{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:57:52Z","timestamp":1790949472116,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Oral squamous cell carcinoma (OSCC) remains a major global health burden despite advances in surgery, radiotherapy, and chemotherapy. The development of novel therapeutic agents with improved efficacy and reduced toxicity is therefore urgently needed. This study investigated the anticancer potential of Viroelixir, a natural formulation derived from green tea and pomegranate extracts and explored its underlying molecular mechanisms in oral cancer cells. Human gingival squamous cell carcinoma cells (Ca9-22), tongue squamous cell carcinoma cells (CAL-27 and SCC-9), and non-tumorigenic oral epithelial cells (GMSM-K) were exposed to serial dilutions of Viroelixir. Cell viability, membrane damage, clonogenic survival, apoptosis, autophagy, redox status, migration, protein expression, and responses to cisplatin or 5-fluorouracil (5-FU) were assessed using MTT and LDH assays, crystal-violet staining, flow cytometry, and wound-healing assays. Viroelixir preferentially reduced Ca9-22 viability and clonogenic survival while having limited effects on GMSM-K, CAL-27, and SCC-9SCC-9 viability over 24 h of Viroelixir exposure. In Ca9-22 cells, Viroelixir increased p21, p27, and p53 and reduced Cyclin D1, a profile consistent with inhibition of G1\/S progression. It promoted mitochondrial apoptosis, reduced autophagy-associated signals and LC3B expression, increased intracellular ROS and mitochondrial superoxide, depleted glutathione, and reduced wound closure while increasing E-cadherin and reducing fibronectin. Viroelixir also reduced phosphorylation of p38, ERK1\/2, STAT3, NF-kappaB, and AKT1. In addition, Viroelixir enhanced the antiproliferative effects of cisplatin and 5-fluorouracil. Viroelixir exhibits a pronounced cell-line-specific anticancer response, with Ca9-22 gingival carcinoma cells displaying substantially greater sensitivity than the other oral cell models tested. This response is associated with coordinated changes in cell-cycle regulatory proteins, mitochondrial apoptosis, autophagy-associated signals, redox homeostasis, and oncogenic signaling. Viroelixir also enhances the antiproliferative effects of cisplatin and 5-FU, supporting further investigation of this formulation in OSCC. These findings support its potential development as a novel adjuvant therapeutic agent for gingival squamous cell carcinoma management.<\/jats:p>","DOI":"10.3390\/ijms27198825","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:39:34Z","timestamp":1790948374000},"page":"8825","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Viroelixir Exhibits Cell-Line-Specific Anticancer Activity and Enhances Chemosensitivity in Oral Squamous Cell Carcinoma: Associated Changes in Apoptosis, Redox Homeostasis, and Oncogenic Signaling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2747-0626","authenticated-orcid":false,"given":"Manal","family":"Dahdah","sequence":"first","affiliation":[{"name":"GREB Research Group, Faculty of Dentistry, Laval University, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2205-8281","authenticated-orcid":false,"given":"Mahmoud","family":"Rouabhia","sequence":"additional","affiliation":[{"name":"GREB Research Group, Faculty of Dentistry, Laval University, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0716-8215","authenticated-orcid":false,"given":"Hawraa","family":"Issa","sequence":"additional","affiliation":[{"name":"DREAM-CV Lab, Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4744-5387","authenticated-orcid":false,"given":"Lionel","family":"Loubaki","sequence":"additional","affiliation":[{"name":"H\u00e9ma-Qu\u00e9bec, 1070 Avenue des Sciences-de-la-Vie, Qu\u00e9bec, QC G1V 5C3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Latifa","family":"Koussih","sequence":"additional","affiliation":[{"name":"D\u00e9partement des Sciences Exp\u00e9rimentales, Universit\u00e9 de Saint-Boniface, Winnipeg, MB R2H 3B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"given":"Mikhlid H.","family":"Almutairi","sequence":"additional","affiliation":[{"name":"Zoology Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1643-0377","authenticated-orcid":false,"given":"Abdelhabib","family":"Semlali","sequence":"additional","affiliation":[{"name":"GREB Research Group, Faculty of Dentistry, Laval University, Qu\u00e9bec, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.oraloncology.2008.06.002","article-title":"Global epidemiology of oral and oropharyngeal cancer","volume":"45","author":"Warnakulasuriya","year":"2009","journal-title":"Oral. 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