RETRACTED: Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule

Kitambi, Satish Srinivas; Toledo, Enrique M.; Usoskin, Dmitry; Wee, Shimei; Harisankar, Aditya; Svensson, Richard; Sigmundsson, Kristmundur; Kalderén, Christina; Niklasson, Mia; Kundu, Soumi; Aranda, Sergi; Westermark, Bengt; Uhrbom, Lene; Andäng, Michael; Damberg, Peter; Nelander, Sven; Arenas, Ernest; Artursson, Per; Walfridsson, Julian; Nilsson, Karin; Hammarström, Lars G.J.; Ernfors, Patrik

doi:10.1016/j.cell.2014.02.021

Cited by 91 publications

(137 citation statements)

References 70 publications

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“…S1 D-F) exhibited cytotoxicity associated with vacuolization ( Fig. S1D) as recently described for incubation with the small hydrophobic molecule vacquinol-1 (13). At the site of contact with d 10 , HeLa cells formed membrane-enclosed vacuoles (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation

Muñoz

Bilyy

Biermann

et al. 2016

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

133

118

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The critical size for strong interaction of hydrophobic particles with phospholipid bilayers has been predicted to be 10 nm. Because of the wide spreading of nonpolar nanoparticles (NPs) in the environment, we aimed to reveal the ability of living organisms to entrap NPs via formation of neutrophil extracellular traps (NETs). Upon interaction with various cell types and tissues, 10-to 40-nmsized NPs induce fast (<20 min) damage of plasma membranes and instability of the lysosomal compartment, leading to the immediate formation of NETs. In contrast, particles sized 100-1,000 nm behaved rather inertly. Resulting NET formation (NETosis) was accompanied by an inflammatory reaction intrinsically endowed with its own resolution, demonstrated in lungs and air pouches of mice. Persistence of small NPs in joints caused unremitting arthritis and bone remodeling. Small NPs coinjected with antigen exerted adjuvant-like activity. This report demonstrates a cellular mechanism that explains how small NPs activate the NETosis pathway and drive their entrapping and resolution of the initial inflammatory response.nanoparticles | size | neutrophils | NETosis | inflammation

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Section: Resultsmentioning

confidence: 99%

Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation

Muñoz

Bilyy

Biermann

et al. 2016

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

133

118

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“…The vacquinol class of compounds, 2-piperidinyl-4-quinolinemethanols, were originally developed as antimalarials (81,82), and in addition to their activity against M. tuberculosis and brain cancer cells, they can inhibit efflux pumps and are of interest in combating multidrug resistance in cancer cells (79,83,84), suggesting the possibility that their uncoupling effects could contribute to a diverse range of activities. The fact that vacquinol also has promising in vivo activity against GBM, a good in vivo pharmacokinetic profile, oral bioavailability, and favorable overall preclinical characteristics (80), in addition to killing M. tuberculosis, makes it an interesting lead for antiinfective development.…”

Section: Resultsmentioning

confidence: 99%

“…This effect is not expected for a virulence-targeting drug lead. Moreover, NSC13316 (37), now known as vacquinol-1, has activity against glioblastoma multiforme (GBM) cancer cells (80), both in vitro and in vivo, and is thought to kill these tumor cells by an unusual mechanism involving a decrease in ATP levels and extensive vacuolization (80). NSC13316 (37) is, therefore, a potentially interesting new antiinfective multitarget drug lead.…”

Section: Resultsmentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

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

147

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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“…Screens have identified small molecules that can induce this form of death in malignant cells, offering hope for new treatments of glioblastoma (Overmeyer et al, 2011;Kitambi et al, 2014). The precise cause of cell death is not clear in some instances of methuosis (Maltese and Overmeyer, 2014), but in acute druginduced vacuolisation, the cytoplasmic swelling causes the plasma membrane to rupture (Overmeyer et al, 2011;Kitambi et al, 2014).…”

Section: Macropinocytosis In Life and Death -Roles For Rasmentioning

confidence: 99%

Uses and abuses of macropinocytosis

Bloomfield

Kay

2016

Journal of Cell Science

167

171

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Macropinocytosis is a means by which eukaryotic cells ingest extracellular liquid and dissolved molecules. It is widely conserved amongst cells that can take on amoeboid form and, therefore, appears to be an ancient feature that can be traced back to an early stage of evolution. Recent advances have highlighted how this endocytic process can be subverted during pathology -certain cancer cells use macropinocytosis to feed on extracellular protein, and many viruses and bacteria use it to enter host cells. Prion and prion-like proteins can also spread and propagate from cell to cell through macropinocytosis. Progress is being made towards using macropinocytosis therapeutically, either to deliver drugs to or cause cell death by inducing catastrophically rapid fluid uptake. Mechanistically, the Ras signalling pathway plays a prominent and conserved activating role in amoebae and in mammals; mutant amoebae with abnormally high Ras activity resemble tumour cells in their increased capacity for growth using nutrients ingested through macropinocytosis. This Commentary takes a functional and evolutionary perspective to highlight progress in understanding and use of macropinocytosis, which is an ancient feeding process used by single-celled phagotrophs that has now been put to varied uses by metazoan cells and is abused in disease states, including infection and cancer.

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RETRACTED: Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule

Cited by 91 publications

References 70 publications

Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation

Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation

Antiinfectives targeting enzymes and the proton motive force

Uses and abuses of macropinocytosis

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