{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T23:11:28Z","timestamp":1776813088345,"version":"3.51.2"},"reference-count":86,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T00:00:00Z","timestamp":1694995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cyprus Institute of Neurology and Genetics (Telethon-Cyprus), Nicosia, Cyprus (MIP)","award":["HFRI-FM17C3-2007"],"award-info":[{"award-number":["HFRI-FM17C3-2007"]}]},{"name":"Hellenic Foundation for Research and Innovation (H.F.R.I.)","award":["HFRI-FM17C3-2007"],"award-info":[{"award-number":["HFRI-FM17C3-2007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The aim of the current study was to (i) extract isolated fractions of watercress flowers enriched in polyphenols, phenethyl isothiocyanate and glucosinolates and (ii) characterize the anticancer mode of action of non-lethal, sub-lethal and lethal concentrations of the most potent extract fraction in primary (A375) and metastatic (COLO-679) melanoma cells as well as non-tumorigenic immortalized keratinocyte (HaCaT) cells. Cytotoxicity was assessed via the Alamar Blue assay, whereas ultrastructural alterations in mitochondria and the endoplasmic reticulum were determined via transmission electron microscopy. Mitochondrial membrane depolarization was determined using Mito-MP dye, whereas apoptosis was evaluated through the activation of caspases-3, -8 and -9. Among all extract fractions, the phenethyl isothiocyanate-enriched one (PhEF) possessed significant cytotoxicity against A375 and COLO-679 cells, while HaCaT cells remained relatively resistant at sub-lethal and lethal concentrations. Additionally, ultrastructural subcellular alterations associated with apoptosis were observed by means of increased mitochondrial area and perimeter, decreased cristae density and a shorter distance of the endoplasmic reticulum to the mitochondria, all taking place during \u201cearly\u201d time points (2\u20134 h) of exposure. Moreover, PhEF induced mitochondrial membrane depolarization associated with \u201clate\u201d time points (24 h) of exposure, thereby leading to the activation of intrinsic apoptosis. Finally, the inhibition of cytosolic Ca2+ efflux reduced levels of caspases-9 and -3 activity, suggesting the involvement of Ca2+ efflux in modulating the activation of intrinsic apoptosis. To conclude, our data demonstrate an association of \u201cearly\u201d ultrastructural alterations in mitochondria and the endoplasmic reticulum with the \u201clate\u201d induction of intrinsic apoptosis via the modulation of Ca2+ efflux.<\/jats:p>","DOI":"10.3390\/nu15184044","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T02:47:52Z","timestamp":1695091672000},"page":"4044","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A Naturally Derived Watercress Flower-Based Phenethyl Isothiocyanate-Enriched Extract Induces the Activation of Intrinsic Apoptosis via Subcellular Ultrastructural and Ca2+ Efflux Alterations in an In Vitro Model of Human Malignant Melanoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6195-6570","authenticated-orcid":false,"given":"Sotiris","family":"Kyriakou","sequence":"first","affiliation":[{"name":"Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4972-6932","authenticated-orcid":false,"given":"Louiza","family":"Potamiti","sequence":"additional","affiliation":[{"name":"Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8680-4044","authenticated-orcid":false,"given":"Nikoletta","family":"Demosthenous","sequence":"additional","affiliation":[{"name":"Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Amery","sequence":"additional","affiliation":[{"name":"The Watercress Company, Dorchester DT2 8QY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3355-9639","authenticated-orcid":false,"given":"Kyle","family":"Stewart","sequence":"additional","affiliation":[{"name":"Watercress Research Limited, Exeter EX5 2GE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul G.","family":"Winyard","sequence":"additional","affiliation":[{"name":"Watercress Research Limited, Exeter EX5 2GE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3241-8615","authenticated-orcid":false,"given":"Rodrigo","family":"Franco","sequence":"additional","affiliation":[{"name":"Redox Biology Centre, University of Nebraska, Lincoln, NE 68583, USA"},{"name":"Department of Veterinary Medicine & Biomedical Sciences, University of Nebraska, Lincoln, NE 68583, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0913-4315","authenticated-orcid":false,"given":"Aglaia","family":"Pappa","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1450-3552","authenticated-orcid":false,"given":"Mihalis I.","family":"Panayiotidis","sequence":"additional","affiliation":[{"name":"Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1207\/S15327914NC421_1","article-title":"Brassica Vegetables and Prostate Cancer Risk: A Review of the Epidemiological Evidence","volume":"42","author":"Kristal","year":"2002","journal-title":"Nutr. 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