Volume 95 Issue 21 | p. 5 | News of The Week
Issue Date: May 22, 2017 | Web Date: May 17, 2017

Route to cancer stem cell death ironed out

Researchers find compound with rare activity against cancer stem cells works by sequestering iron
Department: Science & Technology
Keywords: oncology, cancer stem cells, Fenton chemistry, reactive oxygen species, lysosomes, cell death
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Ironomycin or salinomycin (blue dots) works by sequestering iron, leading to cell death.
Credit: Nature Chemistry
Schematic shows that ironomycin or salinomycin sweeps us iron ions from the cytoplasm and nucleus of cancer stem cells, causing iron to accumulate in lysosomes. The accumulation initiates Fenton chemistry that creates reactive oxygen species, killing the cells.
 
Ironomycin or salinomycin (blue dots) works by sequestering iron, leading to cell death.
Credit: Nature Chemistry

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.

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In ironomycin, a short amine-alkyne chain (red) replaces one of salinomycin’s hydroxyl groups.
Chemical line structure of ironomycin. It is made by replacing a hydroxyl group on salinomycin with a short amine-alkyne chain.
 
In ironomycin, a short amine-alkyne chain (red) replaces one of salinomycin’s hydroxyl groups.

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.

 
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