Researchers have used a novel screening method to identify chemicals that may selectively kill cancer stem cells, a small subset of cancer cells with the ability to self-renew and maintain a tumor (Gupta PB et al. Cell. 2009;138[4]:645-659). The findings have significant clinical implications for treating many types of cancer.
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Salinomycin, an agent identified by a novel method for finding chemicals that may selectively kill cancer stem cells, caused reduced malignancy and increased epithelial differentiation in tumor cells (as gauged by expression of E-cadherin protein) when compared with a control treatment.
“Relative to the other cells in a tumor, cancer stem cells are resistant to many kinds of chemotherapy drugs and to radiation treatment; therefore, it is important to find new therapies that specifically target this class of cell,” said first author Piyush Gupta, PhD, of the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard University, Cambridge, Mass.
No screening tool has been available to identify chemicals that specifically kill cancer stem cells because these cells are rare within tumors and relatively unstable in laboratory experiments. However, Gupta and his colleagues—who include Eric Lander, PhD, and Robert Weinberg, PhD—used genetic manipulations to lock immortalized mammary epithelial cells in a stem cell–like state. This made it possible to create stable cell lines that could be used for screening purposes.
Next, they tested a panel of approximately 16 000 natural and artificial compounds for the ability to kill the stem cell–like cells but not differentiated cancer cells. From this screening, 32 candidates were identified. One compound, the antibacterial salinomycin, decreased the proportion of cancer stem cells by more than 100-fold relative to the chemotherapy drug paclitaxel.
“This article represents an important advance by demonstrating that it is possible to develop high-throughput strategies to find compounds that selectively target cancer stem cells,” said Max Wicha, MD, director of the University of Michigan Comprehensive Cancer Center in Ann Arbor, who was not involved with the research. It also confirms that the vast majority of chemotherapy agents currently in use kill the more differentiated cells in tumors while sparing the cancer stem cell population, which may be why such agents have limited efficacy, he added.
The scientists did not investigate how salinomycin decreases the activity of cancer stem cells, but they know what it does in general. “Salinomycin perturbs the balance of potassium ions across cellular membranes,” said Gupta. “Understanding why cancer stem cells might be especially sensitive to such a perturbation is an important topic for further research.” Nigericin, another potassium ionophore that has structural similarity to salinomycin, also exhibited selective toxicity for the stem cell–like cells.
Additionally, Gupta and his team demonstrated that salinomycin has potent activity in vivo. In tests on mice, salinomycin inhibited mammary tumor growth and induced epithelial differentiation of tumor cells. Gene expression analyses also showed that salinomycin treatment resulted in the loss of expression of breast cancer stem cell genes that had been previously identified by analyses of breast tissues isolated from patients. The authors noted that an important future direction would be to extend the findings of this study to primary tumor cells taken directly from patients.
If, as this study suggests, it is possible to identify agents with specific toxicity for cancer stem cells, a new class of anticancer agents may soon be a high-priority area of investigation. Some anticancer treatments actually impose a strong selection for cancer stem cell survival and expansion, so that in cases in which chemotherapy or radiation treatments fail to completely eradicate the disease, the residual cancer cells will be highly enriched with cancer stem cells. Future cancer therapy might be a combination of traditional drugs that kill differentiated cancer cells with new drugs that target and destroy cancer stem cells that would otherwise remain.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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