{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:43:34Z","timestamp":1787496214256,"version":"build-2736575974"},"reference-count":70,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MICINN","award":["PID2022-1381850B-I00"],"award-info":[{"award-number":["PID2022-1381850B-I00"]}]},{"name":"MICINN","award":["FPU18\/02485"],"award-info":[{"award-number":["FPU18\/02485"]}]},{"name":"MICINN","award":["PRE2020-094225"],"award-info":[{"award-number":["PRE2020-094225"]}]},{"name":"MICINN","award":["FPU20\/03954"],"award-info":[{"award-number":["FPU20\/03954"]}]},{"name":"MICINN","award":["FPU23\/02246"],"award-info":[{"award-number":["FPU23\/02246"]}]},{"name":"MICINN","award":["PRE2022-000741"],"award-info":[{"award-number":["PRE2022-000741"]}]},{"name":"MICINN","award":["BIO-0139"],"award-info":[{"award-number":["BIO-0139"]}]},{"name":"MICINN","award":["PI-0152-2019"],"award-info":[{"award-number":["PI-0152-2019"]}]},{"name":"Universidad de C\u00f3rdoba","award":["PID2022-1381850B-I00"],"award-info":[{"award-number":["PID2022-1381850B-I00"]}]},{"name":"Universidad de C\u00f3rdoba","award":["FPU18\/02485"],"award-info":[{"award-number":["FPU18\/02485"]}]},{"name":"Universidad de C\u00f3rdoba","award":["PRE2020-094225"],"award-info":[{"award-number":["PRE2020-094225"]}]},{"name":"Universidad de C\u00f3rdoba","award":["FPU20\/03954"],"award-info":[{"award-number":["FPU20\/03954"]}]},{"name":"Universidad de C\u00f3rdoba","award":["FPU23\/02246"],"award-info":[{"award-number":["FPU23\/02246"]}]},{"name":"Universidad de C\u00f3rdoba","award":["PRE2022-000741"],"award-info":[{"award-number":["PRE2022-000741"]}]},{"name":"Universidad de C\u00f3rdoba","award":["BIO-0139"],"award-info":[{"award-number":["BIO-0139"]}]},{"name":"Universidad de C\u00f3rdoba","award":["PI-0152-2019"],"award-info":[{"award-number":["PI-0152-2019"]}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["PID2022-1381850B-I00"],"award-info":[{"award-number":["PID2022-1381850B-I00"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["FPU18\/02485"],"award-info":[{"award-number":["FPU18\/02485"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["PRE2020-094225"],"award-info":[{"award-number":["PRE2020-094225"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["FPU20\/03954"],"award-info":[{"award-number":["FPU20\/03954"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["FPU23\/02246"],"award-info":[{"award-number":["FPU23\/02246"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["PRE2022-000741"],"award-info":[{"award-number":["PRE2022-000741"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["BIO-0139"],"award-info":[{"award-number":["BIO-0139"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["PI-0152-2019"],"award-info":[{"award-number":["PI-0152-2019"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CIBERobn","award":["PID2022-1381850B-I00"],"award-info":[{"award-number":["PID2022-1381850B-I00"]}]},{"name":"CIBERobn","award":["FPU18\/02485"],"award-info":[{"award-number":["FPU18\/02485"]}]},{"name":"CIBERobn","award":["PRE2020-094225"],"award-info":[{"award-number":["PRE2020-094225"]}]},{"name":"CIBERobn","award":["FPU20\/03954"],"award-info":[{"award-number":["FPU20\/03954"]}]},{"name":"CIBERobn","award":["FPU23\/02246"],"award-info":[{"award-number":["FPU23\/02246"]}]},{"name":"CIBERobn","award":["PRE2022-000741"],"award-info":[{"award-number":["PRE2022-000741"]}]},{"name":"CIBERobn","award":["BIO-0139"],"award-info":[{"award-number":["BIO-0139"]}]},{"name":"CIBERobn","award":["PI-0152-2019"],"award-info":[{"award-number":["PI-0152-2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Prostate cancer (PCa) is the tumour pathology with the second highest incidence among men worldwide. PCa is strongly influenced by obesity (OB), which increases its aggressiveness. Hence, some metabolic drugs like metformin have emerged as potential anti-tumour agents against several endocrine-related cancers. Likewise, a high adherence to the Mediterranean diet has been associated with lower rates of OB and a reduction in PCa aggressiveness since this diet contains phenolic bioactive compounds such as hydroxytyrosol (HT) that is mainly present in extra virgin olive oil. Thus, we decided to analyse the therapeutic potential of the combination of HT + metformin in different PCa cell models. Specifically, combinations of different doses of HT and metformin were evaluated by analysing the proliferation rate of LNCaP, 22Rv1, DU-145, and PC\u22123 cells using the SynergicFinder method. The results revealed a synergistic effect of HT + metformin in significantly reducing proliferation, especially in LNCaP cells. This anti-tumour effect of HT + metformin was also confirmed in migration and tumoursphere formation assays in LNCaP. The effects on the cell cycle and apoptosis were also assessed by flow-cytometry, and a cycle arrest in the G1 phase and an increase in late apoptosis were observed with the combination of HT + metformin. The phosphorylation levels of critical components of different oncogenic pathways were measured which revealed that the combination of HT + metformin significantly reduced the activity of multiple components of the MAPK, AKT, and TGF-\u03b2 pathways. Overall, the combination of HT + metformin might represent a new therapeutic avenue for the management of PCa patients, an observation that certainly warrants further investigation through a well-designed clinical trial.<\/jats:p>","DOI":"10.3390\/ijms26031341","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T07:44:59Z","timestamp":1738741499000},"page":"1341","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1664-2556","authenticated-orcid":false,"given":"Francisco","family":"Porcel-Pastrana","sequence":"first","affiliation":[{"name":"Maimonides Institute for Biomedical Research of C\u00f3rdoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, University of C\u00f3rdoba, 14014 C\u00f3rdoba, Spain"},{"name":"Hospital Universitario Reina Sof\u00eda (HURS), 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1948-7512","authenticated-orcid":false,"given":"Antonio J.","family":"Montero-Hidalgo","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of C\u00f3rdoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, University of C\u00f3rdoba, 14014 C\u00f3rdoba, Spain"},{"name":"Hospital Universitario Reina Sof\u00eda (HURS), 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6941-6715","authenticated-orcid":false,"given":"Miguel E.","family":"G-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of C\u00f3rdoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, University of C\u00f3rdoba, 14014 C\u00f3rdoba, Spain"},{"name":"Hospital Universitario Reina Sof\u00eda (HURS), 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1313-820X","authenticated-orcid":false,"given":"Ignacio","family":"Gil-Duque","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of C\u00f3rdoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, University of C\u00f3rdoba, 14014 C\u00f3rdoba, Spain"},{"name":"Hospital Universitario Reina Sof\u00eda (HURS), 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1621-4424","authenticated-orcid":false,"given":"Antonio","family":"Prats-Escribano","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of C\u00f3rdoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, University of C\u00f3rdoba, 14014 C\u00f3rdoba, Spain"},{"name":"Hospital Universitario Reina Sof\u00eda (HURS), 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4578-2179","authenticated-orcid":false,"given":"Manuel D.","family":"Gahete","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of C\u00f3rdoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, University of C\u00f3rdoba, 14014 C\u00f3rdoba, Spain"},{"name":"Hospital Universitario Reina Sof\u00eda (HURS), 14004 C\u00f3rdoba, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), 28019 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1204-0371","authenticated-orcid":false,"given":"Andr\u00e9","family":"Sarmento-Cabral","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of C\u00f3rdoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, University of C\u00f3rdoba, 14014 C\u00f3rdoba, Spain"},{"name":"Hospital Universitario Reina Sof\u00eda (HURS), 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7585-1913","authenticated-orcid":false,"given":"Ra\u00fal M.","family":"Luque","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of C\u00f3rdoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, University of C\u00f3rdoba, 14014 C\u00f3rdoba, Spain"},{"name":"Hospital Universitario Reina Sof\u00eda (HURS), 14004 C\u00f3rdoba, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), 28019 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2668-8205","authenticated-orcid":false,"given":"Antonio J.","family":"Le\u00f3n-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Maimonides Institute for Biomedical Research of C\u00f3rdoba (IMIBIC), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Cell Biology, Physiology and Immunology, University of C\u00f3rdoba, 14014 C\u00f3rdoba, Spain"},{"name":"Hospital Universitario Reina Sof\u00eda (HURS), 14004 C\u00f3rdoba, Spain"},{"name":"Department of Pharmacology, School of Pharmacy, University of Seville, 41012 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","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":"555","DOI":"10.1007\/s10555-013-9473-1","article-title":"Metastatic Castration-Resistant Prostate Cancer (CRPC): Preclinical and Clinical Evidence for the Sequential Use of Novel Therapeutics","volume":"33","author":"Mukherji","year":"2014","journal-title":"Cancer Metastasis Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.urolonc.2016.03.021","article-title":"The Comparative Oncologic Effectiveness of Available Management Strategies for Clinically Localized Prostate Cancer","volume":"35","author":"Tyson","year":"2017","journal-title":"Urol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug Repurposing: Progress, Challenges and Recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.jdiacomp.2016.02.008","article-title":"The Impact of Diabetes and Other Metabolic Disorders on Prostate Cancer Prognosis","volume":"30","author":"Polesel","year":"2016","journal-title":"J. Diabetes Complicat."},{"key":"ref_6","first-page":"e1","article-title":"Obesity Is Associated with Biochemical Recurrence after Radical Prostatectomy: A Multi-Institutional Extended Validation Study","volume":"35","author":"Mathieu","year":"2017","journal-title":"Urol. Oncol. Semin. Orig. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/s41391-017-0030-9","article-title":"Serum Cholesterol and Risk of High-Grade Prostate Cancer: Results from the REDUCE Study","volume":"21","author":"Jamnagerwalla","year":"2018","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Fuentes-Fayos, A.C., G-Garc\u00eda, M.E., P\u00e9rez-G\u00f3mez, J.M., Montero-Hidalgo, A.J., Mart\u00edn-Colom, J., Doval-Rosa, C., Blanco-Acevedo, C., Torres, E., Toledano-Delgado, \u00c1., and S\u00e1nchez-S\u00e1nchez, R. (2023). Metformin and Simvastatin Exert Additive Antitumour Effects in Glioblastoma via Senescence-State: Clinical and Translational Evidence. EBioMedicine, 90.","DOI":"10.1016\/j.ebiom.2023.104484"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1159\/000505923","article-title":"Statins Directly Regulate Pituitary Cell Function and Exert Antitumor Effects in Pituitary Tumors","volume":"110","author":"Fanciulli","year":"2020","journal-title":"Neuroendocrinology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1210\/jc.2019-00056","article-title":"Biguanides Exert Antitumoral Actions in Pituitary Tumor Cells Through AMPK-Dependent and -Independent Mechanisms","volume":"104","author":"Dios","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E696","DOI":"10.1210\/clinem\/dgaa877","article-title":"Clinical, Cellular, and Molecular Evidence of the Additive Antitumor Effects of Biguanides and Statins in Prostate Cancer","volume":"106","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1210\/jc.2018-01455","article-title":"Type 2 Diabetes in Neuroendocrine Tumors: Are Biguanides and Statins Part of the Solution?","volume":"104","author":"Gahete","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.coph.2021.06.002","article-title":"Role of Metformin and Other Metabolic Drugs in the Prevention and Therapy of Endocrine-Related Cancers","volume":"60","author":"Gahete","year":"2021","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.eururo.2012.12.004","article-title":"Metformin and Prostate Cancer: Reduced Development of Castration-Resistant Disease and Prostate Cancer Mortality","volume":"63","author":"Spratt","year":"2013","journal-title":"Eur. Urol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1186\/s12967-023-04263-8","article-title":"Metformin and Cancer Hallmarks: Shedding New Lights on Therapeutic Repurposing","volume":"21","author":"Hua","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1158\/1541-7786.MCR-16-0493","article-title":"Metformin Reduces Prostate Tumor Growth, in a Diet-Dependent Manner, by Modulating Multiple Signaling Pathways","volume":"15","author":"Gahete","year":"2017","journal-title":"Mol. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102251","DOI":"10.1016\/j.dsx.2021.102251","article-title":"Metformin Addition to Androgen Deprivation Therapy Effect on Cancer Prostate Patients with Type 2 Diabetes","volume":"15","author":"Aboelnaga","year":"2021","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"622","DOI":"10.18632\/oncotarget.28458","article-title":"Utilizing Metformin to Prevent Metabolic Syndrome Due to Androgen Deprivation Therapy (ADT): A Randomized Phase II Study of Metformin in Non-Diabetic Men Initiating ADT for Advanced Prostate Cancer","volume":"14","author":"Mahalingam","year":"2023","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"GBD 2015 Obesity Collaborators (2017). Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N. Engl. J. Med., 377, 13\u201327.","DOI":"10.1056\/NEJMoa1614362"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1080\/13685538.2018.1430129","article-title":"Bioactive Compounds of the Mediterranean Diet and Prostate Cancer","volume":"21","author":"Saiz","year":"2018","journal-title":"Aging Male"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.phrs.2019.01.045","article-title":"Secoiridoids of Olive and Derivatives as Potential Coadjuvant Drugs in Cancer: A Critical Analysis of Experimental Studies","volume":"142","author":"Celano","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1007\/s00394-018-1864-1","article-title":"Hydroxytyrosol Inhibits Cancer Stem Cells and the Metastatic Capacity of Triple-Negative Breast Cancer Cell Lines by the Simultaneous Targeting of Epithelial-to-Mesenchymal Transition, Wnt\/\u03b2-Catenin and TGF\u03b2 Signaling Pathways","volume":"58","author":"Marchal","year":"2019","journal-title":"Eur. J. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1007\/s00394-018-1638-9","article-title":"Modulation by Hydroxytyrosol of Oxidative Stress and Antitumor Activities of Paclitaxel in Breast Cancer","volume":"58","author":"Quiles","year":"2019","journal-title":"Eur. J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Costantini, F., Di Sano, C., and Barbieri, G. (2020). The Hydroxytyrosol Induces the Death for Apoptosis of Human Melanoma Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218074"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Castej\u00f3n, M.L., Montoya, T., Alarc\u00f3n-de-la-lastra, C., and S\u00e1nchez-hidalgo, M. (2020). Potential Protective Role Exerted by Secoiridoids from Olea europaea L. in Cancer, Cardiovascular, Neurodegenerative, Aging-Related, and Immunoinflammatory Diseases. Antioxidants, 9.","DOI":"10.3390\/antiox9020149"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Vilaplana-P\u00e9rez, C., Au\u00f1\u00f3n, D., Garc\u00eda-Flores, L.A., and Gil-Izquierdo, A. (2014). Hydroxytyrosol and Potential Uses in Cardiovascular Diseases, Cancer, and AIDS. Front. Nutr., 1.","DOI":"10.3389\/fnut.2014.00018"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"390","DOI":"10.2174\/1871520621666210308095712","article-title":"A Comparison of the Anti-Cancer Effects of Free and PLGA-PAA Encapsulated Hydroxytyrosol on the HT-29 Colorectal Cancer Cell Line","volume":"22","author":"Sani","year":"2022","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Le\u00f3n-Gonz\u00e1lez, A.J., S\u00e1ez-Mart\u00ednez, P., Jim\u00e9nez-Vacas, J.M., Herrero-Aguayo, V., Montero-Hidalgo, A.J., G\u00f3mez-G\u00f3mez, E., Madrona, A., Casta\u00f1o, J.P., Espartero, J.L., and Gahete, M.D. (2021). Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells. Antioxidants, 10.","DOI":"10.3390\/antiox10091348"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ibrahim, R.S., Ibrahim, S.S., El-Naas, A., Koklesov\u00e1, L., Kubatka, P., and B\u00fcsselberg, D. (2023). Could Metformin and Resveratrol Support Glioblastoma Treatment? A Mechanistic View at the Cellular Level. Cancers, 15.","DOI":"10.3390\/cancers15133368"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"W488","DOI":"10.1093\/nar\/gkaa216","article-title":"SynergyFinder 2.0: Visual Analytics of Multi-Drug Combination Synergies","volume":"48","author":"Ianevski","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6721","DOI":"10.1158\/1078-0432.CCR-19-1587","article-title":"Transcriptomic Heterogeneity of Androgen Receptor Activity Defines a de Novo Low AR-Active Subclass in Treatment Na\u00efve Primary Prostate Cancer","volume":"25","author":"Spratt","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Libero, M.L., Montero-Hidalgo, A.J., Recinella, L., Luque, R.M., Generali, D., Acquaviva, A., Orlando, G., Ferrante, C., Menghini, L., and Di Simone, S.C. (2024). The Protective Effects of an Aged Black Garlic Water Extract on the Prostate. Nutrients, 16.","DOI":"10.3390\/nu16173025"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.1002\/ptr.8270","article-title":"Anti-inflammatory and Anti-hyperalgesic Effects Induced by an Aqueous Aged Black Garlic Extract in Rodent Models of Ulcerative Colitis and Colitis-associated Visceral Pain","volume":"38","author":"Libero","year":"2024","journal-title":"Phytother. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1158\/0008-5472.CAN-22-1065","article-title":"Establishment of the LNCaP Cell Line\u2013The Dawn of an Era for Prostate Cancer Research","volume":"82","year":"2022","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/pros.10290","article-title":"Molecular Characterization of Human Prostate Carcinoma Cell Lines","volume":"57","author":"Korch","year":"2003","journal-title":"Prostate"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wang, Y., Li, J., and Xia, L. (2023). Plant-Derived Natural Products and Combination Therapy in Liver Cancer. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1116532"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s12094-018-1950-0","article-title":"A Combination of Hydroxytyrosol, Omega-3 Fatty Acids and Curcumin Improves Pain and Inflammation among Early Stage Breast Cancer Patients Receiving Adjuvant Hormonal Therapy: Results of a Pilot Study","volume":"21","author":"Herrera","year":"2019","journal-title":"Clin. Transl. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Sharma, S., Cwiklinski, K., Mahajan, S.D., Schwartz, S.A., and Aalinkeel, R. (2023). Combination Modality Using Quercetin to Enhance the Efficacy of Docetaxel in Prostate Cancer Cells. Cancers, 15.","DOI":"10.3390\/cancers15030902"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"663","DOI":"10.4103\/1735-5362.389956","article-title":"Combination of Metformin and Gallic Acid Induces Autophagy and Apoptosis in Human Breast Cancer Cells","volume":"18","author":"Haghshenas","year":"2023","journal-title":"Res. Pharm. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2174\/2772432819666230504093227","article-title":"A Review on the Efficacy of Plant-Derived Bio-Active Compounds Curcumin and Aged Garlic Extract in Modulating Cancer and Age-Related Diseases","volume":"19","author":"Das","year":"2024","journal-title":"Curr. Rev. Clin. Exp. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Adewale, O.O., Wi\u0144ska, P., Piasek, A., and Cie\u015bla, J. (2024). The Potential of Plant Polysaccharides and Chemotherapeutic Drug Combinations in the Suppression of Breast Cancer. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252212202"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101945","DOI":"10.1016\/j.tranon.2024.101945","article-title":"Metformin as Anticancer Agent and Adjuvant in Cancer Combination Therapy: Current Progress and Future Prospect","volume":"44","author":"Zhu","year":"2024","journal-title":"Transl. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Westaby, D., Jimenez-Vacas, J.M., Padilha, A., Varkaris, A., Balk, S.P., de Bono, J.S., and Sharp, A. (2021). Targeting the Intrinsic Apoptosis Pathway: A Window of Opportunity for Prostate Cancer. Cancers, 14.","DOI":"10.3390\/cancers14010051"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.bbrc.2022.12.069","article-title":"Metformin Enhances Anti-Cancer Properties of Resveratrol in MCF-7 Breast Cancer Cells via Induction of Apoptosis, Autophagy and Alteration in Cell Cycle Distribution","volume":"644","author":"Fatehi","year":"2023","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.freeradbiomed.2022.01.010","article-title":"Metformin Inhibits the Tumor-Promoting Effect of Low-Dose Resveratrol, and Enhances the Anti-Tumor Activity of High-Dose Resveratrol by Increasing Its Reducibility in Triple Negative Breast Cancer","volume":"180","author":"Cheng","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"84190","DOI":"10.18632\/oncotarget.12391","article-title":"Metformin Potentiates Anti-Tumor Effect of Resveratrol on Pancreatic Cancer by down-Regulation of VEGF-B Signaling Pathway","volume":"7","author":"Zhu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1080\/01635581.2020.1783327","article-title":"Combination of Curcumin and Metformin Inhibits Cell Growth and Induces Apoptosis without Affecting the Cell Cycle in LNCaP Prostate Cancer Cell Line","volume":"73","author":"Eslami","year":"2021","journal-title":"Nutr. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/j.1365-2184.2011.00757.x","article-title":"CXCL13 Mediates Prostate Cancer Cell Proliferation through JNK Signalling and Invasion through ERK Activation","volume":"44","author":"Singh","year":"2011","journal-title":"Cell Prolif."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1134\/S160767292006006X","article-title":"Prostate Cancer Growth Inhibition by 1-(3,5-Dimethylphenyl)\u20136-Methyl-1H-Pyrazolo [4,3-c]Pyridin-4(5H)-One via Down-Regulation of Phosphorylation PI3K\/AKT and STA3\/JAK2","volume":"495","author":"Xue","year":"2020","journal-title":"Dokl. Biochem. Biophys."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.bbamcr.2006.10.001","article-title":"Roles of the Raf\/MEK\/ERK Pathway in Cell Growth, Malignant Transformation and Drug Resistance","volume":"1773","author":"McCubrey","year":"2007","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s13046-019-1156-5","article-title":"ACE2 Inhibits Breast Cancer Angiogenesis via Suppressing the VEGFa\/VEGFR2\/ERK Pathway","volume":"38","author":"Zhang","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"110893","DOI":"10.1016\/j.cellsig.2023.110893","article-title":"DUSP2 Affects Bladder Cancer Prognosis by Down-Regulating MEK\/ERK and P38 MAPK Signaling Pathways through PTPN7","volume":"112","author":"Zou","year":"2023","journal-title":"Cell. Signal."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"MTOR Signaling in Growth Control and Disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1128\/MMBR.68.2.320-344.2004","article-title":"ERK and P38 MAPK-Activated Protein Kinases: A Family of Protein Kinases with Diverse Biological Functions","volume":"68","author":"Roux","year":"2004","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e24332","DOI":"10.1002\/jcla.24332","article-title":"The Expression and Significance of P4E-BP1\/4E-BP1 in Prostate Cancer","volume":"36","author":"Wang","year":"2022","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1158\/1541-7786.MCR-17-0696","article-title":"The MTOR Targets 4E-BP1\/2 Restrain Tumor Growth and Promote Hypoxia Tolerance in PTEN-Driven Prostate Cancer","volume":"16","author":"Ding","year":"2018","journal-title":"Mol. Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3754","DOI":"10.1158\/1078-0432.CCR-10-0439","article-title":"Ten Common Genetic Variants Associated with Colorectal Cancer Risk Are Not Associated with Survival after Diagnosis","volume":"16","author":"Tenesa","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/path.1605","article-title":"The Role of C-Jun and c-Fos Expression in Androgen-Independent Prostate Cancer","volume":"204","author":"Edwards","year":"2004","journal-title":"J. Pathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"101470","DOI":"10.1016\/j.isci.2020.101470","article-title":"Smad7 Enhances TGF-\u03b2-Induced Transcription of c-Jun and HDAC6 Promoting Invasion of Prostate Cancer Cells","volume":"23","author":"Thakur","year":"2020","journal-title":"iScience"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.4161\/cc.29339","article-title":"TGF\u03b2-Induced Invasion of Prostate Cancer Cells Is Promoted by c-Jun-Dependent Transcriptional Activation of Snail1","volume":"13","author":"Thakur","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s13046-018-0809-0","article-title":"SPOP Promotes ATF2 Ubiquitination and Degradation to Suppress Prostate Cancer Progression","volume":"37","author":"Ma","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s12943-023-01825-8","article-title":"STAT3\/LKB1 Controls Metastatic Prostate Cancer by Regulating MTORC1\/CREB Pathway","volume":"22","author":"Pencik","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1002\/pros.23000","article-title":"Metformin Represses Androgen-dependent and Androgen-independent Prostate Cancers by Targeting Androgen Receptor","volume":"75","author":"Wang","year":"2015","journal-title":"Prostate"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"E469","DOI":"10.1210\/clinem\/dgaa580","article-title":"Influence of Obesity in the MiRNome: MiR-4454, a Key Regulator of Insulin Response Via Splicing Modulation in Prostate","volume":"106","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.tiv.2007.03.003","article-title":"A Mathematical Approach to Study Combined Effects of Toxicants in Vitro: Evaluation of the Bliss Independence Criterion and the Loewe Additivity Model","volume":"21","author":"Goldoni","year":"2007","journal-title":"Toxicol. Vitr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"eado8231","DOI":"10.1126\/sciadv.ado8231","article-title":"SRSF6 Modulates Histone-Chaperone HIRA Splicing to Orchestrate AR and E2F Activity in Prostate Cancer","volume":"10","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.trsl.2022.08.016","article-title":"Tumor Suppressor Role of RBM22 in Prostate Cancer Acting as a Dual-Factor Regulating Alternative Splicing and Transcription of Key Oncogenic Genes","volume":"253","author":"Closa","year":"2023","journal-title":"Transl. Res."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Rueden, C.T., Schindelin, J., Hiner, M.C., Dezonia, B.E., Walter, A.E., Arena, E.T., and Eliceiri, K.W. (2017). ImageJ2: ImageJ for the next Generation of Scientific Image Data. BMC Bioinform., 18.","DOI":"10.1186\/s12859-017-1934-z"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cyto.990080101","article-title":"A Pragmatic Approach to the Analysis of DNA Histograms with a Definable G1 Peak","volume":"8","author":"Watson","year":"1987","journal-title":"Cytometry"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Vandesompele, J., De Preter, K., Pattyn, F., Poppe, B., Van Roy, N., De Paepe, A., and Speleman, F. (2002). Accurate Normalization of Real-Time Quantitative RT-PCR Data by Geometric Averaging of Multiple Internal Control Genes. Genome Biol., 3.","DOI":"10.1186\/gb-2002-3-7-research0034"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/3\/1341\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:27:18Z","timestamp":1760027238000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/3\/1341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,5]]},"references-count":70,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ijms26031341"],"URL":"https:\/\/doi.org\/10.3390\/ijms26031341","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,5]]}}}