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ONCOLOGY
Route to cancer stem cell death ironed out
CREDIT: ADAPTED FROM NAT. CHEM.
Researchers find that compound with rare activity against cancer stem cells works by sequestering iron
OH O
O O H
O
O
O H O NH
OH
H OH Ironomycin In ironomycin, a short amine-alkyne chain (red) replaces one of salinomycin’s hydroxyl groups.
Cancer stem cells are bad actors. They ento track where the compound goes when in able cancers to metastasize, or spread, and cancer stem cells. They expected it to dishelp revive cancers after the malignancies tribute evenly throughout the cells and were structural complexity of this compound,” go dormant. One of the few agents that can surprised when it localized in lysosomes, says Piyush Gupta of the Whitehead Instieffectively attack them is a small molecule which are cellular compartments with entute and MIT, who discovered salinomycalled salinomycin. But scientists haven’t zymes that break down certain molecules. cin’s activity against cancer stem cells. “It understood how the compound kills the This led them to the mechanism: Salinois also the first to convincingly show that cells. mycin, or ironomycin, binds cellular iron iron plays an unusually important role in Now, researchers have discovered saliand sequesters it in lysosomes. The high regulating the malignant properties of cannomycin’s mechanism (Nat. Chem. 2017, concentration of lysosomal iron then trigcer stem cells. These are both important DOI: 10.1038/nchem.2778). The findings gers a process called ferroptosis—in which contributions that will guide the developreveal a key weakness ment of new therapies of cancer stem cells targeting the most that could lead to the malignant of cancer design of other drugs cells.” to help fight the cells. “Selective mechTo discover the anisms for killing mechanism, Raphaël cancer stem cells have Rodriguez of Institut been a long-standing Curie and France’s goal of cancer drug National Center for discovery, but few Scientific Research, mechanisms have Maryam Mehrpour of Ironomycin or salinomycin (light blue dots) works by sequestering iron, leading to been identified,” says Institut Necker Encell death. Brent R. Stockwell of fants Malades and the Columbia University, French National Institute of Health & Med- iron catalyzes the so-called Fenton reaction, who discovered ferroptosis. “This paper ical Research, and coworkers first tried to producing reactive oxygen species that suggests that iron sequestration in lysocreate a more potent version of salinomybreak lysosomal membranes, oxidize cell somes could be one such effective mechacin by modifying it with groups of varying lipids, and cause cell death. The mechanism nism for targeting cancer stem cells.” polarity and charge. The most potent was is not specific to cancer stem cells, RodriOne possible drawback to a canironomycin, in which one of salinomycin’s guez says, but these cells are more suscepticer-stem-cell-targeting compound is that hydroxyl groups was replaced by a short ble to salinomycin’s or ironomycin’s activity other cells in the tumor might still survive, amine-alkyne chain. Ironomycin has an because they are more dependent on iron he adds. “So you would likely need a comorder of magnitude greater potency than and may be less efficient at scavenging free bination of drugs targeting cancer stem salinomycin at killing breast cancer stem radicals than conventional cells are. cells and non-stem-cell tumor cells. And cells, both in culture and in mice. The study “is the first to characterize there might be toxicity to normal stem They then used in vivo click chemistry on salinomycin’s mechanism of action at a mo- cells, so this would need to be evaluated” ironomycin’s alkyne group to label the comlecular level, which is in itself a major step as research on stem-cell-targeted agents pound with a fluorescent dye, enabling them forward and an impressive feat, given the progresses.—STU BORMAN MAY 22, 2017 | CEN.ACS.ORG | C&EN
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