{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:55:41Z","timestamp":1790178941213,"version":"4.1.0"},"reference-count":61,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T00:00:00Z","timestamp":1729468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministero dello Sviluppo Economico (MISE)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteosarcoma (OS) is the most severe bone tumor in children. A chemotherapy regimen includes a combination of high-dose Methotrexate (MTX), doxorubicin, and cisplatin. These drugs cause acute and chronic side effects, such as infections, thrombocytopenia, neutropenia, DNA damage, and inflammation. Therefore, to identify new therapeutic strategies, effective and with a safety profile, is necessary. The Hedgehog (Hh) signaling pathway involved in tumorigenesis is active in OS. Hh components Patched receptor 1 (PTCH1), Smoothened (SMO), and glioma-associated oncogene homolog transcription factors (GLI1 and GLI2) are overexpressed in OS cell lines and patient samples. Curcumin (CUR)\u2014with antioxidant and anti-cancer properties\u2014downregulates Hh components in cancer, inhibiting progression. This study investigates CUR effects on the MG-63 OS cell line, alone and combined with MTX, to propose a novel therapeutic approach. Our study suggests CUR as a novel therapeutic agent in OS, particularly when combined with MTX. Targeting the Hh signaling pathway, CUR and MTX showed significant pro-apoptotic effects, increasing the BAX\/Bcl-2 ratio and total apoptotic cell percentage. They reduced the expression of Hh pathway components (PTCH1, SMO, GLI1, and GLI2), inhibiting OS cell proliferation, survival, and invasion. CUR and MTX combined determined a \u03b2-Catenin decrease and a trend toward reducing NF-kB and matrix metalloproteinases (MMP-2 and MMP-9). Our findings suggest CUR as a support to OS treatment, improving outcomes and reducing the adverse effects of current therapies.<\/jats:p>","DOI":"10.3390\/ijms252011300","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T03:57:09Z","timestamp":1729483029000},"page":"11300","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Curcumin and Methotrexate: A Promising Combination for Osteosarcoma Treatment via Hedgehog Pathway Inhibition"],"prefix":"10.3390","volume":"25","author":[{"given":"Giulia","family":"Giliberti","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Maddalena","family":"Marrapodi","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Di Feo","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Pota","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Di Martino","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9396-2906","authenticated-orcid":false,"given":"Daniela","family":"Di Pinto","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Di Paola","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Napoli, Italy"},{"name":"Department of Life Sciences, Health and Health Professions, Link Campus University, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Argenziano, M., Tortora, C., Pota, E., Di Paola, A., Di Martino, M., Di Leva, C., Di Pinto, D., and Rossi, F. 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