The cyanobacterial cyclic lipopeptides puwainaphycins F/G are inducing necrosis via cell membrane permeabilization and subsequent unusual actin relocalization
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
22551534
DOI
10.1021/tx300044t
Knihovny.cz E-resources
- MeSH
- Actins chemistry metabolism MeSH
- Cell Death drug effects MeSH
- HeLa Cells MeSH
- Humans MeSH
- Lipopeptides chemistry isolation & purification pharmacology MeSH
- Actin Cytoskeleton drug effects metabolism MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Membrane Permeability drug effects MeSH
- Antineoplastic Agents chemistry isolation & purification pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Cyanobacteria chemistry MeSH
- Calcium metabolism MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Actins MeSH
- Lipopeptides MeSH
- Antineoplastic Agents MeSH
- puwainaphycin F MeSH Browser
- puwainaphycin G MeSH Browser
- Calcium MeSH
Puwainaphycins F and G, moderate cytotoxins, which cause necrotic cell death to mammalian cells, were isolated from the soil cyanobacterium Cylindrospermum alatosporum C24/89. Both compounds have been shown to be cyclic decapeptides containing unusual β-amino fatty acid (2-hydroxy-3-amino-4methyl tetradecanoic acid). Described variants differ in the substitution of threonine by glutamine in the fourth position. Their structures differ from the known puwainaphycins in five amino acids positions as well as in the β-amino fatty acid unit. The rapid interaction of these compounds with the plasma membrane of the mammal cell leads to an elevation of the concentration of intracellular Ca(2+), with kinetics comparable to the well-established calcium ionophore ionomycin. Subsequently, the induction of tyrosine phosphorylation was observed to be followed by the unique transformation of the actin cytoskeleton into ring structures around the nuclei. All of these alterations in the cellular morphology and physiology result in necrotic cell death after ca. 10 h. The IC(50) values were determined to be 2.2 μM for both puwainaphycins. The present data demonstrate the interaction of cyanobacterial secondary metabolites with eukaryotic plasma membrane and point out the possible toxic effects of cyanobacterial lipopeptides for humans.
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