Drug Screening Identifies Niclosamide as an Inhibitor of Breast Cancer Stem-Like Cells

Wang, Yu Chi; Chao, Tai-Kuang; Chang, Cheng‐Chang; Yo, Yi Te; Mu, Yu; Lai, Hung Cheng

doi:10.1371/journal.pone.0074538

Cited by 106 publications

(80 citation statements)

References 31 publications

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“…Clearly, further work is needed to clarify the molecular mechanism of action of the neutral uncouplers, and we briefly investigate below the possible effects of AU1235 on membrane bilayer structure. Finally, we investigated several other compounds that have been reported to act as uncouplers in S. aureus (60): pyrazinocarbazole (33), D2 (34), and D3 (35). Only the pyrazinocarbazole (33) showed uncoupler activity and although it has previously been reported (60) to collapse Δψ selectively in S. aureus, it appears to act here as a protonophore, consistent with its computed pK a (6.2) and logP (4.7) values.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, nitazoxanide (13) has been found to kill both replicating and nonreplicating M. tuberculosis (30)(31)(32)(33), and Nathan and coworkers (30,31) were unable to develop resistant colonies using up to 10 12 cfu, proposing a dual "PMF + unknown target" mechanism of action. Niclosamide (12) has been proposed as a lead for the treatment of type II diabetes (34), and it is also an inhibitor of breast cancer stem-like cells (35) and an inhibitor of Pseudomonas aeruginosa quorum sensing (36). There has also been very recent interest in the development of DNP analogs such as DNP methyl ether (37), for treating diabetes, and of controlledrelease DNP formulations (38) as mild hepatic mitochondrial uncouplers for treating hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes.…”

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confidence: 99%

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Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

169

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There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.T here is a need for new antibiotics, due to the increase in drug resistance (1, 2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3, 4). To discover new drugs, new targets, leads, concepts, and implementations are needed (5, 6).Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9-11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent th...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

169

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“…The Wnt/β-catenin pathway is essential for self-renewal and migration of breast CSCs (46). The Wnt/β-catenin signaling inhibitors salinomycin and niclosamide exert selective inhibitory effects on breast CSCs compared with other cell types (18,(47)(48)(49). As shown here, prodigiosin also exhibits a potent inhibitory effect on Wnt/β-catenin signaling in breast cancer cells through targeting LRP6, DVL2, and GSK3β, leading to the inhibition of β-catenin activity and down-regulation of Wnt target genes, especially cyclin D1.…”

Section: Discussionmentioning

confidence: 99%

Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells

Wang

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

155

112

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Prodigiosin, a natural red pigment produced by numerous bacterial species, has exhibited promising anticancer activity; however, the molecular mechanisms of action of prodigiosin on malignant cells remain unclear. Aberrant activation of the Wnt/β-catenin signaling cascade is associated with numerous human cancers. In this study, we identified prodigiosin as a potent inhibitor of the Wnt/ β-catenin pathway. Prodigiosin blocked Wnt/β-catenin signaling by targeting multiple sites of this pathway, including the lowdensity lipoprotein-receptor-related protein (LRP) 6, Dishevelled (DVL), and glycogen synthase kinase-3β (GSK3β). In breast cancer MDA-MB-231 and MDA-MB-468 cells, nanomolar concentrations of prodigiosin decreased phosphorylation of LRP6, DVL2, and GSK3β and suppressed β-catenin-stimulated Wnt target gene expression, including expression of cyclin D1. In MDA-MB-231 breast cancer xenografts and MMTV-Wnt1 transgenic mice, administration of prodigiosin slowed tumor progression and reduced the expression of phosphorylated LRP6, phosphorylated and unphosphorylated DVL2, Ser9 phosphorylated GSK3β, active β-catenin, and cyclin D1. Through its ability to inhibit Wnt/β-catenin signaling and reduce cyclin D1 levels, prodigiosin could have therapeutic activity in advanced breast cancers.prodigiosin | Wnt/beta-catenin signaling | breast cancer | LRP6 | Dishevelled (DVL)

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“…Other promising compounds are being tested in order to target CD44 + /CD24 −/low tumor cells (Table I), although their potential still needs to be proven (36)(37)(38).…”

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confidence: 99%