Salinomycin Derivatives Kill Breast Cancer Stem Cells by Lysosomal Iron Targeting

Abstract

Salinomycin (1) exhibits a large spectrum of biological activities including the capacity to selectively eradicate cancer stem cells (CSC), making it and its derivatives promising candidates for the development of drug leads against CSC. It has been previously shown that salinomycin and its C20‐propargylamine derivative (Ironomycin (2)) accumulate in lysosomes and sequester iron in this organelle. Herein, a library of salinomycin derivatives is reported, including products of C20‐amination, C1‐esterification, C9‐oxidation, and C28‐dehydration. The biological activity of these compounds is evaluated against transformed human mammary epithelial HMLER CD24low/CD44high cells, a well‐established model of breast CSC, and HMLER CD24high/CD44low cells deprived of CSC properties. Unlike other structural alterations, derivative 4, which displays a cyclopropylamine at position C20, showed a strikingly low IC50 value of 23 nm against HMLER CD24low/CD44high cells. This study provides highly selective molecules to target the CSC niche, a potential interesting advance for drug development to prevent cancer resistance.

CD44 as a tumor biomarker and therapeutic target

“…Although much advancement has been achieved in cancer treatment, there is still a tumor population reacts poorly to current anti-tumor drugs. Recently, aiming at killing CSCs has become a promising therapeutic strategy for cancer population [137], and substantial interest has been emerged in the exploration of specific therapies targeting stemness-related marker of CSCs. CD44, as a well-known constituent of CSC niche, is among the chief potential rewarding anti-cancer targets for tumor management.…”

Emerging agents that target signaling pathways in cancer stem cells

“…Therefore, in this current review, we summarize the small-molecule compounds targeting the Wnt, Hh, Notch, and Hippo pathways to kill CSCs. Although targeting ferroptosis to kill CSCs has recently been invoked, the effects have been strongly established by many studies [143,147,148]. Recently, although biologics have been rapidly developed, smallmolecule compounds are still needed for clinical application.…”

“…They have been shown to be at least ten-fold more potent than salinomycin in vivo and in vitro. In addition, ironomycin can effectively reduce the number of CSCs in docetaxel-resistant xenograft models [143,147]. Furthermore, ebselen, substituting pyrazole, and benzyl isothiourea, which are the inhibitors of DMT1, can selectively target BCSCs by blocking iron in lysosomes [148].…”

Synthesis and Anticancer Activity of Dimeric Polyether Ionophores

“…Finally, compared with the previously obtained multivalent structures of SAL [ 19 , 29 , 30 ] and its other derivatives [ 6 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], the newly synthesized ester-triazole-linked dimers, particularly ‘mixed’ SAL - LAS dimer 15 and SAL - SAL homodimer 22 , should be classified with no doubt not only as the most promising dimeric structures synthesized so far, but also as the most active SAL derivatives in general. Therefore, our results seem to be a good starting point for further studies on the dimerization of polyether ionophores, which is a very efficient synthetic strategy to generate highly bioactive drug candidates.…”

“…As polyether ionophores exhibit a broad spectrum of interesting pharmacological properties, at present, semi-synthetic derivatives of these natural products with improved activity profiles compared to those of the native structures are of top research interests. Although the site-specific modifications of ionophores are non-trivial with respect to their multifunctional nature and possible decomposition during synthesis, a few teams around the world have successfully followed synthetic approaches to generate LAS , MON , and SAL analogs; the modifications have been related mainly to the manipulations of either the C1 carboxyl of these biomolecules [ 6 , 15 , 16 , 17 , 18 , 19 , 20 ], or the C20 hydroxyl of SAL ( Figure 1 a) [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Nevertheless, a definitely less explored direction of research is the synthesis as well as functional evaluation of the multivalent structures of polyether ionophores.…”