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.
Highlights
Ovarian cancer (OC), known as the “silent killer” showing no symptoms at early stages, is the deadliest gynecologic malignancy
We have previously shown that analogs of 1,25-dihydroxyergocalciferol (1,25-dihydroxyvitamin D2, 1,25D2) induced differentiation of human acute myeloid leukemia cells [21,26]
We have tested for the first time if single- and/or double-point modified analogs of the most active form of vitamin D are effective in high-grade serous ovarian cancer (HGSOC) cells
Summary
Ovarian cancer (OC), known as the “silent killer” showing no symptoms at early stages, is the deadliest gynecologic malignancy. Low vitamin D levels were associated with increased risk for various cancers, suggesting a beneficial effect of supplementation or treatment with vitamin D, its active metabolites, or synthetic analogs [3,4]. There are some reports on the activity of calcitriol in commercially available ovarian cancer cells, little is known on the effects of an1,25Ds on HGSOC cells. We compared the effect of a series of structurally related an1,25Ds (PRI-1906, PRI-1907, PRI-5201, PRI-5202, Figure 1) with that of calcitriol in two patient-derived HGSOC cell lines, to investigate if any of these analogs affect ovarian cancer cells and to evaluate the possibility of developing an1,25Ds as potential adjuvants for treatment of HGSOC. Ohincehemxpiglahntaitmiopnafirorittshaeblialcitkyotof ddoowwnnrreegguulala-te tioKni6c7ou[2ld9]b. e that in these cells p53 is mutated [27], which might impair its ability to downregulate Ki67 [29]
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