{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T19:09:33Z","timestamp":1774638573610,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003566","name":"Ministry of Oceans and Fisheries, Republic of Korea","doi-asserted-by":"publisher","award":["RS-2021-KS211475"],"award-info":[{"award-number":["RS-2021-KS211475"]}],"id":[{"id":"10.13039\/501100003566","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education","award":["RS-2021-KS211475"],"award-info":[{"award-number":["RS-2021-KS211475"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Vitamin C, also known as L-ascorbic acid (AA), functions as a pro-oxidant in cancer at high doses and exerts anticancer effects by generating reactive oxygen species (ROS) and selectively inducing damage to cancer cells. However, AA at low doses promotes cancer cell proliferation. The efficacy of high-dose AA therapy is frequently restricted by inadequate intracellular AA uptake, resulting from low expression of sodium-dependent vitamin C transporter 2 (SVCT2). In this study, we investigated whether valproic acid (VPA), a histone deacetylase inhibitor, could circumvent this constraint by increasing the expression of SVCT2 in colorectal cancer cells, including HCT-116 and DLD-1 with low SVCT2 levels. We found that VPA increased SVCT2 expression in both cell lines. Co-treatment with AA and VPA increased the number of apoptotic cells and enhanced intracellular AA uptake via VPA-upregulated SVCT2, followed by increased ROS production in both cell lines. Furthermore, the combination increased the synergistic anticancer effects and suppressed the hormetic dose response of AA in both cell lines. In a xenograft mouse model, co-treatment decreased tumor size and increased the tumor growth inhibition ratio compared to treatment with AA or VPA alone. Accordingly, VPA treatment enhanced SVCT2 expression in colorectal cancer cells, suppressed the hormetic dose-response effect of AA, and improved the potential of high-dose AA therapy as an anticancer agent.<\/jats:p>","DOI":"10.3390\/antiox14070864","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T12:55:00Z","timestamp":1752670500000},"page":"864","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Valproic Acid Enhances the Anticancer Effect of L-Ascorbic Acid by Upregulating Sodium-Dependent Vitamin C Transporter 2 in Colorectal Cancer"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5962-3053","authenticated-orcid":false,"given":"Kawalin","family":"Kantawong","sequence":"first","affiliation":[{"name":"Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hakim Meutia","family":"Diva","sequence":"additional","affiliation":[{"name":"Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phuong T.","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahlim","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misae","family":"Kiba","sequence":"additional","affiliation":[{"name":"Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mi-Gi","family":"Lee","sequence":"additional","affiliation":[{"name":"Gyeonggi Bio Center, Suwon 16229, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5576-9317","authenticated-orcid":false,"given":"Hee","family":"Kang","sequence":"additional","affiliation":[{"name":"Humanitas College, Kyung Hee University, 1732 Deogyeong-daero, Yongin 17104, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6090-507X","authenticated-orcid":false,"given":"Taek-Kyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Ecological Risk Research Department, Korea Institute of Ocean Science & Technology, Geoje 53201, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9964-0176","authenticated-orcid":false,"given":"Sukchan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13604","DOI":"10.1073\/pnas.0506390102","article-title":"Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues","volume":"102","author":"Chen","year":"2005","journal-title":"Proc. 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