{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T22:15:25Z","timestamp":1788387325569,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidad Aut\u00f3noma Metropolitana. Pharmacology Group"},{"id":[{"id":"https:\/\/ror.org\/02kta5139","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma is one of the most aggressive malignancies worldwide, with limited therapeutic options. Boswellia serrata Roxb., an Indian medicinal tree, produces a resin rich in essential oil and boswellic acids, particularly acetyl-11-keto-\u03b2-boswellic acid (AKBA), with demonstrated antiproliferative and pro-apoptotic activities. This study investigated the cytotoxic effects of B. serrata essential oil and AKBA on hepatocarcinoma Huh-7 cells in both monolayer and three-dimensional spheroid cultures and characterized the underlying molecular targets. Essential oil was extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). Cytotoxicity was assessed using the cell counting kit-8 (CCK-8). Three-dimensional spheroid cultures were also established to evaluate anti-tumoral potential. Expression of cyclin D1, cyclin-dependent of kinase 4 (CDK4) (cyclin-dependent kinase inhibitor 1A (p21), E-cadherin, (alpha fetoprotein) AFP, epithelial cell adhesion molecule (EpCAM), Myeloid cell leukemia-1 (Mcl-1), and caspase-3 was analyzed by western blot. In addition, an in silico analysis was performed on the main constituents of B. serrata essential oil targeting 5-lipoxygenase (5LO). The results showed cytotoxic effects, with AKBA exhibiting greater potency than the essential oil. Cytotoxicity was associated with caspase-3-mediated apoptosis, with minimal effects on cell cycle and epithelial\u2013mesenchymal transition markers. The in silico analysis predicted that some compounds may act as competitive inhibitors of the 5LO at the catalytic site and partially activate pro-apoptotic pathways. These data support the potential of B. serrata-derived compounds as novel anti-hepatocarcinoma agents, with AKBA and longifolene as leads for further preclinical and clinical research.<\/jats:p>","DOI":"10.3390\/ijms27135978","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:34:11Z","timestamp":1783071251000},"page":"5978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cytotoxic Activity of Boswellia serrata Roxb. Essential Oil and Acetyl-11-Keto-\u03b2-Boswellic Acid (AKBA) on Hepatocellular Carcinoma Cells: In Vitro and In Silico Study"],"prefix":"10.3390","volume":"27","author":[{"given":"Francisco Javier","family":"Alarcon-Aguilar","sequence":"first","affiliation":[{"name":"Departamento de Ciencias de la Salud, Divisi\u00f3n de Ciencias Biol\u00f3gicas y de la Salud, Universidad Aut\u00f3noma Metropolitana\u2014Iztapalapa, Ciudad de M\u00e9xico 09340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana Laura","family":"Torres-Chac\u00f3n","sequence":"additional","affiliation":[{"name":"Posgrado en Biolog\u00eda Experimental, Divisi\u00f3n de Ciencias Biol\u00f3gicas y de la Salud, Universidad Aut\u00f3noma Metropolitana\u2014Iztapalapa, Ciudad de M\u00e9xico 09340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9943-3780","authenticated-orcid":false,"given":"Alfredo","family":"Su\u00e1rez-Alonso","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias de la Salud, Divisi\u00f3n de Ciencias Biol\u00f3gicas y de la Salud, Universidad Aut\u00f3noma Metropolitana\u2014Iztapalapa, Ciudad de M\u00e9xico 09340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1860-0744","authenticated-orcid":false,"given":"Samuel Enoch","family":"Estrada-Soto","sequence":"additional","affiliation":[{"name":"Facultad de Farmacia, Universidad Aut\u00f3noma del Estado de Morelos, Cuernacava 62209, Estado de Morelos, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Enrique","family":"G\u00f3mez-Quiroz","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias de la Salud, Divisi\u00f3n de Ciencias Biol\u00f3gicas y de la Salud, Universidad Aut\u00f3noma Metropolitana\u2014Iztapalapa, Ciudad de M\u00e9xico 09340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Lu\u00eds Eduardo","family":"Flores S\u00e1enz","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias de la Salud, Divisi\u00f3n de Ciencias Biol\u00f3gicas y de la Salud, Universidad Aut\u00f3noma Metropolitana\u2014Iztapalapa, Ciudad de M\u00e9xico 09340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Vega \u00c1vila","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias de la Salud, Divisi\u00f3n de Ciencias Biol\u00f3gicas y de la Salud, Universidad Aut\u00f3noma Metropolitana\u2014Iztapalapa, Ciudad de M\u00e9xico 09340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9597-1181","authenticated-orcid":false,"given":"Gerardo","family":"Blancas Flores","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias de la Salud, Divisi\u00f3n de Ciencias Biol\u00f3gicas y de la Salud, Universidad Aut\u00f3noma Metropolitana\u2014Iztapalapa, Ciudad de M\u00e9xico 09340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1076-6731","authenticated-orcid":false,"given":"Abraham","family":"Giacoman Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica del Sur, Instituto Mexicano del Seguro Social, Xochitepec 62790, Estado de Morelos, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Mora Ramiro","sequence":"additional","affiliation":[{"name":"Facultad de Farmacia, Universidad Aut\u00f3noma del Estado de Morelos, Cuernacava 62209, Estado de Morelos, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9417-5500","authenticated-orcid":false,"given":"Julio C\u00e9sar","family":"Almanza-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias de la Salud, Divisi\u00f3n de Ciencias Biol\u00f3gicas y de la Salud, Universidad Aut\u00f3noma Metropolitana\u2014Iztapalapa, Ciudad de M\u00e9xico 09340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","unstructured":"GLOBOCAN (2026, June 30). Global Cancer Observatory: Cancer Fact Sheets-Liver Cancer. International Agency for Research on Cancer. Available online: http:\/\/gco.iarc.fr\/today\/home."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102131","DOI":"10.1016\/j.aohep.2025.102131","article-title":"Epidemiology and etiologic trends of hepatocellular carcinoma in cirrhotic patients in Mexico: A multicenter retrospective study (2018\u20132024)","volume":"31","year":"2026","journal-title":"Ann. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/s41571-018-0073-4","article-title":"Molecular therapies and precision medicine for hepatocellular carcinoma","volume":"15","author":"Llovet","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_4","first-page":"498","article-title":"Advances in the treatment of hepatocellular carcinoma: An overview of the current and evolving therapeutic landscape for clinicians","volume":"75","author":"Moris","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_5","first-page":"302","article-title":"Targeting hepatocellular carcinoma: What did we discover so far?","volume":"10","author":"Brito","year":"2016","journal-title":"Oncol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural products as sources of new drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_7","first-page":"255","article-title":"Boswellia serrata, a potential anti-inflammatory agent: An overview","volume":"73","author":"Siddiqui","year":"2011","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1089\/dna.2016.3332","article-title":"Boswellia serrata protects against glutamate-induced oxidative stress and apoptosis in PC12 and N2a Cells","volume":"35","author":"Rajabian","year":"2016","journal-title":"DNA Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2504305","DOI":"10.1155\/2018\/2504305","article-title":"Anti-inflammatory activity of Boswellia serrata extracts: An in vitro study on porcine aortic endothelial cells","volume":"25","author":"Bertocchi","year":"2018","journal-title":"Oxid. Med. Cell. Long."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.jep.2016.06.053","article-title":"Pharmacological evidence for cytotoxic and antitumor properties of boswellic acids from Boswellia serrata","volume":"191","author":"Khan","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Schmiech, M., Ulrich, J., Lang, S.J., B\u00fcchele, B., Paetz, C., St-Gelais, A., Syrovets, T., and Simmet, T. (2021). 11-Keto-\u03b1-boswellic acid, a novel triterpenoid from Boswellia spp. with chemotaxonomic potential and antitumor activity against triple-negative breast cancer cells. Molecules, 26.","DOI":"10.3390\/molecules26020366"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.32604\/or.2025.062386","article-title":"3-O-Acetyl-11-Keto-\u03b2-boswellic acid suppresses colitis-associated colorectal cancer by inhibiting the NF-Kb signaling pathway and remodeling gut microbiota","volume":"33","author":"Xu","year":"2025","journal-title":"Oncol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Elnawasany, S., Mansour, M., Elsayad, H., Elzoghby, A., and Shehata, N. (2023). Anti-cancer effect of nano-encapsulated boswellic acids, curcumin, and naringenin against HepG-2 cell line. BMC Complement. Med. Ther., 23.","DOI":"10.1186\/s12906-023-04096-4"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Khan, M.A., Singh, M., Khan, M.S., Najmi, A.K., and Ahmad, S. (2014). Caspase mediated synergistic effect of Boswellia serrata extract in combination with doxorubicin against human hepatocellular carcinoma. Biomed. Res. Int., 294143.","DOI":"10.1155\/2014\/294143"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10834","DOI":"10.1038\/s41598-026-42328-y","article-title":"Synergistic anticancer activity of frankincense aqueous extract with sorafenib in HepG2 cells and its UHPLC\u2013QTOF\u2013MS\/MS-based metabolomic profiling","volume":"16","author":"Ragab","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/s41589-020-0544-7","article-title":"Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products","volume":"16","author":"Gilbert","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"ref_17","first-page":"1420","article-title":"Lipid signaling in gastrointestinal and hepatic cancers: Role of 5-lipoxygenase-activating protein inhibitors in cell survival","volume":"36","author":"Fan","year":"2021","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1111\/jgh.15184","article-title":"5-Lipoxygenase promotes epithelial\u2013mesenchymal transition through the ERK signaling pathway in gastric cancer","volume":"36","author":"Lin","year":"2020","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"349","DOI":"10.30574\/gscbps.2024.26.1.0027","article-title":"Exploring the anticancer potential of Boswellia serrata: A comprehensive review","volume":"26","author":"Olabintan","year":"2024","journal-title":"GSC Biol. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1055\/a-0881-3000","article-title":"Wound healing potential of the standardized extract of Boswellia serrata on experimental diabetic foot ulcer via inhibition of inflammatory, angiogenetic and apoptotic markers","volume":"85","author":"Pengzong","year":"2019","journal-title":"Planta Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/lam.12683","article-title":"Synergistic antimicrobial activity of Boswellia serrata Roxb. ex Colebr. (Burseraceae) essential oil with various azoles against pathogens associated with skin, scalp and nail infections","volume":"63","author":"Sadhasivam","year":"2016","journal-title":"Lett. Appl. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/ptr.2008","article-title":"Inhibition of angiotensin converting enzyme (ace) by flavonoids isolated from Ailanthus excelsa (Roxb) (Simaroubaceae)","volume":"21","author":"Loizzo","year":"2007","journal-title":"Phytother. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.tox.2009.11.013","article-title":"Linalool preferentially induces robust apoptosis of a variety of leukemia cells via upregulating p53 and cyclin-dependent kinase inhibitors","volume":"268","author":"Gu","year":"2010","journal-title":"Toxicology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"122","DOI":"10.2174\/138945011793591626","article-title":"Complex interactions between phytochemicals. The multi-target therapeutic concept of phytotherapy","volume":"12","author":"Efferth","year":"2011","journal-title":"Curr. Drug Targets"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Guastaldi, F.P.S., and Mahadik, B. (2026). Bone tissue engineering: Recent advances and translation to clinical application. J. Funct. Biomat., 17.","DOI":"10.3390\/jfb17020075"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nature03579","article-title":"An inhibitor of Bcl-2 family proteins induces regression of solid tumours","volume":"435","author":"Oltersdorf","year":"2005","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/sj.bjp.0706817","article-title":"Acetyl-keto-\u03b2-boswellic acid inhibits proliferation through a p21 dependent pathway in colon cancer cells","volume":"148","author":"Liu","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Cucarull, B., Tutusaus, A., Rider, P., Hern\u00e1ez-Alsina, T., Cu\u00f1o, C., Garc\u00eda de Frutos, P., Colell, A., Mar\u00ed, M., and Morales, A. (2022). Hepatocellular carcinoma: Molecular pathogenesis and therapeutic advances. Cancers, 14.","DOI":"10.3390\/cancers14030621"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/nature04872","article-title":"New signals from the invasive front","volume":"441","author":"Christofori","year":"2006","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"339","DOI":"10.15171\/apb.2017.041","article-title":"The different mechanisms of cancer drug resistance: A brief review","volume":"7","author":"Mansoori","year":"2017","journal-title":"Adv. Pharm. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1159\/000452744","article-title":"Nrf2- and Bach1 may play a role in the modulation of ultraviolet a-induced oxidative stress by acetyl-11-keto-\u03b2-boswellic acid in skin keratinocytes","volume":"30","author":"Yang","year":"2017","journal-title":"Ski. Pham. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2205604","DOI":"10.1002\/advs.202205604","article-title":"Allosteric activation of 15-lipoxygenase-1 by boswellic acid induces the lipid mediator class switch to promote resolution of inflammation","volume":"10","author":"Pace","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Roy, N.K., Parama, D., Banik, K., Bordoloi, D., Devi, A.K., Thakur, K.K., Padmavathi, G., Shakibaei, M., Fan, L., and Sethi, G. (2019). An Update on pharmacological potential of boswellic acids against chronic diseases. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20174101"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Chatzipieris, F.P., Petsas, E., Lambrinidis, G., Vassiliou, S., and Chasapis, C.T. (2026). Recent advances in dual COX\/LOX inhibitor design (2020-2024): Establishing \u201cthe Rule of Four for inflammation. Life, 16.","DOI":"10.3390\/life16010163"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e232875","DOI":"10.1148\/radiol.232875","article-title":"Interventional oncology meets immuno-oncology: Combination therapies for hepatocellular carcinoma","volume":"313","author":"Bitar","year":"2024","journal-title":"J. Radiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e00743","DOI":"10.1002\/cbdv.202500743","article-title":"Exploring chemical variability in the essential oil of Artemisia absinthium L. in relation to different phenological stages and geographical location","volume":"22","author":"Malaspina","year":"2025","journal-title":"Chem. Biodivers."},{"key":"ref_38","first-page":"A3B.1","article-title":"Trypan blue exclusion test of cell viability","volume":"21","author":"Strober","year":"2001","journal-title":"Curr. Protoc. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and autoDockTools4. Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera-A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","article-title":"Comparative protein modelling by satisfaction of spatial restraints","volume":"234","author":"Blundell","year":"1993","journal-title":"J. Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1021\/acs.jctc.0c01006","article-title":"Accelerating AutoDock4 with GPUs and gradient-based local search","volume":"17","author":"Tillack","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1109\/TCBB.2024.3467127","article-title":"Vina-GPU 2.1: Towards further optimizing docking speed and precision of AutoDock Vina and its derivatives","volume":"21","author":"Tang","year":"2024","journal-title":"IEEE\/ACM Trans. Comp. Biol. Bioinf."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0: New docking methods, expanded force field and phyton bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13321-019-0362-7","article-title":"DockRMSD: An open-source toll for atom mapping and RMSD calculation of symmetric molecules through graph isomorphism","volume":"11","author":"Bell","year":"2019","journal-title":"J. Cheminform."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5978\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:41:05Z","timestamp":1783071665000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5978"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":46,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135978"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135978","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,3]]}}}