Structure–Activity Relationships in Salinomycin: Cytotoxicity and Phenotype Selectivity of Semi‐synthetic Derivatives

Borgström, Björn; Huang, Xiaoli; Hegardt, Cecilia; Oredsson, Stina; Strand, Daniel

doi:10.1002/chem.201603621

Cited by 32 publications

(33 citation statements)

References 36 publications

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“… 36 We recently demonstrated that salinomycin derivatives such as ethyl carbonate 3 with modifications to this position exhibit both increased basal toxicity and enhanced activity against breast cancer stem cells. 24 , 25 …”

Section: Resultsmentioning

confidence: 99%

The Molecular Basis for Inhibition of Stemlike Cancer Cells by Salinomycin

et al. 2018

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Tumors are phenotypically heterogeneous and include subpopulations of cancer cells with stemlike properties. The natural product salinomycin, a K+-selective ionophore, was recently found to exert selectivity against such cancer stem cells. This selective effect is thought to be due to inhibition of the Wnt signaling pathway, but the mechanistic basis remains unclear. Here, we develop a functionally competent fluorescent conjugate of salinomycin to investigate the molecular mechanism of this compound. By subcellular imaging, we demonstrate a rapid cellular uptake of the conjugate and accumulation in the endoplasmic reticulum (ER). This localization is connected to induction of Ca2+ release from the ER into the cytosol. Depletion of Ca2+ from the ER induces the unfolded protein response as shown by global mRNA analysis and Western blot analysis of proteins in the pathway. In particular, salinomycin-induced ER Ca2+ depletion up-regulates C/EBP homologous protein (CHOP), which inhibits Wnt signaling by down-regulating β-catenin. The increased cytosolic Ca2+ also activates protein kinase C, which has been shown to inhibit Wnt signaling. These results reveal that salinomycin acts in the ER membrane of breast cancer cells to cause enhanced Ca2+ release into the cytosol, presumably by mediating a counter-flux of K+ ions. The clarified mechanistic picture highlights the importance of ion fluxes in the ER as an entry to inducing phenotypic effects and should facilitate rational development of cancer treatments.

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Section: Resultsmentioning

confidence: 99%

The Molecular Basis for Inhibition of Stemlike Cancer Cells by Salinomycin

et al. 2018

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“…However, a more systematic toxicology study may be required to examine the presence of delayed or latent toxicity to mammals. We also expect that toxicities could be alleviated by synthesizing less cytotoxic chemical derivatives, as tried in previous studies (42,43), or by conjugating the active compound to a delivery vehicle specific for virus-infected lung epithelial cells. Particularly, Brogström et al suggested that modifications to the C20 hydroxy group within the C-ring of salinomycin ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Particularly, Brogström et al suggested that modifications to the C20 hydroxy group within the C-ring of salinomycin ( Fig. 1A) would be beneficial in the context of selectivity (43). The combined therapeutic approach with salinomycin derivatives and a lower-dose NA inhibitor may also be valuable when the stockpiles of OSV-P are insufficient to respond to an influenza pandemic or when OSV-resistant viruses are circulating globally.…”

Section: Discussionmentioning

confidence: 99%

Salinomycin Inhibits Influenza Virus Infection by Disrupting Endosomal Acidification and Viral Matrix Protein 2 Function

Jang

Shin

Yoon

et al. 2018

J Virol

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Screening of chemical libraries with 2,000 synthetic compounds identified salinomycin as a hit against influenza A and B viruses, with 50% effective concentrations ranging from 0.4 to 4.3 M in cells. This compound is a carboxylic polyether ionophore that exchanges monovalent ions for protons across lipid bilayer membranes. Monitoring the time course of viral infection showed that salinomycin blocked nuclear migration of viral nuclear protein (NP), the most abundant component of the viral ribonucleoprotein (vRNP) complex. It caused cytoplasmic accumulation of NP, particularly within perinuclear endosomes, during virus entry. This was primarily associated with failure to acidify the endosomal-lysosomal compartments. Similar to the case with amantadine (AMT), proton channel activity of viral matrix protein 2 (M2) was blocked by salinomycin. Using purified retroviral Gag-based virus-like particles (VLPs) with M2, it was proved that salinomycin directly affects the kinetics of a proton influx into the particles but in a manner different from that of AMT. Notably, oral administration of salinomycin together with the neuraminidase inhibitor oseltamivir phosphate (OSV-P) led to enhanced antiviral effect over that with either compound used alone in influenza A virus-infected mouse models. These results provide a new paradigm for developing antivirals and their combination therapy that control both host and viral factors. IMPORTANCE Influenza virus is a main cause of viral respiratory infection in humans as well as animals, occasionally with high mortality. Circulation of influenza viruses resistant to the matrix protein 2 (M2) inhibitor, amantadine, is highly prevalent. Moreover, the frequency of detection of viruses resistant to the neuraminidase inhibitors, including oseltamivir phosphate (OSV-P) or zanamivir, is also increasing. These issues highlight the need for discovery of new antiviral agents with different mechanisms. Salinomycin as the monovalent cation-proton antiporter exhibited consistent inhibitory effects against influenza A and B viruses. It plays multifunctional roles by blocking endosomal acidification and by inactivating the proton transport function of M2, the key steps for influenza virus uncoating. Notably, salinomycin resulted in marked therapeutic effects in influenza virus-infected mice when combined with OSV-P, suggesting that its chemical derivatives could be developed as an adjuvant antiviral therapy to treat influenza infections resistant or less sensitive to existing drugs.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anticancer Activity of Dimeric Polyether Ionophores

et al. 2020

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Polyether ionophores represent a group of natural lipid-soluble biomolecules with a broad spectrum of bioactivity, ranging from antibacterial to anticancer activity. Three seem to be particularly interesting in this context, namely lasalocid acid, monensin, and salinomycin, as they are able to selectively target cancer cells of various origin including cancer stem cells. Due to their potent biological activity and abundant availability, some research groups around the world have successfully followed semi-synthetic approaches to generate original derivatives of ionophores. However, a definitely less explored avenue is the synthesis and functional evaluation of their multivalent structures. Thus, in this paper, we describe the synthetic access to a series of original homo- and heterodimers of polyether ionophores, in which (i) two salinomycin molecules are joined through triazole linkers, or (ii) salinomycin is combined with lasalocid acid, monensin, or betulinic acid partners to form ‘mixed’ dimeric structures. Of note, all 11 products were tested in vitro for their antiproliferative activity against a panel of six cancer cell lines including the doxorubicin resistant colon adenocarcinoma LoVo/DX cell line; five dimers (14–15, 17–18 and 22) were identified to be more potent than the reference agents (i.e., both parent compound(s) and commonly used cytostatic drugs) in selective targeting of various types of cancer. Dimers 16 and 21 were also found to effectively overcome the resistance of the LoVo/DX cancer cell line.

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Structure–Activity Relationships in Salinomycin: Cytotoxicity and Phenotype Selectivity of Semi‐synthetic Derivatives

Cited by 32 publications

References 36 publications

The Molecular Basis for Inhibition of Stemlike Cancer Cells by Salinomycin

The Molecular Basis for Inhibition of Stemlike Cancer Cells by Salinomycin

Salinomycin Inhibits Influenza Virus Infection by Disrupting Endosomal Acidification and Viral Matrix Protein 2 Function

Synthesis and Anticancer Activity of Dimeric Polyether Ionophores

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