{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:46:00Z","timestamp":1785422760420,"version":"3.56.0"},"reference-count":69,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"100th Anniversary Chulalongkorn University Fund for Doctoral Scholarship"},{"id":[{"id":"https:\/\/ror.org\/028wp3y58","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Thailand Science Research and Innovation Fund Chulalongkorn University"},{"id":[{"id":"https:\/\/ror.org\/028wp3y58","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Faculty of Allied Health Sciences Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fisetin is a bioactive flavanol with reported anticancer activity, although its mechanisms in leukaemia and potential for combination therapy remain incompletely understood. This study investigated the cytotoxic and mechanistic effects of fisetin, alone and combined with pinocembrin, in human leukaemia cells. Cell viability, apoptosis, and cell cycle progression were assessed by flow cytometry; protein expression in Jurkat cells was assessed by Western blotting; and molecular docking was used to evaluate interactions with the Fas receptor. Drug interactions were quantified using ZIP synergy analysis, and cytotoxicity and clonogenic survival were evaluated using soft-agar colony formation assays in K562 cells. Fisetin significantly reduced cell viability and induced apoptosis, accompanied by caspase-8 cleavage, p62 accumulation, and CDK4 downregulation, consistent with activation of extrinsic apoptosis, impaired autophagic flux, and cell cycle inhibition in Jurkat cells. Docking analysis supported a potential interaction with the Fas receptor, which was confirmed using the Fas receptor antagonist Met-12. Co-treatment with pinocembrin enhanced fisetin-mediated cytotoxicity and produced synergistic effects, particularly in Jurkat cells (ZIP score &gt; 10), while synergistic interactions at specific sub-IC50 concentrations were also observed in K562 cells. Combination treatment further enhanced caspase-8 activation, reduced CDK4 expression in Jurkat cells, and significantly suppressed clonogenic survival in K562 cells compared with single-agent treatments. These findings suggest that fisetin promotes caspase-8-dependent apoptosis, potentially involving Fas-associated signalling, and highlight fisetin\u2013pinocembrin combination therapy as a promising strategy for leukaemia treatment.<\/jats:p>","DOI":"10.3390\/ijms27125622","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:09:17Z","timestamp":1782270557000},"page":"5622","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic Induction of Caspase-8-Mediated Leukaemic Cell Death by Fisetin and Pinocembrin"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7802-2343","authenticated-orcid":false,"given":"Narawan","family":"Kaewthawee","sequence":"first","affiliation":[{"name":"Program in Clinical Hematology Sciences, Department of Clinical Microscopy, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankita","family":"Sharma","sequence":"additional","affiliation":[{"name":"Research Innovation & International Affairs, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James Michael","family":"Brimson","sequence":"additional","affiliation":[{"name":"Research Innovation & International Affairs, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirikalaya","family":"Brimson","sequence":"additional","affiliation":[{"name":"Department of Clinical Microscopy, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41572-024-00525-x","article-title":"Acute lymphoblastic leukaemia","volume":"10","author":"Pagliaro","year":"2024","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1002\/ajh.27708","article-title":"Adult Acute Lymphoblastic Leukemia: 2025 Update on Diagnosis, Therapy, and Monitoring","volume":"100","author":"Kantarjian","year":"2025","journal-title":"Am. J. Hematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e577","DOI":"10.1038\/bcj.2017.53","article-title":"Acute lymphoblastic leukemia: A comprehensive review and 2017 update","volume":"7","author":"Terwilliger","year":"2017","journal-title":"Blood Cancer J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1586\/ehm.11.8","article-title":"Adverse effects of treatment in childhood acute lymphoblastic leukemia: General overview and implications for long-term cardiac health","volume":"4","author":"Ness","year":"2011","journal-title":"Expert. Rev. Hematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S182","DOI":"10.1016\/j.htct.2024.05.006","article-title":"Patient-reported outcomes of treatment and adverse effects following acute lymphoblastic leukemia: A low- and middle-income country cross-sectional study","volume":"46","author":"Chapchap","year":"2024","journal-title":"Hematol. Transfus. Cell Ther."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Maher, T., Ahmad Raus, R., Daddiouaissa, D., Ahmad, F., Adzhar, N.S., Latif, E.S., Abdulhafiz, F., and Mohammed, A. (2021). Medicinal Plants with Anti-Leukemic Effects: A Review. Molecules, 26.","DOI":"10.3390\/molecules26092741"},{"key":"ref_7","first-page":"41","article-title":"A comprehensive review of phytochemical approaches in treatment of acute myeloid leukemia: Associated pathways and molecular mechanisms","volume":"17","author":"Sajana","year":"2025","journal-title":"Chin. Herb. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"107620","DOI":"10.1016\/j.fbio.2025.107620","article-title":"Fisetin as a multifunctional bioactive flavonoid: A comprehensive review of its pharmacology, mechanism of action, safety profile, clinical trials, and future directions in therapeutics","volume":"73","author":"Khan","year":"2025","journal-title":"Food Biosci."},{"key":"ref_9","unstructured":"Mushtaq, M., and Anwar, F. (2021). Chapter 17\u2014Fisetin: A senolytic drug. A Centum of Valuable Plant Bioactives, Academic Press."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1089\/ars.2012.4901","article-title":"Fisetin: A dietary antioxidant for health promotion","volume":"19","author":"Khan","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7877","DOI":"10.1007\/s00210-025-04912-3","article-title":"Fisetin: A multitarget flavonol bridging oxidative stress, inflammation, aging, and cancer","volume":"399","author":"Chahal","year":"2026","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107232","DOI":"10.1016\/j.jddst.2025.107232","article-title":"Unveiling the therapeutic potential of Fisetin: Bridging traditional knowledge with modern medicine","volume":"112","author":"Telrandhe","year":"2025","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"174492","DOI":"10.1016\/j.ejphar.2021.174492","article-title":"Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review","volume":"910","author":"Ravula","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/fsn3.1872","article-title":"Fisetin: An anticancer perspective","volume":"9","author":"Imran","year":"2021","journal-title":"Food Sci. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1055\/s-0043-1772219","article-title":"Fisetin\u2019s Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies","volume":"10","author":"Qaed","year":"2023","journal-title":"Glob. Med. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1186\/s40001-023-01271-8","article-title":"Biological effects and mechanisms of fisetin in cancer: A promising anti-cancer agent","volume":"28","author":"Zhou","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/s41419-023-06154-8","article-title":"Autophagy: Regulator of cell death","volume":"14","author":"Liu","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrm3735","article-title":"Self-consumption: The interplay of autophagy and apoptosis","volume":"15","author":"Baehrecke","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mustafa, M., Ahmad, R., Tantry, I.Q., Ahmad, W., Siddiqui, S., Alam, M., Abbas, K., Hassan, M.I., and Habib, S. (2024). Apoptosis: A Comprehensive Overview of Signaling Pathways, Morphological Changes, and Physiological Significance and Therapeutic Implications. Cells, 13.","DOI":"10.3390\/cells13221838"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1146\/annurev-pathmechdis-051222-115023","article-title":"Apoptosis in Cancer Biology and Therapy","volume":"20","author":"Moyer","year":"2025","journal-title":"Annu. Rev. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"205","DOI":"10.15171\/apb.2019.024","article-title":"Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics","volume":"9","author":"Jan","year":"2019","journal-title":"Adv. Pharm. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/s41419-024-06712-8","article-title":"Research progress on morphology and mechanism of programmed cell death","volume":"15","author":"Chen","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/bs.apcsb.2021.01.003","article-title":"Intrinsic and extrinsic pathways of apoptosis: Role in cancer development and prognosis","volume":"125","author":"Kashyap","year":"2021","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S33","DOI":"10.1016\/j.freeradbiomed.2015.07.117","article-title":"PP42\u2014Fisetin regulates TPA-induced breast cancer cell invasion by suppressing matrix metalloproteinase-9 activation via the PKC\/ROS\/MAPK pathways","volume":"86","author":"Noh","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.cbi.2019.02.020","article-title":"Fisetin suppresses migration, invasion and stem-cell-like phenotype of human non-small cell lung carcinoma cells via attenuation of epithelial to mesenchymal transition","volume":"303","author":"Tabasum","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1080\/01635581.2020.1836241","article-title":"Fisetin Inhibits Autophagy in HepG2 Cells via PI3K\/Akt\/mTOR and AMPK Pathway","volume":"73","author":"Sundarraj","year":"2021","journal-title":"Nutr. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Afroze, N., Pramodh, S., Shafarin, J., Bajbouj, K., Hamad, M., Sundaram, M.K., Haque, S., and Hussain, A. (2022). Fisetin Deters Cell Proliferation, Induces Apoptosis, Alleviates Oxidative Stress and Inflammation in Human Cancer Cells, HeLa. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031707"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.canlet.2012.01.008","article-title":"Activation of reactive oxygen species\/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells","volume":"319","author":"Jang","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/j.toxrep.2015.07.004","article-title":"Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells","volume":"2","author":"Lim","year":"2015","journal-title":"Toxicol. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5781","DOI":"10.1007\/s13277-015-4118-3","article-title":"Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling","volume":"37","author":"Adan","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8973","DOI":"10.1007\/s13277-015-3597-6","article-title":"The pleiotropic effects of fisetin and hesperetin on human acute promyelocytic leukemia cells are mediated through apoptosis, cell cycle arrest, and alterations in signaling networks","volume":"36","author":"Adan","year":"2015","journal-title":"Tumour Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"110482","DOI":"10.5493\/wjem.v15.i4.110482","article-title":"Pinocembrin as a novel anti-cancer agent: Exploring preclinical evidence along with therapeutic potential","volume":"15","author":"Singla","year":"2025","journal-title":"World J. Exp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"172","DOI":"10.3892\/mmr.2025.13537","article-title":"The role of Bcl-2 in controlling the transition between autophagy and apoptosis (Review)","volume":"32","author":"Palabiyik","year":"2025","journal-title":"Mol. Med. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"22426","DOI":"10.1038\/s41598-025-95903-0","article-title":"Jurkat T-cell lines exhibit marked genomic instability affecting karyotype, mutational profile, gene expression, immunophenotype and function","volume":"15","author":"Wilson","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.procbio.2023.04.005","article-title":"Improved low water solubility of fisetin by enzymatic encapsulation reaction using cycloamylose produced by cyclodextrin glucanotransferase","volume":"130","author":"Jeong","year":"2023","journal-title":"Process Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.1039\/C6FO00583G","article-title":"Potentiation of luteolin cytotoxicity by flavonols fisetin and quercetin in human chronic lymphocytic leukemia cell lines","volume":"7","author":"Sak","year":"2016","journal-title":"Food Funct."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1080\/14756360601162063","article-title":"Phosphoprotein levels, MAPK activities and NFkappaB expression are affected by fisetin","volume":"22","author":"Queiroz","year":"2007","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_38","first-page":"811","article-title":"Anti-cancer effects of fisetin on mammary carcinoma cells via regulation of the PI3K\/Akt\/mTOR pathway: In vitro and in vivo studies","volume":"42","author":"Sun","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Sobczak, A., Dominiak, K., Sztenc, B., Jadach, B., Wo\u017aniak-Braszak, A., Baranowski, M., Bilski, P., Majchrzak-Celi\u0144ska, A., Krajka-Ku\u017aniak, V., and Jeli\u0144ska, A. (2025). Anticancer Potential of Fisetin Against Glioblastoma: In Vitro Evaluation, Radiostability Assessment, and Preliminary PLGA Encapsulation. Polymers, 17.","DOI":"10.3390\/polym17223074"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/mc.22512","article-title":"Fisetin inhibits cellular proliferation and induces mitochondria-dependent apoptosis in human gastric cancer cells","volume":"56","author":"Sabarwal","year":"2017","journal-title":"Mol. Carcinog."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s00204-011-0754-6","article-title":"Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1\/2-mediated activation of caspase-8-\/caspase-3-dependent pathway","volume":"86","author":"Ying","year":"2012","journal-title":"Arch. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"24753","DOI":"10.18632\/aging.203713","article-title":"Fisetin inhibits the proliferation, migration and invasion of pancreatic cancer by targeting PI3K\/AKT\/mTOR signaling","volume":"13","author":"Xiao","year":"2021","journal-title":"Aging"},{"key":"ref_43","first-page":"481","article-title":"Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells","volume":"5","author":"Ash","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s12257-019-0326-9","article-title":"Fisetin Inhibits Cell Proliferation and Induces Apoptosis via JAK\/STAT3 Signaling Pathways in Human Thyroid TPC 1 Cancer Cells","volume":"25","author":"Liang","year":"2020","journal-title":"Biotechnol. Bioprocess Eng."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"G1060","DOI":"10.1152\/ajpgi.90490.2008","article-title":"Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin","volume":"296","author":"Lim","year":"2009","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.cell.2005.07.002","article-title":"Bcl-2 Antiapoptotic Proteins Inhibit Beclin 1-Dependent Autophagy","volume":"122","author":"Pattingre","year":"2005","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Siedlecka-Kroplewska, K., Kmiec, Z., and Zmijewski, M.A. (2025). The Interplay Between Autophagy and Apoptosis in the Mechanisms of Action of Stilbenes in Cancer Cells. Antioxidants, 14.","DOI":"10.3390\/antiox14030339"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/s41580-018-0033-y","article-title":"Autophagy as a promoter of longevity: Insights from model organisms","volume":"19","author":"Hansen","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/s41580-020-0241-0","article-title":"Mechanisms governing autophagosome biogenesis","volume":"21","author":"Nakatogawa","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"10147","DOI":"10.1038\/s41598-019-46657-z","article-title":"LC3-positive structures are prominent in autophagy-deficient cells","volume":"9","author":"Runwal","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Kumar, A.V., Mills, J., and Lapierre, L.R. (2022). Selective Autophagy Receptor p62\/SQSTM1, a Pivotal Player in Stress and Aging. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.793328"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1002\/jcb.30447","article-title":"Fisetin induces apoptosis in colorectal cancer cells by suppressing autophagy and down-regulating nuclear factor erythroid 2-related factor 2 (Nrf2)","volume":"124","author":"Pandey","year":"2023","journal-title":"J. Cell Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9603271251335220","DOI":"10.1177\/09603271251335220","article-title":"Physalin A induces apoptosis through conjugating with Fas-FADD cell death receptor in human oral squamous carcinoma cells and suppresses HSC-3 cell xenograft tumors in NOD\/SCID mice","volume":"44","author":"Chueh","year":"2025","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.molcel.2016.01.009","article-title":"Structural Basis and Functional Role of Intramembrane Trimerization of the Fas\/CD95 Death Receptor","volume":"61","author":"Fu","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/s41418-025-01493-9","article-title":"CD95\/Fas stoichiometry in future precision medicine","volume":"32","author":"Sica","year":"2025","journal-title":"Cell Death Differ."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1038\/cdd.2011.208","article-title":"A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency","volume":"19","author":"Chodorge","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_57","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_58","doi-asserted-by":"crossref","first-page":"123452","DOI":"10.1016\/j.saa.2023.123452","article-title":"Inhibition mechanism of fisetin on acetylcholinesterase and its synergistic effect with galantamine","volume":"305","author":"Shi","year":"2024","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1007\/s12032-025-02664-x","article-title":"Fisetin as a chemoprotective and chemotherapeutic agent: Mechanistic insights and future directions in cancer therapy","volume":"42","author":"Fatima","year":"2025","journal-title":"Med. Oncol."},{"key":"ref_60","first-page":"176","article-title":"Apoptosis Induction with Combined Use of Cisplatin and Fisetin in Cisplatin-Resistant Ovarian Cancer Cells (A2780)","volume":"13","author":"Jafarzadeh","year":"2021","journal-title":"Avicenna J. Med. Biotechnol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/s13048-023-01308-w","article-title":"The effect of paclitaxel- and fisetin-loaded PBM nanoparticles on apoptosis and reversal of drug resistance gene ABCG2 in ovarian cancer","volume":"16","author":"McFadden","year":"2023","journal-title":"J. Ovarian Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6987","DOI":"10.1007\/s13277-015-4526-4","article-title":"Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8\/caspase-3 and the mitochondria-dependent apoptotic pathway","volume":"37","author":"Lin","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"E119","DOI":"10.1002\/mc.22053","article-title":"N-acetyl-L-cysteine enhances fisetin-induced cytotoxicity via induction of ROS-independent apoptosis in human colonic cancer cells","volume":"53","author":"Wu","year":"2014","journal-title":"Mol. Carcinog."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7913","DOI":"10.1007\/s00210-024-03145-0","article-title":"Fisetin and\/or capecitabine causes changes in apoptosis pathways in capecitabine-resistant colorectal cancer cell lines","volume":"397","author":"Zehra","year":"2024","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7489","DOI":"10.1007\/s11033-023-08664-2","article-title":"Naringenin in combination with quercetin\/fisetin shows synergistic anti-proliferative and migration reduction effects in breast cancer cell lines","volume":"50","author":"Shahbazi","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"177361","DOI":"10.1016\/j.ejphar.2025.177361","article-title":"Synergistic combination of doxorubicin with fisetin for the treatment of lymphoma","volume":"992","author":"Singh","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"W324","DOI":"10.1093\/nar\/gkae300","article-title":"SwissDock 2024: Major enhancements for small-molecule docking with Attracting Cavities and AutoDock Vina","volume":"52","author":"Bugnon","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3925","DOI":"10.1021\/acs.jcim.3c00054","article-title":"Attracting Cavities 2.0: Improving the Flexibility and Robustness for Small-Molecule Docking","volume":"63","author":"Goullieux","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"114032","DOI":"10.1016\/j.biopha.2022.114032","article-title":"Current advances on the therapeutic potential of pinocembrin: An updated review","volume":"157","author":"Elbatreek","year":"2023","journal-title":"Biomed. Pharmacother."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5622\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T05:53:24Z","timestamp":1782366804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5622"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,22]]},"references-count":69,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125622"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125622","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,22]]}}}