There is growing evidence for a subpopulation of cells in breast cancer, known as breast cancer stem cells, that may be responsible for disease recurrence, resistance to conventional treatments, and perhaps metastasis. A team of US scientists has now shown that it is possible to selectively kill breast cancer stem cells (CSCs) using the ionophore antibiotic, salinomycin.
Patient-derived CSCs are difficult to collect and maintain in culture and a key aspect of the work was an ability to generate relatively homogenous and stable populations of CSC-like cells that could then be used for screening. Induction of epithelial-mesenchymal transition (EMT) in normal or neoplastic mammary epithelial cell populations had previously been shown to result in the enrichment of cells with stem cell-like properties and the researchers showed that normal and cancer cell populations experimentally induced into EMT also show increased resistance to chemotherapy drug treatment. Using two populations of mammary epithelial cells – one that had been induced to undergo EMT and one which had not – the team screened around 16,000 compounds and found that just 32 of them showed selective toxicity towards the cells that had undergone EMT. On the basis of potency and selectivity, salinomycin was chosen for further studies and was also found to decrease the proportion of CSCs that occur naturally as a subpopulation of breast cancer cells. Pre-treatment with salinomycin was found to decrease the tumour-seeding ability of cancer cell lines more than 100-fold compared with paclitaxel pre-treatment, and salinomycin also reduced mammary tumour size in mice to a greater extent than the chemotherapy drug, paclitaxel, or vehicle. Similar methodology could potentially be used to identify compounds that selectively kill CSCs from other types of cancer including leukemia, brain cancer, lung cancer, prostate cancer and melanoma, but it will be important to extend the findings to primary tumour cells from patients.
Salinomycin is used in farming to prevent coccidiodomycosis in poultry, and to alter gut flora in order to improve nutrient absorption in ruminants. The compound interferes with potassium transport across mitochondrial membranes, reducing intracellular energy production. It may also disrupt Na+/Ca2+ exchange in skeletal, and in some cases, cardiac muscle, allowing a fatal accumulation of intracellular calcium. Cases of animal poisoning with ionophore antibiotics have been widely described and the symptoms, which include progressive muscle weakening, appear to be similar to those seen following accidental exposure in man. Although the current study focussed largely on salinomycin, around 30% of the primary screen hits were confirmed on retesting, and expanding the screen may provide active compounds that may be more suitable for further development. The mechanism(s) by which salinomycin exhibits selective toxicity for CSCs is not known, but less toxic compounds that selectively target CSCs – but not normal stem cells – could find a place in future cancer therapies.
The study was published in the August 13th advance online issue of Cell.
Alox5 is known to be essential for processing fatty acids to leukotrienes, key components of the inflammatory response, and inhibitors of Alox5 have been developed for the treatment of asthma. Using the approved (for asthma) Alox5 inhibitor, Zileuton, the scientists at The Jackson Laboratory were able to demonstrate a greater therapeutic effect in the CML model than the gold standard, Gleevec. Combining the two therapeutics provided an even better response.