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Portoamides A and B are mitochondrial toxins and induce cytotoxicity on the proliferative cell layer of in vitro microtumours
Interdisciplinary Ctr Marine and Environm Res, Portugal; Univ Porto, Portugal.
Interdisciplinary Ctr Marine and Environm Res, Portugal; Univ Porto, Portugal.
Interdisciplinary Ctr Marine and Environm Res, Portugal; Univ Porto, Portugal.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.ORCID iD: 0000-0002-4952-445X
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2020 (English)In: Toxicon, ISSN 0041-0101, E-ISSN 1879-3150, Vol. 175, p. 49-56Article in journal (Refereed) Published
Abstract [en]

Cyanobacteria are known to produce many toxins and other secondary metabolites. The study of their specific mode of action may reveal the biotechnological potential of such compounds. Portoamides A and B (PAB) are cyclic peptides isolated from the cyanobacteria Phormidium sp. due to their growth repression effect on microalgae and were shown to be cytotoxic against certain cancer cell lines. In the present work, viability was assessed on HCT116 colon cancer cells grown as monolayer culture and as multicellular spheroids (MTS), non-carcinogenic cells and on zebrafish larvae. HCT116 cells and epithelial RPE-1(hTERT) cells showed very similar degrees of sensitivities to PAB. PAB were able to penetrate the MTS, showing a four-fold high IC50 compared to monolayer cultures. The toxicity of PAB was similar at 4 degrees C and 37 degrees C suggesting energy-independent uptake. PAB exposure decreased ATP production, mitochondrial maximal respiration rates and induced mitochondrial membrane hyperpolarization. PAB induced general organelle stress response, indicated by an increase of the mitochondrial damage sensor PINK-1, and of phosphorylation of eIF2 alpha, characteristic for endoplasmic reticulum stress. In summary, these findings show general toxicity of PAB on immortalized cells, cancer cells and zebrafish embryos, likely due to mitochondrial toxicity.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD , 2020. Vol. 175, p. 49-56
Keywords [en]
Cyanobacteria; Natural compounds; Mitochondria; Spheroid
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:liu:diva-164684DOI: 10.1016/j.toxicon.2019.12.159ISI: 000517854100007PubMedID: 31887317OAI: oai:DiVA.org:liu-164684DiVA, id: diva2:1417547
Note

Funding Agencies|project CYANCAN - Uncovering the cyanobacterial chemical diversity: the search for novel anticancer compounds [PTDC/MEDQUI/30944/2017]; NORTE 2020; Portugal 2020; European Union through the ERDFEuropean Union (EU); Foundation for Science and Technology [UID/Multi/04423/2019]; FCTPortuguese Foundation for Science and Technology [SFRH/BPD/112287/2015, SFRH/BD/108314/2015]; CancerfondenSwedish Cancer Society; VetenskapsradetSwedish Research Council; Radiumhemmets forskningsfonder; Knut och Alice Wallenbergs stiftelseKnut & Alice Wallenberg Foundation; [SFRH/BD/139131/2018]

Available from: 2020-03-29 Created: 2020-03-29 Last updated: 2020-03-29

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