{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T23:21:41Z","timestamp":1776295301076,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T00:00:00Z","timestamp":1727654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Invitalia Brevetti+","award":["BRE0000830"],"award-info":[{"award-number":["BRE0000830"]}]},{"name":"Invitalia Brevetti+","award":["ECS00000024"],"award-info":[{"award-number":["ECS00000024"]}]},{"name":"Invitalia Brevetti+","award":["CUP B83C22002890005"],"award-info":[{"award-number":["CUP B83C22002890005"]}]},{"name":"European Union\u2014Next Generation EU, within the PNRR project \u201cRome Technopole\u2014Innovation Ecosystem\u201d","award":["BRE0000830"],"award-info":[{"award-number":["BRE0000830"]}]},{"name":"European Union\u2014Next Generation EU, within the PNRR project \u201cRome Technopole\u2014Innovation Ecosystem\u201d","award":["ECS00000024"],"award-info":[{"award-number":["ECS00000024"]}]},{"name":"European Union\u2014Next Generation EU, within the PNRR project \u201cRome Technopole\u2014Innovation Ecosystem\u201d","award":["CUP B83C22002890005"],"award-info":[{"award-number":["CUP B83C22002890005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glioblastoma (GBL) is one of the more malignant primary brain tumors; it is currently treated by a multimodality strategy including surgery, and radio- and chemotherapy, mainly consisting of temozolomide (TMZ)-based chemotherapy. Tumor relapse often occurs due to the establishment of TMZ resistance, with a patient median survival time of &lt;2 years. The identification of natural molecules with strong anti-tumor activity led to the combination of these compounds with conventional chemotherapeutic agents, developing protocols for integrated anticancer therapies. Curcumin (CUR), resveratrol (RES), and its glucoside polydatin (PLD) are widely employed in the pharmaceutical and nutraceutical fields, and several studies have demonstrated that the combination of these natural products was more cytotoxic than the individual compounds alone against different cancers. Some of us recently demonstrated the synergistic efficacy of the sublingual administration of a new nutraceutical formulation of CUR+PLD in reducing tumor size and improving GBL patient survival. To provide some experimental evidence to reinforce these clinical results, we investigated if pretreatment with a combination of CUR+PLD can improve TMZ cytotoxicity on GBL cells by analyzing the effects on cell cycle, viability, morphology, expression of proteins related to cell proliferation, differentiation, apoptosis or autophagy, and the actin network. Cell viability was assessed using the MTT assay or a CytoSmart cell counter. CalcuSyn software was used to study the CUR+PLD synergism. The morphology was evaluated by optical and scanning electron microscopy, and protein expression was analyzed by Western blot. Flow cytometry was used for the cell cycle, autophagic flux, and apoptosis analyses. The results provide evidence that CUR and PLD, acting in synergy with each other, strongly improve the efficacy of alkylating anti-tumor agents such as TMZ on drug-resistant GBL cells through their ability to affect survival, differentiation, and tumor invasiveness.<\/jats:p>","DOI":"10.3390\/ijms251910572","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T03:57:52Z","timestamp":1727755072000},"page":"10572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Synergistic Combination of Curcumin and Polydatin Improves Temozolomide Efficacy on Glioblastoma Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1142-4752","authenticated-orcid":false,"given":"Annalucia","family":"Serafino","sequence":"first","affiliation":[{"name":"Institute of Translational Pharmacology, National Research Council of Italy (CNR), 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9137-5446","authenticated-orcid":false,"given":"Ewa Krystyna","family":"Krasnowska","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, National Research Council of Italy (CNR), 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Roman\u00f2","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, National Research Council of Italy (CNR), 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6560-293X","authenticated-orcid":false,"given":"Alex","family":"De Gregorio","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, National Research Council of Italy (CNR), 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7522-7483","authenticated-orcid":false,"given":"Marisa","family":"Colone","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Italian National Institute of Health (ISS), 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6051-8261","authenticated-orcid":false,"given":"Maria Luisa","family":"Dupuis","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Italian National Institute of Health (ISS), 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8245-8642","authenticated-orcid":false,"given":"Massimo","family":"Bonucci","sequence":"additional","affiliation":[{"name":"Association for Research on Integrative Oncology Therapies (ARTOI) Foundation, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7741-4979","authenticated-orcid":false,"given":"Giampietro","family":"Ravagnan","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, National Research Council of Italy (CNR), 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0143-2978","authenticated-orcid":false,"given":"Annarita","family":"Stringaro","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Italian National Institute of Health (ISS), 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Pia","family":"Fuggetta","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, National Research Council of Italy (CNR), 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1056\/NEJM200011093431901","article-title":"Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents","volume":"343","author":"Esteller","year":"2000","journal-title":"N. 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