toxicity to normal stem cells, so this would need to be evaluated” as research on stem-cell-targeted agents progresses.