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

Abstract

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.

The Effect of Vitamin D and Its Analogs in Ovarian Cancer

“…One study reported higher levels in ovarian tumors compared with healthy tissue [31], while others found that the VDR level was lower in tumors than in normal ovaries [32]. Treatment of OC cell lines with 1,25D3 or its analogs has no effect on VDR mRNA levels, while it might increase protein levels in a cell line-dependent manner [30,33]. Interestingly, the effect of 1,25D3 or its analogs on the expression of CYP24A1 in different OC cell lines does not predict their anticancer effect [30].…”

“…The heterogeneity of OC is mirrored by the diversity of the existing cell lines. Even those cell lines that were obtained from the same type of tumors show high diversity in their sensitivity to vitamin D and its analogs [30]. This might be due to differences in their mutational landscape, but also in the expression of the components of the vitamin D system.…”

In Silico Prediction of the Metabolic Resistance of Vitamin D Analogs against CYP3A4 Metabolizing Enzyme

“…They also have a low resistance to vitamin D metabolizing enzymes [ 10 ]. The current search is for vitamin D analogs of therapeutic potential against leukemia [ 7 , 11 , 12 ] and solid tumors, including breast [ 13 ], lung [ 14 ], prostate [ 15 ], colorectal [ 16 , 17 ], skin [ 18 ], and ovarian cancer [ 19 ]. We have developed analogs of 1,25D that exceed the potency of the parent 1,25D against cancer cells in vitro and in vivo, and that are less calcaemic and more enzymatically stable [ 10 ].…”

First Experimental Quantitative Charge Density Studies of Advanced Intermediate of Vitamin D Analogues

“…This shows the influence of the exocyclic methylene on the biological activity of vitamin D analogues and its importance in vitamin-D based drug design. Very recently, we first demonstrated that vitamin D analogues might be a new treatment for ovarian cancer [ 9 ].…”