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

Advanced epithelial ovarian cancer responds poorly to current treatments, creating an urgent need for novel therapeutic strategies. 1,25-dihydroxyvitamin D 3 (1,25D 3 ) 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 (Na 2 SeO 3 ) has been identified as a chemopreventive agent that inhibits the growth of multiple cancer types. In this study, we demonstrated that combined treatment with Na 2 SeO 3 and 1,25D 3 exerts enhanced anti-proliferative efficacy against ovarian cancer cells both in vitro and in vivo. Specifically, 1,25D 3 upregulated the expression of vitamin D receptor (VDR) and Selenoprotein-P1 (SEPP1), and this effect was further enhanced by Na 2 SeO 3 co-treatment. Consistently, Na 2 SeO 3 augmented the suppressive effect of 1,25D 3 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 1,25D 3 (0.3 μg/kg) combined with Na 2 SeO 3 outperformed 1,25D 3 monotherapy, with no significant hypercalcemia, ascites formation, or metastasis observed throughout the treatment period. These findings indicate that Na 2 SeO 3 acts in combination with 1,25D 3 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 1,25D 3 in ovarian cancer therapy.