Abstract
Vacuolar-H(+)-ATPase plays a critical role in the cellular balance of protons, thus regulating intracellular pH and contributing to apoptosis resistance, drug resistance, and invasive and metastatic behavior of cells. NiK-12192, a vacuolar-H(+)-ATPase inhibitor, caused a reduction in the volume and/or acidity of lysosomes, a polarization of alphavbeta5 integrin distribution, and a number of floating live cells, whereas signs of apoptosis appeared only after 72 h of treatment. In conclusion, NiK-12192, by affecting vacuolar- H(+)-ATPase activity (and intracellular pH), causes a modification of structures crucial for cell adhesion and induces cell death, likely by a modality involving an anoikis-mediated apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Autophagy / drug effects
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Benzamides / pharmacology*
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Cell Adhesion / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Colonic Neoplasms / ultrastructure
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Dose-Response Relationship, Drug
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Flow Cytometry
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HCT116 Cells
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HL-60 Cells
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HT29 Cells
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Humans
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Hydrogen-Ion Concentration / drug effects
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Indoles / pharmacology*
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Inhibitory Concentration 50
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Lysosomes / chemistry
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Lysosomes / drug effects*
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Lysosomes / metabolism
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Membrane Potential, Mitochondrial / drug effects
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Microscopy, Confocal
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Microscopy, Electron
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Phagosomes / drug effects
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Phagosomes / metabolism
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Phagosomes / ultrastructure
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Receptors, Vitronectin / metabolism
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Vacuolar Proton-Translocating ATPases / antagonists & inhibitors*
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Vacuolar Proton-Translocating ATPases / metabolism
Substances
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4-(5,6-dichloro-1H-indol-2-yl)-3-ethoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzamide
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Benzamides
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Indoles
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Receptors, Vitronectin
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integrin alphaVbeta5
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Vacuolar Proton-Translocating ATPases