Biological Effects of a Simplified Synthetic Analogue of Ion-Channel-Forming Polytheonamide?B on Plasma Membrane and Lysosomes |
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Authors: | Yun-Wei Xue Dr Atsushi Hayata Dr Hiroaki Itoh Prof?Dr Masayuki Inoue |
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Institution: | Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan |
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Abstract: | 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. |
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Keywords: | cytotoxic agents ion channels mechanisms of action natural products peptides |
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