{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T06:47:39Z","timestamp":1775198859097,"version":"3.50.1"},"reference-count":56,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Serbian Ministry of Science, Technological Development, and Innovations","award":["Agreement No. 451-03-137\/2025-03\/200111"],"award-info":[{"award-number":["Agreement No. 451-03-137\/2025-03\/200111"]}]},{"name":"Serbian Ministry of Science, Technological Development, and Innovations","award":["Agreement No. 451-03-136\/2025-03\/200111"],"award-info":[{"award-number":["Agreement No. 451-03-136\/2025-03\/200111"]}]},{"DOI":"10.13039\/501100010301","name":"Faculty of Medical Sciences University of Kragujevac","doi-asserted-by":"crossref","award":["Grant No: JP 16\/22"],"award-info":[{"award-number":["Grant No: JP 16\/22"]}],"id":[{"id":"10.13039\/501100010301","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Recent advances in enone chemistry have enabled the development of structurally optimized derivatives with improved anticancer selectivity. In this study, the cytotoxic activity and underlying mechanisms of sodium salts of four \u03b1,\u03b2-unsaturated enones (ES1\u2013ES4), synthesized from vanillin-based scaffolds, were evaluated in human colorectal carcinoma (HCT-116), cervical adenocarcinoma (HeLa), and normal lung fibroblast (MRC-5) cell lines. All compounds exhibited concentration- and time-dependent cytotoxicity, with ES2 showing the highest potency (IC50 = 14.25 \u03bcM in HCT-116 and 18.12 \u03bcM in HeLa at 72 h) and minimal toxicity toward MRC-5 cells (IC50 &gt; 90 \u03bcM). Although cisplatin demonstrated greater overall cytotoxicity, the enone salts displayed significantly higher selectivity indices, indicating a more favorable therapeutic window. Phase-contrast microscopy revealed characteristic morphological features of apoptosis, including cell rounding and membrane blebbing. Mechanistic investigations confirmed mitochondrial-mediated apoptosis, evidenced by increased early and late apoptotic populations, Bax upregulation, Bcl-2 downregulation, and caspase-3 activation. JC-10 staining demonstrated mitochondrial membrane depolarization accompanied by cytochrome c release. In addition, cell cycle analysis revealed pronounced G2\/M phase arrest, particularly in HCT-116 cells. Collectively, these findings indicate that vanillin-derived enone sodium salts exert selective anticancer effects through mitochondrial apoptosis and cell cycle disruption, supporting their potential as low-toxicity anticancer candidates.<\/jats:p>","DOI":"10.3390\/molecules31071141","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:41:53Z","timestamp":1774878113000},"page":"1141","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective Cytotoxicity of Sodium Enone Salts Through Mitochondrial Dysfunction and Cell Cycle Arrest in Human Cancer Cells"],"prefix":"10.3390","volume":"31","author":[{"given":"Nikola","family":"Mirkovi\u0107","sequence":"first","affiliation":[{"name":"Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"},{"name":"Department of Vascular Surgery, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Mitrovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirela","family":"Jevti\u0107","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, General Hospital U\u017eice, 31000 U\u017eice, Serbia"},{"name":"Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5806-7174","authenticated-orcid":false,"given":"Katarina","family":"Panti\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"},{"name":"Clinic for Pulmonology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petar","family":"\u010canovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivana","family":"Nikoli\u0107","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Jakovljevi\u0107","sequence":"additional","affiliation":[{"name":"Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"},{"name":"Department of General Surgery, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Kosti\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"},{"name":"Center for Research on Harmful Effects of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jelena","family":"\u017divi\u0107","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"},{"name":"Clinic for Gastroenterology and Hepatology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jelena","family":"Ne\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"},{"name":"Department of Endocrinology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nenad","family":"Zorni\u0107","sequence":"additional","affiliation":[{"name":"Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"},{"name":"Department of Anesthesiology and Reanimation, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stevan","family":"Eri\u0107","sequence":"additional","affiliation":[{"name":"Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"},{"name":"Department of Anesthesiology and Reanimation, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jovana","family":"Mu\u0161kinja","sequence":"additional","affiliation":[{"name":"Department of Science, Institute for Information Technologies, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3571-0091","authenticated-orcid":false,"given":"Marija","family":"\u0160orak","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"},{"name":"Department of Biomedically Assisted Fertilization, Clinic of Gynecology and Obstetrics, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marija","family":"An\u0111elkovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medical Sciences, University of 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