{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T15:39:44Z","timestamp":1777390784782,"version":"3.51.4"},"reference-count":60,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colon cancer (CC) is a common malignancy characterized by poor prognostic outcomes and considerable mortality. Oxaliplatin (OXP) is commonly used in the treatment of CC; however, its efficacy may be limited by side effects and the development of resistance. \u03b2-sitosterol (\u03b2-Sit), a phytosterol derived from plants, has been documented to be effective in the treatment of tumors. This study aimed to investigate the potential of \u03b2-Sit to enhance the antitumor efficacy of OXP in COLO-205 cells, focusing on apoptosis induction and suppression of the vascular endothelial growth factor A (VEGF-A)\/survival pathway. Molecular docking studies were performed to assess the binding affinity of \u03b2-Sit with the target proteins B-cell lymphoma 2 (Bcl-2), phosphoinositide 3-kinase (PI3K), and VEGF receptor-2 (VEGFR-2). COLO-205 cells were treated with OXP, \u03b2-Sit, or a combination of OXP + \u03b2-Sit for 48 h. The combination treatment substantially lowered the IC50 achieved with 3.24 \u00b5M of OXP and 36.01 \u00b5M of \u03b2-Sit, compared to 25.64 \u00b5M for OXP alone and 275.9 \u00b5M for \u03b2-Sit alone, demonstrating a pronounced synergistic impact. The combined therapy altered the cell cycle distribution by decreasing the number of cells in the G0\/G, S, and G2\/M phases, coupled with an increase in the Sub-G1 population. Furthermore, apoptosis was augmented by a shift in cell death from necrosis to late apoptosis, as indicated by an increased BAX\/BCL2 ratio relative to each treatment alone. Moreover, the inhibitory effect on angiogenesis was enhanced via the reduction of VEGF-A, and \u03b2-catenin and nuclear factor \u03baB (NF-\u03baB-p65) were suppressed, thereby preventing the growth and survival of resistant cancer cells. Additionally, molecular docking supported high binding affinities of \u03b2-Sit to Bcl-2, PI3K, and VEGFR-2. This study highlights the potential of \u03b2-Sit to enhance the anti-cancer efficacy of OXP in CC.<\/jats:p>","DOI":"10.3390\/ijms262210897","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T13:51:08Z","timestamp":1762782668000},"page":"10897","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["\u03b2-Sitosterol Enhances the Anticancer Efficacy of Oxaliplatin in COLO-205 Cells via Apoptosis and Suppression of VEGF-A, NF-\u03baB-p65, and \u03b2-Catenin"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1524-7247","authenticated-orcid":false,"given":"Sahar","family":"Khateeb","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fahad M.","family":"Almutairi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5880-973X","authenticated-orcid":false,"given":"Adel I.","family":"Alalawy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9249-3649","authenticated-orcid":false,"given":"Amnah","family":"Obidan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4955-5705","authenticated-orcid":false,"given":"Mody","family":"Albalawi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rehab","family":"Al-Massabi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2613-7553","authenticated-orcid":false,"given":"Hanan Abdulrahman","family":"Sagini","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Sciences, University of Jeddah, Jeddah 21959, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8189-5998","authenticated-orcid":false,"given":"Samah S.","family":"Abuzahrah","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Sciences, University of Jeddah, Jeddah 21959, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eman F. S.","family":"Taha","sequence":"additional","affiliation":[{"name":"Health Radiation Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority (EAEA), Cairo 11787, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101174","DOI":"10.1016\/j.tranon.2021.101174","article-title":"Global Colorectal Cancer Burden in 2020 and Projections to 2040","volume":"14","author":"Xi","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1056\/NEJM199704033361402","article-title":"Improved Survival with Pre-Operative Radiotherapy in Resectable Rectal Cancer","volume":"336","author":"Cedermark","year":"1997","journal-title":"N. Engl. J. 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