{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:01:26Z","timestamp":1790787686667,"version":"4.1.0"},"reference-count":117,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T00:00:00Z","timestamp":1700611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o de Amaparo \u00e0 Pesquisa do Estado de Goi\u00e1s (FAPEG)","award":["202010267000183"],"award-info":[{"award-number":["202010267000183"]}]},{"name":"Funda\u00e7\u00e3o de Amaparo \u00e0 Pesquisa do Estado de Goi\u00e1s (FAPEG)","award":["MFAG-27142"],"award-info":[{"award-number":["MFAG-27142"]}]},{"name":"MUR-PNRR M4C2I1.3 PE6 project PE00000019 Heal Italia","award":["202010267000183"],"award-info":[{"award-number":["202010267000183"]}]},{"name":"MUR-PNRR M4C2I1.3 PE6 project PE00000019 Heal Italia","award":["MFAG-27142"],"award-info":[{"award-number":["MFAG-27142"]}]},{"name":"Italian Association for Cancer Research (AIRC)","award":["202010267000183"],"award-info":[{"award-number":["202010267000183"]}]},{"name":"Italian Association for Cancer Research (AIRC)","award":["MFAG-27142"],"award-info":[{"award-number":["MFAG-27142"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products. Among the latter, flavonoids, the most prevalent polyphenols in plants, have shown remarkable competence in improving TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice with minimal side effects. Here, we summarize the molecular mechanisms, such as the upregulation of death receptor (DR)4 and DR5 and downregulation of key anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones, flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss limitations, mainly related to bioavailability issues, and future perspectives regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based therapies.<\/jats:p>","DOI":"10.3390\/ijms242316596","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T03:54:37Z","timestamp":1700625277000},"page":"16596","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["TRAIL-Sensitizing Effects of Flavonoids in Cancer"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0940-2252","authenticated-orcid":false,"given":"Anderson","family":"Luiz-Ferreira","sequence":"first","affiliation":[{"name":"Inflammatory Bowel Disease Research Laboratory, Department of Biological Sciences, Institute of Biotechnology, Federal University of Catal\u00e3o (UFCAT), Catal\u00e3o 75704020, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5755-3672","authenticated-orcid":false,"given":"Teresa","family":"Pacifico","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1lefe Cardoso","family":"Cruz","sequence":"additional","affiliation":[{"name":"Inflammatory Bowel Disease Research Laboratory, Department of Biological Sciences, Institute of Biotechnology, Federal University of Catal\u00e3o (UFCAT), Catal\u00e3o 75704020, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Laudisi","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1339-9076","authenticated-orcid":false,"given":"Giovanni","family":"Monteleone","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6354-2443","authenticated-orcid":false,"given":"Carmine","family":"Stolfi","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_2","unstructured":"GBD 2019 Cancer Risk Factors Collaborators (2022). 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