{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:10:22Z","timestamp":1789992622381,"version":"4.0.1"},"reference-count":75,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Drug repurposing provides an opportunity to identify anticancer activities among established pharmacological agents. Labetalol (LB), an \u03b11- and non-selective \u03b2-adrenergic receptor antagonist, has been insufficiently investigated in melanoma. This study evaluated the potential anti-melanoma activity of LB in A375 human melanoma cells, compared its effects with those observed in HaCaT immortalized non-tumoral keratinocytes, and investigated the cellular mechanisms associated with LB-induced cytotoxicity. Materials and Methods: A375 and HaCaT cells were exposed to 75\u2013500 \u03bcM LB for 24 h. Cell viability and lysosomal dye retention were assessed using MTT and NRU assays. A DMSO-only concentration series (0.075\u20130.50% v\/v) was additionally evaluated by MTT in both cell lines. Mitochondrial membrane potential, mitochondrial staining patterns, nuclear morphology, cytoskeletal organization, caspase-3\/7 and caspase-9 activities, and plasma membrane integrity were evaluated using JC-1, MitoTracker Red CMXRos, immunofluorescence, luminescence-based caspase assays, and AO\/PI staining. The acute irritation potential of 500 \u03bcM LB was assessed using the HET-CAM assay. Results: DMSO alone did not significantly reduce viability over the investigated concentration range in either cell line. LB reduced A375 cell viability in a concentration-dependent manner, with a 24 h IC50 of 422.5 \u03bcM and a viability of 33.61% at 500 \u03bcM. Under the same experimental conditions, HaCaT viability remained at 89.01% at 500 \u03bcM, and an IC50 was not reached within the investigated concentration range. At the highest concentration, neutral red uptake and the JC-1 aggregate\/monomer ratio decreased to approximately 33% and 24% of the corresponding control values, respectively. The apoptotic index increased from approximately 3% in control cells to 31%, while caspase-3\/7 and caspase-9 activities increased to approximately 482% and 324% of the control. Qualitative imaging demonstrated mitochondrial staining redistribution, cytoskeletal disorganization, apoptosis-associated morphology, and loss of plasma membrane integrity at higher concentrations. In the HET-CAM assay, 500 \u03bcM LB produced a mean irritation score of 0.71 \u00b1 0.27, within the non-irritant range. Conclusions: LB displayed concentration-dependent in vitro cytotoxicity in A375 melanoma cells, whereas HaCaT keratinocytes showed limited changes under the investigated conditions. LB treatment was also associated with mitochondria-associated apoptotic signaling in A375 cells. These findings provide preliminary evidence supporting further investigation of LB within a melanoma-directed drug-repurposing strategy. Additional studies are required to establish receptor dependence, achievable local exposure, safety, and translational relevance.<\/jats:p>","DOI":"10.3390\/medicina62091802","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:25:43Z","timestamp":1789986343000},"page":"1802","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical Evaluation of Labetalol for Cutaneous Melanoma Drug Repurposing: Cytotoxic Activity in A375 Cells and Mitochondria-Associated Apoptotic Signaling"],"prefix":"10.3390","volume":"62","author":[{"given":"Richard","family":"Dahma","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Faculty of Medicine, Doctoral School, Victor Babe\u0219 University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timi\u015foara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2631-7028","authenticated-orcid":false,"given":"Elena-Alina","family":"Moac\u0103","sequence":"additional","affiliation":[{"name":"University Clinic of Toxicology, Drug Industry, Management, Marketing and Dermatopharmacy, Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Faculty of Pharmacy, Victor Babe\u0219 University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Iasmina-Alexandra","family":"Predescu","sequence":"additional","affiliation":[{"name":"University Clinic of Toxicology, Drug Industry, Management, Marketing and Dermatopharmacy, Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Faculty of Pharmacy, Victor Babe\u0219 University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Ana-Cristiane","family":"Dragomir","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Faculty of Medicine, Doctoral School, Victor Babe\u0219 University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timi\u015foara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Oana-Andrada","family":"Iftode","sequence":"additional","affiliation":[{"name":"University Clinic of Toxicology, Drug Industry, Management, Marketing and Dermatopharmacy, Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Faculty of Pharmacy, Victor Babe\u0219 University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3536-6099","authenticated-orcid":false,"given":"Stela","family":"Iurciuc","sequence":"additional","affiliation":[{"name":"Emergency City Hospital Timisoara, Gheorghe Dima Street Nr. 5, 300254 Timisoara, Romania"},{"name":"Department of Cardiology, Victor Babe\u015f University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Diana","family":"Haj Ali","sequence":"additional","affiliation":[{"name":"University Clinic of Toxicology, Drug Industry, Management, Marketing and Dermatopharmacy, Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Faculty of Pharmacy, Victor Babe\u0219 University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9890-2277","authenticated-orcid":false,"given":"Ioana","family":"Maca\u015foi","sequence":"additional","affiliation":[{"name":"University Clinic of Toxicology, Drug Industry, Management, Marketing and Dermatopharmacy, Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Faculty of Pharmacy, Victor Babe\u0219 University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Maria","family":"Sala-C\u00eertog","sequence":"additional","affiliation":[{"name":"Discipline of Biochemistry, Department of Biochemistry and Pharmacology, Faculty of Medicine, Victor Babe\u0219 University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iulia-Najette","family":"Crintea","sequence":"additional","affiliation":[{"name":"Emergency Clinical Municipal Hospital Timisoara, Blvd. Regele Mihai I, No. 5, 300079 Timi\u015foara, Romania"},{"name":"University Clinic of Emergency, Department of Surgery I, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Alina-Doina","family":"T\u0103nase","sequence":"additional","affiliation":[{"name":"Discipline of Professional Legislation in Dentistry, Faculty of Dental Medicine, Victor Babes University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timi\u015foara, Romania"},{"name":"Methodological and Research Center Medical Law, Medical Malpractice and Research Ethics, Victor Babe\u0219 University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilena","family":"Dinu\u0163i","sequence":"additional","affiliation":[{"name":"Discipline of Biochemistry, Department of Biochemistry and Pharmacology, Faculty of Medicine, Victor Babe\u0219 University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"\u021a\u0103poi, D.A., Derewicz, D., Gheorghi\u0219an-G\u0103l\u0103\u021beanu, A.-A., Dumitru, A.V., Ciongariu, A.M., and Costache, M. 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