Biological Activities of Cyclic and Acyclic B-Type Laxaphycins in SH-SY5Y Human Neuroblastoma Cells
Identificadores
Identificadores
URI: http://hdl.handle.net/20.500.11940/16587
PMID: 32679743
DOI: 10.3390/md18070364
ISSN: 1660-3397
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Fecha de publicación
2020Título de revista
Marine Drugs
Tipo de contenido
Journal Article
DeCS
autofagia | apoptosis | concentración inhibidora 50 | TOR serina-treonina cinasas | fosforilación | antineoplásicos | mitocondrias | proteina cinasas activadas por AMP | línea celular | humanos | péptidos | relación estructura-actividad | neuroblastoma | conformación de proteínasMeSH
Apoptosis | Peptides | Antineoplastic Agents | Protein Conformation | Mitochondria | Autophagy | TOR Serine-Threonine Kinases | Cell Line | Humans | Structure-Activity Relationship | Phosphorylation | AMP-Activated Protein Kinases | Neuroblastoma | Inhibitory Concentration 50Resumen
Laxaphycins are a family of non-ribosomal lipopeptides that have been isolated from several cyanobacteria. Some of these compounds have presented cytotoxic activities, but their mechanism of action is poorly understood. In this work, the already described laxaphycins B and B3, and acyclolaxaphycins B and B3 were isolated from the marine cyanobacteria Anabaena torulosa. Moreover, two new acyclic compounds, [des-(Ala(4)-Hle(5))] acyclolaxaphycins B and B3, were purified from the herviborous gastropod Stylocheilus striatus, with this being the first description of biotransformed laxaphycins. The structure of these new compounds was elucidated, together with the absolute configuration of acyclolaxaphycins B and B3. The bioactivities of the six peptides were determined in SH-SY5Y human neuroblastoma cells. Laxaphycins B and B3 were cytotoxic (IC50: 1.8 and 0.8 microM, respectively) through the induction of apoptosis. In comparison, acyclic laxaphycins did not show cytotoxicity but affected mitochondrial functioning, so their effect on autophagy-related protein expression was analyzed, finding that acyclic peptides affected this process by increasing AMPK phosphorylation and inhibiting mTOR. This work confirms the pro-apoptotic properties of cyclic laxaphycins B and is the first report indicating the effects on autophagy of their acyclic analogs. Moreover, gastropod-derived compounds presented ring opening and amino-acids deletion, a biotransformation that had not been previously described.