Biological Effects of a Simplified Synthetic Analogue of Ion-Channel-Forming Polytheonamide B on Plasma Membrane and Lysosomes
| Autor: | Masayuki Inoue, Yun-Wei Xue, Hiroaki Itoh, Atsushi Hayata |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Peptide
Apoptosis 010402 general chemistry 01 natural sciences Catalysis Neutralization Membrane Potentials Humans Cytotoxicity Cellular localization Ion channel Fluorescent Dyes chemistry.chemical_classification 010405 organic chemistry Chemistry Organic Chemistry Cell Membrane Intracellular Signaling Peptides and Proteins Depolarization General Chemistry Hydrogen-Ion Concentration 0104 chemical sciences Membrane Spectrometry Fluorescence Biophysics MCF-7 Cells Lysosomes Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Chemistry (Weinheim an der Bergstrasse, Germany). 25(66) |
| ISSN: | 1521-3765 |
| Popis: | Polytheonamide B (1) is a linear 48-mer natural peptide with alternating d- and l-amino acid residues. Compound 1 forms conducting channels for monovalent ions and exhibits potent cytotoxicity against MCF-7 cells. Previously, we reported that nanomolar concentrations of 1 induce plasma membrane depolarization and lysosomal pH disruption, which triggers apoptosis. Here, we report the cellular localization and biological action of a simplified synthetic analogue of 1, polytheonamide mimic 3. Compared with 1, the toxicity of 3 against MCF-7 cells is 16 times weaker. Although its plasma membrane depolarization effect is only 3.6 times lower, more 3 (20-fold) is required to neutralize lysosomal pH. Thus, the effective concentrations for lysosomal neutralization and cytotoxicity by 3 are comparable. These results strongly suggest that the activity of 3 against the lysosomal membrane is more important for apoptotic cell death than its effects on the plasma membrane, and provide valuable information regarding the unique behavior of polytheonamide-based molecules. |
| Databáze: | OpenAIRE |
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