{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T07:47:34Z","timestamp":1782200854282,"version":"3.54.5"},"reference-count":28,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Quebec Network for Intersectoral Research in Sustainable Oral and Bone Health"},{"name":"Emile Beaulieu foundation-Universit\u00e9 Laval"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>This study aimed to investigate the selective anticancer activity of the curcumin analog PAC (3,5-Bis-4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone). Normal gingival epithelial cells (GECs), cancerous gingival cells (Ca9-22) and tongue squamous carcinoma cells (CAL27) were exposed to increasing concentrations of PAC (0\u201310 \u00b5M) for 24 h. Cell viability and cytotoxicity were evaluated using MTT and LDH assays, while apoptosis and caspase activation were analyzed by Annexin V\/PI staining and flow cytometry. Gene-expression profiling was performed using RT2 Profiler PCR arrays. PAC significantly inhibited Ca9-22 and CAL27 cell proliferation in a concentration-dependent manner, with an IC50 value of 5 \u00b5M, while exerting no noticeable cytotoxic effects on normal GEC. PAC treatment induced significant early and late apoptosis associated with increased caspase activity in both oral cancer cell lines. Transcriptomic analyses revealed extensive modulation of apoptosis-related genes. In Ca9-22 cells, PAC predominantly suppressed anti-apoptotic and survival-associated genes, including BCL2, BIRC3, BIRC5, XIAP, CFLAR, and NFKB1. In contrast, CAL27 cells exhibited a more pronounced pro-apoptotic transcriptional profile characterized by upregulation of TP53, APAF1, CASP1, BID, and TNF. Gene interaction network analyses further demonstrated that PAC targets highly interconnected apoptotic signaling pathways. Collectively, these findings demonstrate that PAC exerts potent selective anticancer activity against OSCC cells through modulation of intrinsic and extrinsic apoptotic pathways. These results further support the therapeutic potential of PAC as a promising multitarget candidate for oral cancer treatment.<\/jats:p>","DOI":"10.3390\/life16071041","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:13:37Z","timestamp":1782195217000},"page":"1041","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Curcumin Analogue PAC Induces Selective Apoptosis-Related Transcriptomic Reprogramming in Oral Squamous Carcinoma Cells"],"prefix":"10.3390","volume":"16","author":[{"given":"Sara","family":"Benchekroun","sequence":"first","affiliation":[{"name":"Groupe de Recherche en \u00c9cologie Buccale, Facult\u00e9 de M\u00e9decine Dentaire, Universit\u00e9 Laval, Quebec, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meriem","family":"Hammache","sequence":"additional","affiliation":[{"name":"Groupe de Recherche en \u00c9cologie Buccale, Facult\u00e9 de M\u00e9decine Dentaire, Universit\u00e9 Laval, Quebec, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4415-0751","authenticated-orcid":false,"given":"Fatiha","family":"Chandad","sequence":"additional","affiliation":[{"name":"Groupe de Recherche en \u00c9cologie Buccale, Facult\u00e9 de M\u00e9decine Dentaire, Universit\u00e9 Laval, Quebec, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0337-6412","authenticated-orcid":false,"given":"Mikhlid H.","family":"Almutairi","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6942-0519","authenticated-orcid":false,"given":"Adam","family":"Daich","sequence":"additional","affiliation":[{"name":"URCOM UR 3221, Universit\u00e9 Le Havre Normandie, Normandie Universit\u00e9, 76600 Le Havre, France"},{"name":"2INC3M, FR, CNRS 3038, 25 Rue Philippe Lebon, BP 1123, 76063 Le Havre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8101-0531","authenticated-orcid":false,"given":"Mohammed","family":"Badwelan","sequence":"additional","affiliation":[{"name":"Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2205-8281","authenticated-orcid":false,"given":"Mahmoud","family":"Rouabhia","sequence":"additional","affiliation":[{"name":"Groupe de Recherche en \u00c9cologie Buccale, Facult\u00e9 de M\u00e9decine Dentaire, Universit\u00e9 Laval, Quebec, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5797-8304","authenticated-orcid":false,"given":"Abdelhabib","family":"Semlali","sequence":"additional","affiliation":[{"name":"Groupe de Recherche en \u00c9cologie Buccale, Facult\u00e9 de M\u00e9decine Dentaire, Universit\u00e9 Laval, Quebec, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1615\/CritRevOncog.2023046835","article-title":"Conventional Therapies of Oral Cancers: Highlights on Chemotherapeutic Agents and Radiotherapy, Their Adverse Effects, and the Cost Burden of Conventional Therapies","volume":"28","author":"Shah","year":"2023","journal-title":"Crit. Rev. Oncog."},{"key":"ref_2","first-page":"11884","article-title":"Essentials of oral cancer","volume":"8","author":"Rivera","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100988","DOI":"10.1016\/j.disamonth.2020.100988","article-title":"Epidemiologic aspects of oral cancer","volume":"66","author":"Sarode","year":"2020","journal-title":"Dis. Mon."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1002\/ijc.32871","article-title":"Global trends in oral and pharyngeal cancer incidence and mortality","volume":"147","author":"Bosetti","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41368-023-00249-w","article-title":"Oral squamous cell carcinomas: State of the field and emerging directions","volume":"15","author":"Tan","year":"2023","journal-title":"Int. J. Oral Sci."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Nair, S., Bonner, J.A., and Bredel, M. (2022). EGFR Mutations in Head and Neck Squamous Cell Carcinoma. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073818"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"397","DOI":"10.4103\/jomfp.JOMFP_164_20","article-title":"Cyclin D1 in oral premalignant lesions and oral squamous cell carcinoma: An immunohistochemical study","volume":"24","author":"Moharil","year":"2020","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Usman, S., Jamal, A., Teh, M.T., and Waseem, A. (2020). Major Molecular Signaling Pathways in Oral Cancer Associated With Therapeutic Resistance. Front. Oral Health, 1.","DOI":"10.3389\/froh.2020.603160"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s40463-022-00556-y","article-title":"Hereditary oral squamous cell carcinoma associated with CDKN2A germline mutation: A case report","volume":"51","author":"Jeong","year":"2022","journal-title":"J. Otolaryngol. Head. Neck Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/modpathol.3800948","article-title":"H-Ras mutation modulates the expression of major cell cycle regulatory proteins and disease prognosis in oral carcinoma","volume":"20","author":"Sathyan","year":"2007","journal-title":"Mod. Pathol."},{"key":"ref_11","first-page":"1569","article-title":"p53 mutations in oral cavity carcinoma","volume":"23","author":"Ragos","year":"2018","journal-title":"J. BUON"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: Molecular mechanisms of action","volume":"740","author":"Dasari","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.18632\/oncotarget.27531","article-title":"Exosome mediated miR-155 delivery confers cisplatin chemoresistance in oral cancer cells via epithelial-mesenchymal transition","volume":"11","author":"Kirave","year":"2020","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Semlali, A., Ajala, I., Beji, S., Al-Zharani, M.M., and Rouabhia, M. (2023). Synergistic Effect of Anethole and Platinum Drug Cisplatin against Oral Cancer Cell Growth and Migration by Inhibiting MAPKase, Beta-Catenin, and NF-\u03baB Pathways. Pharmaceuticals, 16.","DOI":"10.3390\/ph16050700"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5018","DOI":"10.3390\/cimb45060319","article-title":"Synergistic Effects of New Curcumin Analog (PAC) and Cisplatin on Oral Cancer Therapy","volume":"45","author":"Semlali","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.cyto.2003.11.015","article-title":"In vitro analyses of tissue structure and interleukin-1beta expression and production by human oral mucosa in response to Candida albicans infections","volume":"25","author":"Mostefaoui","year":"2004","journal-title":"Cytokine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"398207","DOI":"10.1155\/2012\/398207","article-title":"Disruption of the ECM33 gene in Candida albicans prevents biofilm formation, engineered human oral mucosa tissue damage and gingival cell necrosis\/apoptosis","volume":"2012","author":"Rouabhia","year":"2012","journal-title":"Mediat. Inflamm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11701","DOI":"10.1038\/s41598-021-90754-x","article-title":"The curcumin analog (PAC) suppressed cell survival and induced apoptosis and autophagy in oral cancer cells","volume":"11","author":"Semlali","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Almalki, E., Al-Amri, A., Alrashed, R., Al-Zharani, M., and Semlali, A. (2023). The Curcumin Analog PAC Is a Potential Solution for the Treatment of Triple-Negative Breast Cancer by Modulating the Gene Expression of DNA Repair Pathways. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119649"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Semlali, A., Al Amri, A., Azzi, A., Al Shahrani, O., Arafah, M., Kohailan, M., Aljebreen, A.M., Alharbi, O., Almadi, M.A., and Azzam, N.A. (2015). Expression and New Exon Mutations of the Human Beta Defensins and Their Association on Colon Cancer Development. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0126868"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105200","DOI":"10.1016\/j.archoralbio.2021.105200","article-title":"Effects of tetrahydrocannabinols on human oral cancer cell proliferation, apoptosis, autophagy, oxidative stress, and DNA damage","volume":"129","author":"Semlali","year":"2021","journal-title":"Arch. Oral Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"The Cancer Genome Atlas Research Network, Collisson, E.A., Mills, G.B., Shaw, K.R., Ozenberger, B.A., Ellrott, K., Shmulevich, I., Sander, C., and Stuart, J.M. (2013). The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet., 45, 1113\u20131120.","DOI":"10.1038\/ng.2764"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.3109\/10428194.2013.855307","article-title":"Targeting the apoptosis pathway in hematologic malignancies","volume":"55","author":"Zaman","year":"2014","journal-title":"Leuk. Lymphoma"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nrc.2016.138","article-title":"Cell cycle proteins as promising targets in cancer therapy","volume":"17","author":"Otto","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Schiliro, C., and Firestein, B.L. (2021). Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. Cells, 10, Correction in Cells\u00a02022. 11, 3593.","DOI":"10.3390\/cells11223593"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1615\/CritRevEukaryotGeneExpr.2021038714","article-title":"A Pan-Cancer Analysis of the BIRC Gene Family and Its Association with Prognosis, Tumor Microenvironment, and Therapeutic Targets","volume":"31","author":"Wu","year":"2021","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"791","DOI":"10.4161\/auto.23785","article-title":"CFLAR\/c-FLIPA star in the autophagy, apoptosis and necroptosis alliance","volume":"9","author":"He","year":"2013","journal-title":"Autophagy"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3892\/ol.2024.14284","article-title":"CFLAR: A novel diagnostic and prognostic biomarker in soft tissue sarcoma, which positively modulates the immune response in the tumor microenvironment","volume":"27","author":"Liu","year":"2024","journal-title":"Oncol. Lett."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/7\/1041\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T07:02:53Z","timestamp":1782198173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/7\/1041"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":28,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["life16071041"],"URL":"https:\/\/doi.org\/10.3390\/life16071041","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,23]]}}}