{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:08:41Z","timestamp":1788566921162,"version":"build-2803163510"},"reference-count":95,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010731","name":"Faculty of Medicine, Chiang Mai University","doi-asserted-by":"publisher","award":["125\/2568"],"award-info":[{"award-number":["125\/2568"]}],"id":[{"id":"10.13039\/501100010731","id-type":"DOI","asserted-by":"publisher"}]},{"award":["125\/2568"],"award-info":[{"award-number":["125\/2568"]}],"id":[{"id":"https:\/\/ror.org\/05m2fqn25","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cannabis-derived compounds are increasingly used as adjuncts in cancer therapy due to their reported antiproliferative and pro-apoptotic effects. However, potential drug\u2013herb interactions with standard anticancer agents\u2014namely sorafenib\u2014remain unclear. This study investigated the interaction between cannabis and sorafenib, together with transcriptomic alterations in human hepatoma HepG2 cells. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the Combenefit program. RNA sequencing was performed to characterize gene expression changes across treatment groups. Combination analysis demonstrated concentration-dependent synergistic effects at intermediate doses. Transcriptomic profiling revealed that the combination treatment induced a broader and more distinct set of differentially expressed genes compared with single treatments. Integrated enrichment analyses showed consistent activation of stress- and inflammation-related pathways, including tumor necrosis factor-\u03b1 via nuclear factor-kappaB (TNF\/NF-\u03baB), mitogen-activated protein kinase (MAPK), janus kinase\/signal transducers and activators of transcription (JAK\u2013STAT), oxidative stress, and p53-mediated apoptosis, alongside suppression of metabolic and proliferative processes. While several pathways were shared across treatments, the combination group exhibited a more coordinated transcriptional response, including enrichment of integrated stress response, cytokine signaling, endoplasmic reticulum stress, and epigenetic regulation. These findings were supported by increased reactive oxygen species production and apoptosis, particularly in the combination group. Overall, cannabis may potentiate sorafenib activity through enhanced cellular stress and anti-proliferative signaling.<\/jats:p>","DOI":"10.3390\/ijms27104342","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T16:26:37Z","timestamp":1778689597000},"page":"4342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of Changes in the Transcriptome Profile of Human Hepatoma HepG2 Cells Exposed to Combined Sorafenib and Cannabis Treatment"],"prefix":"10.3390","volume":"27","author":[{"given":"Krittakarn","family":"Udomkritayachai","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theeraphat","family":"Thiamsuk","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takdanai","family":"Jarujamrat","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panaphas","family":"Kudikhong","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sira","family":"Raksakhom","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phitsamai","family":"Suphattana","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natthanan","family":"Khankham","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palapoom","family":"Thanawong","sequence":"additional","affiliation":[{"name":"Multidisciplinary and Interdisciplinary School, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3251-0462","authenticated-orcid":false,"given":"Supakit","family":"Khacha-ananda","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3000605231179928","DOI":"10.1177\/03000605231179928","article-title":"Sorafenib as first-line treatment for patients with primary hepatocellular carcinoma: An outcome evaluation","volume":"51","author":"Nguyen","year":"2023","journal-title":"J. Int. Med. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"345","DOI":"10.4254\/wjh.v5.i7.345","article-title":"Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma","volume":"5","author":"Zhai","year":"2013","journal-title":"World J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/s41392-020-0187-x","article-title":"The mechanisms of sorafenib resistance in hepatocellular carcinoma: Theoretical basis and therapeutic aspects","volume":"5","author":"Tang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_5","first-page":"e20210263","article-title":"Current state of cannabis use, policies, and research across sixteen countries: Cross-country comparisons and international perspectives","volume":"44","author":"Ransing","year":"2022","journal-title":"Trends Psychiatry Psychother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1186\/s12935-025-03870-3","article-title":"Cannabidiol (CBD) as a potential therapeutic agent for liver cancer: A comprehensive review of current evidence","volume":"25","author":"Esmaeli","year":"2025","journal-title":"Cancer Cell Int."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Graczyk, M., Lewandowska, A.A., and Dzier\u017canowski, T. (2021). The Therapeutic Potential of Cannabis in Counteracting Oxidative Stress and Inflammation. Molecules, 26.","DOI":"10.3390\/molecules26154551"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Hanganu, B., Lazar, D.E., Manoilescu, I.S., Mocanu, V., Butcovan, D., Buhas, C.L., Szalontay, A.S., and Ioan, B.G. (2022). Controversial Link between Cannabis and Anticancer Treatments-Where Are We and Where Are We Going? A Systematic Review of the Literature. Cancers, 14.","DOI":"10.3390\/cancers14164057"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s42238-023-00174-z","article-title":"Anticancer properties of cannabidiol and \u03949-tetrahydrocannabinol and synergistic effects with gemcitabine and cisplatin in bladder cancer cell lines","volume":"5","author":"Whynot","year":"2023","journal-title":"J. Cannabis Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Brunetti, P., Pichini, S., Pacifici, R., Busard\u00f2, F.P., and Del Rio, A. (2020). Herbal Preparations of Medical Cannabis: A Vademecum for Prescribing Doctors. Medicina, 56.","DOI":"10.3390\/medicina56050237"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Aare, M., Lazarte, J.M., Nathani, A., Boirie, B., Turley, T.N., Copland, J.A., and Singh, M. (2026). Synergistic Anticancer Activity of Cannabinoids and Terpenes Against Triple-Negative Breast Cancer Resistance. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27062730"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Marz\u0119da, P., Wr\u00f3blewska-\u0141uczka, P., Drozd, M., Florek-\u0141uszczki, M., Za\u0142uska-Ogryzek, K., and \u0141uszczki, J.J. (2022). Cannabidiol Interacts Antagonistically with Cisplatin and Additively with Mitoxantrone in Various Melanoma Cell Lines\u2014An Isobolographic Analysis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126752"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"114801","DOI":"10.1016\/j.biopha.2023.114801","article-title":"Cannabis-derived products antagonize platinum drugs by altered cellular transport","volume":"163","author":"Buchtova","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bar-Sela, G., Cohen, I., Campisi-Pinto, S., Lewitus, G.M., Oz-Ari, L., Jehassi, A., Peer, A., Turgeman, I., Vernicova, O., and Berman, P. (2020). Cannabis Consumption Used by Cancer Patients during Immunotherapy Correlates with Poor Clinical Outcome. Cancers, 12, Erratum in Cancers 2022, 14, 1957.","DOI":"10.3390\/cancers14081957"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Afrin, F., Chi, M., Eamens, A.L., Duchatel, R.J., Douglas, A.M., Schneider, J., Gedye, C., Woldu, A.S., and Dun, M.D. (2020). Can Hemp Help? Low-THC Cannabis and Non-THC Cannabinoids for the Treatment of Cancer. Cancers, 12.","DOI":"10.3390\/cancers12041033"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Woerdenbag, H.J., Olinga, P., Kok, E.A., Brugman, D.A.P., van Ark, U.F., Ramcharan, A.S., Lebbink, P.W., Hoogwater, F.J.H., Knapen, D.G., and de Groot, D.J.A. (2023). Potential, Limitations and Risks of Cannabis-Derived Products in Cancer Treatment. Cancers, 15.","DOI":"10.3390\/cancers15072119"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"105667","DOI":"10.1016\/j.tiv.2023.105667","article-title":"Cannabinoids and standardized cannabis extracts inhibit migration, invasion, and induce apoptosis in MCF-7 cells through FAK\/MAPK\/Akt\/NF-\u03baB signaling","volume":"93","author":"Suttithumsatid","year":"2023","journal-title":"Toxicol. Vitr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1007\/s13205-021-03102-1","article-title":"Cannabis with breast cancer treatment: Propitious or pernicious?","volume":"12","author":"Schoeman","year":"2022","journal-title":"3 Biotech."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1002\/cam4.1312","article-title":"The current state and future perspectives of cannabinoids in cancer biology","volume":"7","author":"Zeyland","year":"2018","journal-title":"Cancer Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.tox.2009.01.024","article-title":"Modulation of \u03949-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase","volume":"259","author":"Takeda","year":"2009","journal-title":"Toxicology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.bcp.2018.06.025","article-title":"Appraising the \u201centourage effect\u201d: Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer","volume":"157","author":"Tundidor","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1158\/2767-9764.CRC-23-0243","article-title":"Statistical Assessment of Drug Synergy from In Vivo Combination Studies Using Mouse Tumor Models","volume":"3","author":"Mao","year":"2023","journal-title":"Cancer Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103952","DOI":"10.18632\/oncotarget.21895","article-title":"Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism","volume":"8","author":"Kashif","year":"2017","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lederer, S., Dijkstra, T.M.H., and Heskes, T. (2018). Additive Dose Response Models: Explicit Formulation and the Loewe Additivity Consistency Condition. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00031"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1872-034X.2012.01113.x","article-title":"Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update","volume":"43","author":"Gauthier","year":"2013","journal-title":"Hepatol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1007\/s12672-024-01356-8","article-title":"Exploring the therapeutic potential of cannabinoids in cancer by modulating signaling pathways and addressing clinical challenges","volume":"15","author":"Faiz","year":"2024","journal-title":"Discov. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"116445","DOI":"10.1016\/j.biopha.2024.116445","article-title":"Synergistic effect of cannabidiol with dasatinib on lung cancer by SRC\/PI3K\/AKT signal pathway","volume":"173","author":"Ye","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6191","DOI":"10.1021\/acsomega.4c11108","article-title":"Cannabinoids as Promising Inhibitors of HER2-Tyrosine Kinase: A Novel Strategy for Targeting HER2-Positive Ovarian Cancer","volume":"10","author":"Lamtha","year":"2025","journal-title":"ACS Omega"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1124\/jpet.116.236968","article-title":"Quantitative Analyses of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture","volume":"360","author":"Deng","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"153884","DOI":"10.1016\/j.tox.2024.153884","article-title":"Investigation of cannabidiol-induced cytotoxicity in human hepatic cells","volume":"506","author":"Chen","year":"2024","journal-title":"Toxicology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s00204-019-02395-9","article-title":"Chemosensitization of hepatocellular carcinoma cells to sorafenib by \u03b2-caryophyllene oxide-induced inhibition of ABC export pumps","volume":"93","author":"Briz","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20622","DOI":"10.1038\/s41598-020-77674-y","article-title":"Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma","volume":"10","author":"Go","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Jeon, Y., Kim, T., Kwon, H., Kim, J.-K., Park, Y.-T., Ham, J., and Kim, Y.-J. (2023). Cannabidiol Enhances Cabozantinib-Induced Apoptotic Cell Death via Phosphorylation of p53 Regulated by ER Stress in Hepatocellular Carcinoma. Cancers, 15.","DOI":"10.3390\/cancers15153987"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Melones-Herrero, J., Delgado-Aliseda, P., Figueiras, S., Vel\u00e1zquez-Guti\u00e9rrez, J., Quiroga, A.G., Cal\u00e9s, C., and S\u00e1nchez-P\u00e9rez, I. (2024). Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147739"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ye, L., Yang, X., Guo, E., Chen, W., Lu, L., Wang, Y., Peng, X., Yan, T., Zhou, F., and Liu, Z. (2014). Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096664"},{"key":"ref_36","first-page":"1","article-title":"Mechanisms of Action and Pharmacokinetics of Cannabis","volume":"25","author":"Chayasirisobhon","year":"2020","journal-title":"Perm. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E995","DOI":"10.1152\/ajpendo.90217.2008","article-title":"Spermidine\/spermine-N1-acetyltransferase: A key metabolic regulator","volume":"294","author":"Pegg","year":"2008","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.18632\/oncotarget.13582","article-title":"Spermidine\/spermine N1-acetyltransferase regulates cell growth and metastasis via AKT\/\u03b2-catenin signaling pathways in hepatocellular and colorectal carcinoma cells","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_39","first-page":"3471","article-title":"AngII induces HepG2 cells to activate epithelial-mesenchymal transition","volume":"16","author":"Qi","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101785","DOI":"10.1016\/j.aohep.2025.101785","article-title":"MCM3 promotes hepatocellular carcinoma progression via Epithelial-mesenchymal Transition through AKT\/Twist signaling pathway","volume":"30","author":"Tang","year":"2025","journal-title":"Ann. Hepatol."},{"key":"ref_41","first-page":"1094","article-title":"Dysregulation of PLOD2 Promotes Tumor Metastasis and Invasion in Hepatocellular Carcinoma","volume":"11","author":"Li","year":"2023","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"824","DOI":"10.21037\/jgo-23-217","article-title":"Expression and clinical significance of ENC1 in gastrointestinal tumors: Bioinformatics analysis based on a public gene database","volume":"14","author":"Liu","year":"2023","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8826","DOI":"10.1111\/jcmm.15520","article-title":"Ectodermal-neural cortex 1 as a novel biomarker predicts poor prognosis and induces metastasis in breast cancer by promoting Wnt\/\u03b2-catenin pathway","volume":"24","author":"Zhou","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"106059","DOI":"10.1016\/j.biocel.2021.106059","article-title":"The two faces of the Integrated Stress Response in cancer progression and therapeutic strategies","volume":"139","author":"Licari","year":"2021","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e202403014","DOI":"10.26508\/lsa.202403014","article-title":"An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation","volume":"8","author":"Kleijn","year":"2025","journal-title":"Life Sci. Alliance"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3856","DOI":"10.1101\/cshperspect.a028472","article-title":"Cytokines in Cancer Immunotherapy","volume":"10","author":"Waldmann","year":"2018","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_47","first-page":"23","article-title":"Mammalian DNA repair: HATs and HDACs make their mark through histone acetylation","volume":"750","author":"Gong","year":"2013","journal-title":"Mutat. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"153097","DOI":"10.1016\/j.bbrc.2025.153097","article-title":"The role of histone acetyltransferases in tumorigenesis and their therapeutic potential: A review","volume":"795","author":"Lin","year":"2026","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15780","DOI":"10.1038\/s41598-019-52362-8","article-title":"Cannabidiol Regulates Gene Expression in Encephalitogenic T cells Using Histone Methylation and noncoding RNA during Experimental Autoimmune Encephalomyelitis","volume":"9","author":"Yang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"18707","DOI":"10.1074\/jbc.M113.545210","article-title":"Histone modifications are associated with \u03949-tetrahydrocannabinol-mediated alterations in antigen-specific T cell responses","volume":"289","author":"Yang","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Prini, P., Penna, F., Sciuccati, E., Alberio, T., and Rubino, T. (2017). Chronic \u03948-THC Exposure Differently Affects Histone Modifications in the Adolescent and Adult Rat Brain. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102094"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/s41419-024-06940-y","article-title":"Integrative single-cell RNA-seq and spatial transcriptomics analyses reveal diverse apoptosis-related gene expression profiles in EGFR-mutated lung cancer","volume":"15","author":"Izumi","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s43556-026-00427-2","article-title":"Metabolic reprogramming in cancer: Dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities","volume":"7","author":"Yu","year":"2026","journal-title":"Mol. Biomed."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Chichirau, B.E., Diechler, S., Posselt, G., and Wessler, S. (2019). Tyrosine Kinases in Helicobacter pylori Infections and Gastric Cancer. Toxins, 11.","DOI":"10.3390\/toxins11100591"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1038\/35009130","article-title":"Role of NF-kappaB in p53-mediated programmed cell death","volume":"404","author":"Ryan","year":"2000","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"45","DOI":"10.20517\/2394-4722.2017.03","article-title":"DNA damage-induced nuclear factor-kappa B activation and its roles in cancer progression","volume":"3","author":"Wang","year":"2017","journal-title":"J. Cancer Metastasis Treat."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"716","DOI":"10.3892\/etm.2012.647","article-title":"Effect of NF-\u03baB inhibitors on the chemotherapy-induced apoptosis of the colon cancer cell line HT-29","volume":"4","author":"Liu","year":"2012","journal-title":"Exp. Ther. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1139\/O10-008","article-title":"Involvement of NF-kappaB activation in the apoptosis induced by extracellular adenosine in human hepatocellular carcinoma HepG2 cells","volume":"88","author":"Wu","year":"2010","journal-title":"Biochem. Cell Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"44123","DOI":"10.1038\/srep44123","article-title":"Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"39432","DOI":"10.1038\/s41598-025-23009-8","article-title":"Targeting the p38\/MAPK pathway to induce apoptosis: A multidimensional mechanistic exploration of Mentha and its active compound diosmetin against liver cancer","volume":"15","author":"Song","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1126\/science.272.5266.1347","article-title":"Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase","volume":"272","author":"Wang","year":"1996","journal-title":"Science"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1038\/aps.2017.5","article-title":"New knowledge of the mechanisms of sorafenib resistance in liver cancer","volume":"38","author":"Zhu","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Vij, P., Hussain, M.S., Satapathy, S.K., Cobos, E., and Tripathi, M.K. (2024). The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma. Cancers, 16.","DOI":"10.20944\/preprints202409.0951.v1"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1038\/s41401-020-00522-2","article-title":"Sodium propionate exerts anticancer effect in mice bearing breast cancer cell xenograft by regulating JAK2\/STAT3\/ROS\/p38 MAPK signaling","volume":"42","author":"Park","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e11401","DOI":"10.15252\/msb.202211401","article-title":"Coordination of MAPK and p53 dynamics in the cellular responses to DNA damage and oxidative stress","volume":"18","author":"Hanson","year":"2022","journal-title":"Mol. Syst. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/sj.bjc.6605530","article-title":"TNF-\u03b1\/NF-\u03baB\/Snail pathway in cancer cell migration and invasion","volume":"102","author":"Wu","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Stramucci, L., Pranteda, A., and Bossi, G. (2018). Insights of Crosstalk between p53 Protein and the MKK3\/MKK6\/p38 MAPK Signaling Pathway in Cancer. Cancers, 10.","DOI":"10.3390\/cancers10050131"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s42003-024-06052-5","article-title":"Platinum iodido drugs show potential anti-tumor activity, affecting cancer cell metabolism and inducing ROS and senescence in gastrointestinal cancer cells","volume":"7","author":"Lorenzo","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_69","first-page":"103","article-title":"Molecular Targets of the Phytocannabinoids: A Complex Picture","volume":"103","author":"Morales","year":"2017","journal-title":"Prog. Chem. Org. Nat. Prod."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/s41420-023-01578-9","article-title":"Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70","volume":"9","author":"Wang","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/sj.onc.1204101","article-title":"Reciprocal down-regulation of p53 and SOD2 gene expression-implication in p53 mediated apoptosis","volume":"20","author":"Drane","year":"2001","journal-title":"Oncogene"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Chakraborti, S. (2022). The Role of Cannabis Species on Oxidative Stress in Cancer Cells. Handbook of Oxidative Stress in Cancer: Therapeutic Aspects, Springer Nature.","DOI":"10.1007\/978-981-16-5422-0"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Zhang, X., Qin, Y., Pan, Z., Li, M., Liu, X., Chen, X., Qu, G., Zhou, L., Xu, M., and Zheng, Q. (2019). Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells. Biomolecules, 9.","DOI":"10.3390\/biom9080302"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1080\/02841860701678787","article-title":"\u03949-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells","volume":"47","author":"Galanti","year":"2008","journal-title":"Acta Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6615","DOI":"10.1158\/0008-5472.CAN-05-4566","article-title":"\u03949-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation","volume":"66","author":"Caffarel","year":"2006","journal-title":"Cancer Res."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Pungsrinont, T., Kallenbach, J., and Baniahmad, A. (2021). Role of PI3K-AKT-mTOR Pathway as a Pro-Survival Signaling and Resistance-Mediating Mechanism to Therapy of Prostate Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222011088"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/cdd.2011.98","article-title":"mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1\u2013JNK pathway","volume":"19","author":"Kato","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"188952","DOI":"10.1016\/j.bbcan.2023.188952","article-title":"PI3K signaling-regulated metabolic reprogramming: From mechanism to application","volume":"1878","author":"Su","year":"2023","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.jfda.2018.01.005","article-title":"Tetrahydrocurcumin ameliorates free fatty acid-induced hepatic steatosis and improves insulin resistance in HepG2 cells","volume":"26","author":"Chen","year":"2018","journal-title":"J. Food Drug Anal."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1177\/1947601911409738","article-title":"The Role of p53 in Metabolic Regulation","volume":"2","year":"2011","journal-title":"Genes. Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e16156","DOI":"10.1016\/j.heliyon.2023.e16156","article-title":"Cannabis sativa L. modulates altered metabolic pathways involved in key metabolisms in human breast cancer (MCF-7) cells: A metabolomics study","volume":"9","author":"Erukainure","year":"2023","journal-title":"Heliyon"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e664","DOI":"10.1038\/cddis.2013.151","article-title":"Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells","volume":"4","author":"Dando","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_83","first-page":"e70561","article-title":"Antiproliferative Effects of Cannabinoids and Cisplatin in Cervical Cancer Cells","volume":"9","author":"Mathibela","year":"2026","journal-title":"Cancer Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"9918379","DOI":"10.1155\/2021\/9918379","article-title":"Exploring the Crosstalk between Inflammation and Epithelial-Mesenchymal Transition in Cancer","volume":"2021","author":"Chattopadhyay","year":"2021","journal-title":"Mediat. Inflamm."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1172\/JCI36183","article-title":"Biomarkers for epithelial-mesenchymal transitions","volume":"119","author":"Zeisberg","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"15449","DOI":"10.1073\/pnas.1004900107","article-title":"Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes","volume":"107","author":"Taube","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.7150\/thno.15625","article-title":"Role of the CXCL8-CXCR1\/2 Axis in Cancer and Inflammatory Diseases","volume":"7","author":"Ha","year":"2017","journal-title":"Theranostics"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1750-2187-3-15","article-title":"Gadd45 in stress signaling","volume":"3","author":"Liebermann","year":"2008","journal-title":"J. Mol. Signal"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Acquavia, M.A., Tesoro, C., Pascale, R., Ostuni, A., Matera, I., Bianco, G., Scrano, L., Bufo, S.A., Ciriello, R., and Di Capua, A. (2023). Legal Cannabis sativa L. Dried Inflorescences: Cannabinoids Content and Cytotoxic Activity against Human HepG2 Cell Line. Appl. Sci., 13.","DOI":"10.3390\/app13084960"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.1093\/bioinformatics\/btw230","article-title":"Combenefit: An interactive platform for the analysis and visualization of drug combinations","volume":"32","author":"Fornari","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.gpb.2022.01.004","article-title":"SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets","volume":"20","author":"Zheng","year":"2022","journal-title":"Genom. Proteom. Bioinform."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1\u03b1-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A graphical gene-set enrichment tool for animals and plants","volume":"36","author":"Ge","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: An R\/Bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4342\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T04:28:39Z","timestamp":1779424119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":95,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104342"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104342","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]}}}