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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Selective Cytotoxicity of Sodium Enone Salts Through Mitochondrial Dysfunction and Cell Cycle Arrest in Human Cancer Cells

by
Nikola Mirković
1,2,†,
Marina Mitrović
3,†,
Mirela Jevtić
4,5,
Katarina Pantić
5,6,*,
Petar Čanović
3,
Ivana Nikolić
3,*,
Stefan Jakovljević
1,7,
Marina Kostić
8,9,
Jelena Živić
10,11,
Jelena Nešić
10,12,
Nenad Zornić
1,13,
Stevan Erić
1,13,
Jovana Muškinja
14,
Marija Šorak
15,16 and
Marija Anđelković
3
1
Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
2
Department of Vascular Surgery, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
3
Department of Biochemistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
4
Department of Gynecology and Obstetrics, General Hospital Užice, 31000 Užice, Serbia
5
Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
6
Clinic for Pulmonology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
7
Department of General Surgery, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
8
Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
9
Center for Research on Harmful Effects of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
10
Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
11
Clinic for Gastroenterology and Hepatology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
12
Department of Endocrinology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
13
Department of Anesthesiology and Reanimation, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
14
Department of Science, Institute for Information Technologies, University of Kragujevac, 34000 Kragujevac, Serbia
15
Department of Gynecology and Obstetrics, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
16
Department of Biomedically Assisted Fertilization, Clinic of Gynecology and Obstetrics, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
 
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*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2026, 31(7), 1141; https://doi.org/10.3390/molecules31071141
Submission received: 1 February 2026 / Revised: 12 March 2026 / Accepted: 17 March 2026 / Published: 30 March 2026
(This article belongs to the Section Medicinal Chemistry)
Versions Notes

Abstract

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 α,β-unsaturated enones (ES1–ES4), 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 μM in HCT-116 and 18.12 μM in HeLa at 72 h) and minimal toxicity toward MRC-5 cells (IC50 > 90 μM). 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.
Keywords: enone salts; mitochondrial apoptosis; HCT-116; HeLa; vanillin derivatives enone salts; mitochondrial apoptosis; HCT-116; HeLa; vanillin derivatives

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MDPI and ACS Style

Mirković, N.; Mitrović, M.; Jevtić, M.; Pantić, K.; Čanović, P.; Nikolić, I.; Jakovljević, S.; Kostić, M.; Živić, J.; Nešić, J.; et al. Selective Cytotoxicity of Sodium Enone Salts Through Mitochondrial Dysfunction and Cell Cycle Arrest in Human Cancer Cells. Molecules 2026, 31, 1141. https://doi.org/10.3390/molecules31071141

AMA Style

Mirković N, Mitrović M, Jevtić M, Pantić K, Čanović P, Nikolić I, Jakovljević S, Kostić M, Živić J, Nešić J, et al. Selective Cytotoxicity of Sodium Enone Salts Through Mitochondrial Dysfunction and Cell Cycle Arrest in Human Cancer Cells. Molecules. 2026; 31(7):1141. https://doi.org/10.3390/molecules31071141

Chicago/Turabian Style

Mirković, Nikola, Marina Mitrović, Mirela Jevtić, Katarina Pantić, Petar Čanović, Ivana Nikolić, Stefan Jakovljević, Marina Kostić, Jelena Živić, Jelena Nešić, and et al. 2026. "Selective Cytotoxicity of Sodium Enone Salts Through Mitochondrial Dysfunction and Cell Cycle Arrest in Human Cancer Cells" Molecules 31, no. 7: 1141. https://doi.org/10.3390/molecules31071141

APA Style

Mirković, N., Mitrović, M., Jevtić, M., Pantić, K., Čanović, P., Nikolić, I., Jakovljević, S., Kostić, M., Živić, J., Nešić, J., Zornić, N., Erić, S., Muškinja, J., Šorak, M., & Anđelković, M. (2026). Selective Cytotoxicity of Sodium Enone Salts Through Mitochondrial Dysfunction and Cell Cycle Arrest in Human Cancer Cells. Molecules, 31(7), 1141. https://doi.org/10.3390/molecules31071141

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