{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:18:38Z","timestamp":1785417518945,"version":"3.56.0"},"reference-count":69,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"publisher","award":["APVV-22-0383"],"award-info":[{"award-number":["APVV-22-0383"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]},{"award":["APVV-22-0383"],"award-info":[{"award-number":["APVV-22-0383"]}],"id":[{"id":"https:\/\/ror.org\/037nx0e70","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Grant Agency of the Ministry of Education of the Slovak Republic and the Slovak Academy of Sciences","award":["VEGA 2\/0030\/23"],"award-info":[{"award-number":["VEGA 2\/0030\/23"]}]},{"name":"Grant Agency of the Ministry of Education of the Slovak Republic and the Slovak Academy of Sciences","award":["VEGA 2\/0150\/26"],"award-info":[{"award-number":["VEGA 2\/0150\/26"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In medicinal chemistry, halogen substitution is often used to enhance the biological activity of anticancer compounds. Phenethyl isothiocyanate (PEITC), a natural compound found in cruciferous vegetables, exhibits anti-cancer activity by modulating oxidative stress and apoptosis-related pathways. This study compared the effects of PEITC and its chlorinated derivative, Cl-PEITC, on human leukemia cell lines, including multidrug-resistant (MDR) variants that overexpress P-glycoprotein (P-gp). We evaluated cell viability, apoptosis, reactive oxygen species (ROS) production, the modulation of the NRF2\/KEAP1 signaling pathway, NF-\u03baB p65 protein expression, DNA fragmentation, and autophagy in SKM-1, MOLM-13 and their MDR variants SKM\/VCR and MOLM\/VCR cells. Cl-PEITC exhibited stronger antiproliferative and cytotoxic effects than PEITC in all tested cell lines and maintained similar activity in P-gp-positive resistant cells. In contrast, resistant sublines showed reduced sensitivity to PEITC. Cl-PEITC induced higher ROS production and enhanced apoptosis, accompanied by the activation of caspases-3, -8, and -9 and PARP1 cleavage. It also caused more pronounced DNA fragmentation. Both PEITC and Cl-PEITC modulated autophagy-related markers, as demonstrated by increased LC3-II\/LC3-I conversion and decreased p62 protein levels. In addition, these compounds modulated NRF2\/KEAP1 and reduced NF-\u03baB p65 expression in a concentration-dependent manner. These findings suggest that the chlorination of PEITC enhances its antileukemic activity and could retain its efficacy against P-gp-associated MDR.<\/jats:p>","DOI":"10.3390\/ijms27135869","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:55:11Z","timestamp":1782780911000},"page":"5869","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chlorination of Phenethyl Isothiocyanate Potentiates Cytotoxicity and Apoptosis in Multidrug-Resistant Leukemia Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Alberto","family":"Yoldi Vergara","sequence":"first","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5561-7490","authenticated-orcid":false,"given":"Anna","family":"Bertova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szilvia","family":"Kontar","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0804-5126","authenticated-orcid":false,"given":"Martina","family":"Ksinanova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4318-1080","authenticated-orcid":false,"given":"Kristina","family":"Simonicova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6497-1899","authenticated-orcid":false,"given":"Martin","family":"Simkovic","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinsk\u00e9ho 9, 812 37 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7603-4491","authenticated-orcid":false,"given":"Zdena","family":"Sulova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2174-786X","authenticated-orcid":false,"given":"Albert","family":"Breier","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 841 04 Bratislava, Slovakia"},{"name":"Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinsk\u00e9ho 9, 812 37 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8681-7796","authenticated-orcid":false,"given":"Denisa","family":"Imrichova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 841 04 Bratislava, Slovakia"},{"name":"Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinsk\u00e9ho 9, 812 37 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/d41573-026-00001-z","article-title":"2025 FDA Approvals","volume":"25","author":"Mullard","year":"2026","journal-title":"Nat. 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