Salinomycin as a potent anticancer stem cell agent: State of the art and future directions

Abstract

Cancer stem cells (CSCs) are a small subpopulation of cells within a tumor that can both self-renew and differentiate into other cell types forming the heterogeneous tumor bulk. Since CSCs are involved in all aspects of cancer development, including tumor initiation, cell proliferation, metastatic dissemination, therapy resistance, and recurrence, they have emerged as attractive targets for cancer treatment and management. Salinomycin, a widely used antibiotic in poultry farming, was identified by the Weinberg group as a potent anti-CSC agent in 2009. As a polyether ionophore, salinomycin exerts broad-spectrum activities, including the important anti-CSC function. Studies on the mechanism of action of salinomycin against cancer have been continuously and rapidly published since then. Thus, it is imperative for us to update its literature of recent research findings in this area. We here summarize the notable work reported on salinomycin's anticancer activities, intracellular binding target(s), effects on tumor microenvironment, safety, derivatives, and tumor-specific drug delivery; after that we also discuss the translational potential of salinomycin toward clinical application based on current multifaceted understandings.

Keywords: anticancer stem cell agent; drug binding target; drug derivatives; nano-drug delivery; salinomycin.

Figure 1

Cancer stem cell and salinomycin's activities [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Possible mechanisms of salinomycin's anticancer effects. Cyto c, cytochrome c; EMT, epithelial–mesenchymal transition; IRP2, iron‐responsive element‐binding protein 2; MMPs, matrix metallopeptidases; TFs, transcription factors [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Promising reported derivatives and conjugates of salinomycin. Chemical structures were drawn using ACD/ChemSketch software. Literature of all structures was cited in the text. Red circles: modifications on the C20 position of salinomycin; green circles: modification on the C1 position of salinomycin; blue circles: modification on the C17 and C21 positions of salinomycin [Color figure can be viewed at wileyonlinelibrary.com]