Cooperative Suppression of Ovarian Cancer Growth by 1,25-Dihydroxyvitamin D3 and Sodium Selenite Mediated Through SEPP1 Induction

Sep 22, 2026

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Advanced epithelial ovarian cancer shows poor responses to current therapies, creating demand for new treatment approaches. This study demonstrates that combined sodium selenite (Na2SeO3) and 1,25-dihydroxyvitamin D3 (1,25D3) produces stronger anti-proliferative effects on ovarian cancer cells in vitro and in vivo. 1,25D3 increases VDR and SEPP1 expression, further enhanced by Na2SeO3, while VDR or SEPP1 knockout abolishes the synergy. Mechanistic work supports SEPP1 as a direct VDR target with VDREs, and low-dose combination outperforms 1,25D3 alone without notable hypercalcemia, ascites, or metastasis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Background and clinical limitations

Rationale for vitamin D3 and sodium selenite

Study objective and approach

Synergy hypothesis for low-dose 1,25D3

Mechanistic focus on VDR and SEPP1

Cancer Medicine RESEARCH ARTICLE OPEN ACCESS Cooperative Suppression of Ovarian Cancer Growth by 1,25-Dihydroxyvitamin D3 and Sodium Selenite Mediated Through SEPP1 Induction Yanmin Zhang1,2,3,4 | Yaxi Shi4 | Wenlong Bai1,4 1School of Life Sciences, Henan Institute of Science and Technology, Xinxiang, China | 2Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China | 3Henan Gynecological Diseases (Gynecology Oncology) Clinical Research Center, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China | 4School of Life Sciences, Henan University, Kaifeng, China Correspondence: Wenlong Bai ([wbaiful@gmail.com](wbaiful@gmail.com)) Received: 23 May 2026 | Revised: 7 August 2026 | Accepted: 18 August 2026 Keywords: 1,25D3 | Na2SeO3 | ovarian cancer | SEPP1 | VDR ABSTRACT Advanced epithelial ovarian cancer responds poorly to current treatments, creating an urgent need for novel therapeutic strategies. 1,25-dihydroxyvitamin D3 (1,25D3) exerts potent anti-proliferative effects on ovarian cancer cells in vitro, but the concentrations required for growth suppression in cell culture are not readily achievable in vivo, and higher doses induce hypercalcemia, which hinders its clinical translation. Sodium selenite (Na2SeO3) has been identified as a chemopreventive agent that inhibits the growth of multiple cancer types. In this study, we demonstrated that combined treatment with Na2SeO3 and 1,25D3 exerts enhanced anti-proliferative efficacy against ovarian cancer cells both in vitro and in vivo. Specifically, 1,25D3 upregulated the expression of vitamin D receptor (VDR) and Selenoprotein-P1 (SEPP1), and this effect was further enhanced by Na2SeO3 cotreatment. Consistently, Na2SeO3 augmented the suppressive effect of 1,25D3 on ovarian cancer cell proliferation, demonstrating synergistic inhibitory activity. Notably, knockout (KO) of either VDR or SEPP1 abrogated this synergistic effect. Mechanistic investigations confirmed that SEPP1 is a direct target gene of VDR, and functional vitamin D response elements (VDREs) are present within its genomic locus. In vivo, low-dose 1,25D3 (0.3 μg/kg) combined with Na2SeO3 outperformed 1,25D3 monotherapy, with no significant hypercalcemia, ascites formation, or metastasis observed throughout the treatment period. These findings indicate that Na2SeO3 acts in combination with 1,25D3 to induce SEPP1 expression, thereby enhancing the antitumor efficacy of low-dose 1,25D₃ against ovarian tumors. This study provides a promising strategy for the safe and effective application of 1,25D3 in ovarian cancer therapy. 1 | Introduction Ovarian cancer is dubbed the “king of gynecological cancers”and stands as the deadliest among gynecological malignancies [1, 2]. Notably, its mortality rate in China has risen by 3% annually since 2016 [3], with comparable upward trends documented in other countries globally [4] . Owing to the insidious nature of its onset, more than 70% of ovarian cancer cases are diagnosed at advanced stages, and 5-year survival rates remain below 30% [5]. The limited therapeutic efficacy of current treatments for advanced ovarian cancer underscores the urgent need to develop novel therapeutic strategies [6] . Multiple epidemiological studies have reported an inverse association between ovarian cancer mortality and ultraviolet B exposure [7, 8], which drives approximately 90% of endogenous vitamin D3 production [9] . Consistently, elevated plasma vitamin D levels are associated with reduced ovarian cancer risk 3 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2026 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd. Cancer Medicine, 2026; 15:e7

FAQs

How does the combination of Na2SeO3 and 1,25D3 affect ovarian cancer cells?

The combined treatment enhances anti-proliferative efficacy against ovarian cancer cells both in vitro and in vivo, showing synergistic inhibitory activity compared with 1,25D3 alone.

What molecular pathway mediates the synergy between 1,25D3 and Na2SeO3?

1,25D3 upregulates VDR and SEPP1, and Na2SeO3 further enhances this effect. SEPP1 is supported as a direct target of VDR with functional VDREs in its genomic locus, and knocking out VDR or SEPP1 eliminates the synergy.

Does low-dose combination therapy cause major side effects in vivo?

Low-dose 1,25D3 combined with Na2SeO3 outperforms monotherapy without significant hypercalcemia, ascites formation, or metastasis observed during the treatment period.

Sep 22, 2026

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