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Author Parks, Alexandre ♦ Marceau, François
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ABLATION ♦ ABUNDANCE ♦ ANTIMITOTIC DRUGS ♦ APOPTOSIS ♦ BIOLOGICAL MARKERS ♦ CELL CYCLE ♦ CHOLESTEROL ♦ COMPARTMENTS ♦ CONCENTRATION RATIO ♦ INHIBITION ♦ LYMPHOMAS ♦ OLIGOSACCHARIDES ♦ TOXICITY ♦ TUMOR CELLS
Abstract Cation trapping in acidic cell compartments determines an antiproliferative effect that has a potential interest in oncology, as shown by clinical data and trials involving chloroquine and hydroxychloroquine. To further characterize the mechanism of this effect, we studied a series of 6 substituted triethylamine (s-Et{sub 3}N) drugs that encompasses a wide range of liposolubility (amiodarone, quinacrine, chloroquine, hydroxychloroquine, lidocaine, and procainamide). Three tumor cell lines and primary human endothelial cells were exploited in proliferation assays (48 h, cell counts). Accumulation of the autophagic effector LC3 II and the apoptotic marker cleaved PARP1 (immunoblots), cytotoxicity, cell cycle analysis and endocytic function were further tested in the p53-null histiocytic lymphoma U937 line. A profound and desynchronized antiproliferative effect was observed in response to all s-Et{sub 3}Ns with essentially no cell type specificity. Predictors of s-Et{sub 3}N potency were liposolubility and the acute accumulation of the autophagic effector LC3 II (6 h-treatments). For each s-Et{sub 3}N, there was an antiproliferative concentration range where cytotoxicity and apoptosis were not triggered in U937 cells (24–48 h-treatments). Quinacrine was the most potent cytostatic drug (1–5 μM). Co-treatment of cells with inhibitors of cholesterol, β-cyclodextrin or lovastatin, partially reversed the antiproliferative effect of each s-Et{sub 3}N. The cytopathology induced by cationic drug accumulation includes a cytostatic effect. Its intensity is cell type- and p53-independent, but predicted by the inhibition of autophagic flux and by the liposolubility of individual drugs and alleviated by cholesterol ablation. The superiority of quinacrine, biomarker value of LC3 II and antagonism by a statin may be clinically relevant. - Highlights: • Cation trapping in acidic cell compartments induces a cytostatic effect. • A series of substituted triethylamines has been studied in 4 cell types. • Cytostatic potency is predicted by lipophilicity and autophagic flux inhibition. • β-Cyclodextrin or lovastatin co-treatment reverses the antiproliferative effect.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2016-08-15
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 305


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