Vitamin D Analogs Regulate the Vitamin D System and Cell Viability in Ovarian Cancer Cells

International Journal of Molecular Sciences

Andrzej Kutner¹  Urszula Nowak²  Ewa Marcinkowska²  Karina Piatek³  Teresa Manhardt³  Nadja Kupper³  Martin Schepelmann³  Enikö Kallay³  Dan Cacsire Castillo-Tong⁴  Michał Chodyński⁵ 

[1] Department of Bioanalysis and Drug Analysis, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland;Faculty of Biotechnology, University of Wrocław, Joliot-Curie 14a, 50-383 Wrocław, Poland;Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria;Translational Gynecology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria;Łukasiewicz Research Network—Industrial Chemistry Institute, 8 Rydygiera, 01-793 Warsaw, Poland;

关键词: vitamin D;    vitamin D analogs;    25 vitamin D 24-hydroxylase;    CYP24A1;    proliferation;    high-grade serous ovarian cancer cells;   

DOI  :  10.3390/ijms23010172

来源: DOAJ

【 摘 要 】

Background: Ovarian cancer (OC) is one of the most lethal cancers in women. The active form of vitamin D₃, 1,25-dihydroxyvitamin D₃ (1,25D₃, calcitriol) has anticancer activity in several cancers, including ovarian cancer, but the required pharmacological doses may cause hypercalcemia. We hypothesized that newly developed, low calcemic, vitamin D analogs (an1,25Ds) may be used as anticancer agents instead of calcitriol in ovarian cancer cells. Methods: We used two patient-derived high-grade serous ovarian cancer (HGSOC) cell lines with low (13781) and high (14433) mRNA expression levels of the gene encoding 1,25-dihydroxyvitamin D₃ 24-hydroxylase CYP24A1, one of the main target genes of calcitriol. We tested the effect of calcitriol and four structurally related series of an1,25Ds (PRI-1906, PRI-1907, PRI-5201, PRI-5202) on cell number, viability, the expression of CYP24A1, and the vitamin D receptor (VDR). Results: CYP24A1 mRNA expression increased in a concentration-dependent manner after treatment with all compounds. In both cell lines, after 4 h, PRI-5202 was the most potent analog (in 13781 cells: EC₅₀ = 2.98 ± 1.10 nmol/L, in 14433 cells: EC₅₀ = 0.92 ± 0.20 nmol/L), while PRI-1907 was the least active one (in 13781 cells: EC₅₀ = n/d, in 14433 cells: EC₅₀ = n/d). This difference among the analogs disappeared after 5 days of treatment. The 13781 cells were more sensitive to the an1,25Ds compared with 14433 cells. The an1,25Ds increased nuclear VDR levels and reduced cell viability, but only in the 13781 cell line. Conclusions: The an1,25Ds had different potencies in the HGSOC cell lines and their efficacy in increasing CYP24A1 expression was cell line- and chemical structure-dependent. Therefore, choosing sensitive cancer cell lines and further optimization of the analogs’ structure might lead to new treatment options against ovarian cancer.

【 授权许可】

Unknown