Salinomycin Prevents Tumor Regeneration by Killing Cancer Stem Cells

A search for drugs to kill the epithelial cancer stem cells (CSCs) that may be responsible for failure of traditional chemotherapy has yielded a surprisingly potent candidate compound.

The idea that a nucleus of CSCs survives chemotherapy and regenerates new, drug resistant tumors has generated considerable interest in identifying drugs that could eliminate this threat. However, several technical problems, including the scarcity of CSCs and their rapid loss of stem cell-like properties when grown in tissue culture, have hindered this search.

Now, in a paper published in the August 13, 2009, online edition of the journal Cell, investigators at the Massachusetts Institute of Technology (Cambridge, USA) and Harvard Medical School (Cambridge, MA, USA) reported the development of a method to enrich cultures of CSCs by manipulating adult cancer cells so that they would undergo "epithelial-to-mesenchymal transition,” or EMT. EMT is a program of development of biological cells characterized by loss of cell adhesion, repression of E-cadherin expression, and increased cell mobility. It is essential for numerous developmental processes including formation of mesoderm and the neural tube. Initiation of tumor metastasis involves invasion, which has many phenotypic similarities to EMT, including a loss of cell-cell adhesion mediated by E-cadherin repression and an increase in cell mobility.

The investigators used this pool of CSCs to screen more than 16,000 potential drugs in an automated high-throughput assay system. They identified 30 compounds with various levels of anti-CSC toxicity, and one drug in particular - salinomycin - with a potent ability to kill CSCs.

Salinomycin is an ionophore antibiotic used in farming for the prevention of coccidiodomycosis in poultry and to alter gut flora in order to improve nutrient absorption in ruminants. Salinomycin interferes with potassium transport across mitochondrial membranes, resulting in low intracellular energy production. The Na+/Ca2+ exchange mechanism may also be disrupted allowing a fatal accumulation of intracellular calcium. This mechanism particularly affects skeletal muscle in all animals, and cardiac muscle in a few species.

In the current study, it was found that salinomycin reduced the proportion of CSCs by more than 100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibited mammary tumor growth in vivo and induced increased epithelial differentiation of tumor cells. In addition, global gene expression analyses revealed that salinomycin treatment resulted in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients.

"Many therapies kill the bulk of a tumor only to see it regrow," said senior author Dr. Eric Lander, professor of biology at the Massachusetts Institute of Technology and professor of systems biology at Harvard Medical School. "This raises the prospect of new kinds of anticancer therapies."

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Massachusetts Institute of Technology
Harvard Medical School