{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T01:26:46Z","timestamp":1783646806021,"version":"3.55.0"},"reference-count":87,"publisher":"Georg Thieme Verlag KG","issue":"04","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Drug Res (Stuttg)"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\n          Introduction Osteosarcoma (OS) is one of the most common bone neoplasms in\n                    adolescents. Notable short- and long-term toxic effects of OS chemotherapy\n                    regimens have been reported. Hence, new chemotherapeutic agents with the ability\n                    to potentiate OS chemotherapy drugs and protect non-tumorous tissues are\n                    required.<\/jats:p><jats:p>\n          Methods Saos-2 cells were treated with Methotrexate (MTX) and Quercetin\n                    (Que) (a polyphenolic flavonoid with anti-tumor effects) alone and in\n                    combination. MTT assay was performed to investigate the cytotoxicity of the\n                    drugs. Moreover, apoptosis-involved genes, including miR-223, p53,\n                        BCL-2, CBX7, and CYLD expression were analyzed via qRT-PCR. Annexin\n                    V-FITC\/PI kit was employed to assess the apoptosis rate.<\/jats:p><jats:p>\n          Results The MTT results showed that Que increases MTX cytotoxicity on OS\n                    cells. The measured IC50s are 142.3\u2009\u00b5M for QUE and\n                    13.7\u2009ng\/ml for MTX. A decline in MTX IC50 value was observed\n                    from 13.7\u2009ng\/ml to 8.45\u2009ng\/ml in the presence of\n                    Que. Moreover, the mRNA expression outcomes indicated that the combination\n                    therapy significantly up-regulates the tumor suppressor genes, such as p53,\n                    CBX7, and CYLD, and declines anti-apoptotic genes BCL-2 and miR-223, which can\n                    lead to proliferation inhibition and apoptosis inducement. Furthermore, the\n                    apoptosis rate increased significantly from 6.03% in the control group\n                    to 38.35% in Saos-2 cells that were treated with the combination of MTX\n                    and Que.<\/jats:p><jats:p>\n          Conclusion Que, with the potential to boost the anticancer activity of MTX\n                    on Saos-2 cancer cells through proliferation inhibition and apoptosis induction,\n                    is a good candidate for combination therapy.<\/jats:p>","DOI":"10.1055\/a-1709-0658","type":"journal-article","created":{"date-parts":[[2022,4,6]],"date-time":"2022-04-06T23:50:54Z","timestamp":1649289054000},"page":"226-233","source":"Crossref","is-referenced-by-count":11,"title":["Quercetin and Methotrexate in Combination have Anticancer Activity in\n                    Osteosarcoma Cells and Repress Oncogenic MicroRNA-223"],"prefix":"10.1055","volume":"72","author":[{"given":"Erfan","family":"Mohammadi","sequence":"additional","affiliation":[{"name":"Drug Applied Research Center, Tabriz University of Medical Sciences,\n                    Tabriz, Iran"},{"name":"Department of Biology, Faculty of Natural Sciences, University of\n                    Tabriz, Tabriz, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Forough","family":"Alemi","sequence":"additional","affiliation":[{"name":"Drug Applied Research Center, Tabriz University of Medical Sciences,\n                    Tabriz, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masomeh","family":"Maleki","sequence":"additional","affiliation":[{"name":"Drug Applied Research Center, Tabriz University of Medical Sciences,\n                    Tabriz, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faezeh","family":"Malakoti","sequence":"additional","affiliation":[{"name":"Drug Applied Research Center, Tabriz University of Medical Sciences,\n                    Tabriz, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nader","family":"Farsad-Akhtar","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Natural Sciences, University of\n                    Tabriz, Tabriz, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahman","family":"Yousefi","sequence":"additional","affiliation":[{"name":"Drug Applied Research Center, Tabriz University of Medical Sciences,\n                    Tabriz, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2022,4,6]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.mayocp.2012.01.015","article-title":"Common musculoskeletal tumors of childhood and adolescence","volume":"87","author":"CA S Arndt","year":"2012","journal-title":"Mayo Clinic proceedings"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.ctrv.2006.05.005","article-title":"Primary bone osteosarcoma in the pediatric age: state of the art.","volume":"32","author":"A Longhi","year":"2006","journal-title":"Cancer treatment reviews"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"153176","DOI":"10.1016\/j.prp.2020.153176","article-title":"miR-192 enhances sensitivity of methotrexate drug to MG-63 osteosarcoma cancer\n                    cells","volume":"216","author":"M Bazavar","year":"2020","journal-title":"Pathology-Research and Practice"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1615\/CritRevOncog.2015013713","article-title":"Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate\n                    Therapies","volume":"20","author":"J J Morrow","year":"2015","journal-title":"Critical reviews in oncogenesis"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/1097-0142(19800701)46:1<178::AID-CNCR2820460130>3.0.CO;2-C","article-title":"Definitions of osteosarcoma, chondrosarcoma, and fibrosarcoma of bone","volume":"46","author":"N G Sanerkin","year":"1980","journal-title":"Cancer"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.bone.2013.02.016","article-title":"Modeling distinct osteosarcoma subtypes in vivo using Cre:lox and\n                    lineage-restricted transgenic shRNA","volume":"55","author":"A J Mutsaers","year":"2013","journal-title":"Bone"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/sj.ejhg.5201012","article-title":"Multiple primary malignancies in osteosarcoma patients. 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