Abstract
BackgroundCancer stem cells (CSCs) have been invoked in resistance, recurrence and metastasis of cancer. Consequently, curative cancer treatments may be contingent on CSC selective approaches. Of particular interest in this respect is the ionophore salinomycin, a natural product shown to be 100-fold more active against CSCs than clinically used paclitaxel. We have previously reported that synthetic salinomycin derivatives display increased activity against breast cancer cell lines. Herein we specifically investigate the CSC selectivity of the most active member in each class of C20-O-acylated analogs as well as a C1-methyl ester analog incapable of charge-neutral metal ion transport.MethodsJIMT-1 breast cancer cells were treated with three C20-O-acylated analogs, the C1-methyl ester of salinomycin, and salinomycin. The effects of treatment on the CSC-related CD44+/CD24− and the aldehyde dehydrogenase positive (ALDH+) populations were determined using flow cytometry. The survival ability of CSCs after treatment was investigated with a colony formation assay under serum free conditions. The effect of the compounds on cell migration was evaluated using wound-healing and Boyden chamber assays. The expression of vimentin, related to mesenchymal traits and expression of E-cadherin and β-catenin, related to the epithelial traits, were investigated using immunofluorescence microscopy.ResultsTreatment with each of the three C20-acylated analogs efficiently decreased the putative CSC population as reflected by reduction of the CD44+/CD24− and ALDH+ populations already at a 50 nM concentration. In addition, colony forming efficiency and cell migration were reduced, and the expression of the epithelial markers E-cadherin and β-catenin at the cell surface were increased. In contrast, salinomycin used at the same concentration did not significantly influence the CSC population and the C1-methyl ester was inactive even at a 20 μM concentration.ConclusionsSynthetic structural analogs of salinomycin, previously shown to exhibit increased activity against cancer cells, also exhibited improved activity against CSCs across several assays even at nanomolar concentrations where salinomycin was found inactive. The methyl ester analog of salinomycin, incapable of charge-neutral metal ion transport, did not show activity in CSC assays, lending experimental support to ionophoric stress as the molecular initiating event for the CSC effects of salinomycin and related structures.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2142-3) contains supplementary material, which is available to authorized users.
Highlights
Cancer stem cells (CSCs) have been invoked in resistance, recurrence and metastasis of cancer
C20-O-acylated analogs are more efficient than salinomycin against breast CSCs at a 50 nM concentration Breast CSCs have been identified based on a high expression of CD44 paired with absent/low expression of CD24 on the cell surface [44]
We have previously shown that salinomycin (1) gave the highest selective activity against CD44+/CD24− cells at ~ IC25 in the breast cancer cell line JIMT-1 [35]
Summary
Cancer stem cells (CSCs) have been invoked in resistance, recurrence and metastasis of cancer. Breast cancer is the leading cause of cancer death among women worldwide Often, this outcome is a consequence of recurrence following years of disease-free life after a completed initial treatment [1]. Several studies have shown enrichment of CSCs following conventional chemotherapeutic treatment, both in vivo and in cancer cell lines [3, 4]. This has lead to the proposal that the chemotherapeutic drugs mainly target bulk cancer cells while sparing cells with CSC properties [5, 6]. Curative treatments may be contingent on therapies that target both CSCs and bulk cancer cells, presumably by a combination of conventional therapies and CSC selective drugs. It is well known that salinomycin is a potent ionophore with the capacity to transport alkali metal ions and it has been suggested that it acts in biological membranes by promoting potassium ion efflux [27, 28]
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