Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
Department of Bioanalysis and Drug Analysis, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland.
Int J Mol Sci. 2021 Dec 24;23(1):172. doi: 10.3390/ijms23010172.
Ovarian cancer (OC) is one of the most lethal cancers in women. The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D, 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.
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 D 24-hydroxylase , 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 , and the vitamin D receptor (VDR).
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: EC = 2.98 ± 1.10 nmol/L, in 14433 cells: EC = 0.92 ± 0.20 nmol/L), while PRI-1907 was the least active one (in 13781 cells: EC = n/d, in 14433 cells: EC = 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.
The an1,25Ds had different potencies in the HGSOC cell lines and their efficacy in increasing 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.
卵巢癌（OC）是女性中最致命的癌症之一。维生素 D 的活性形式 1,25-二羟维生素 D（1,25D，骨化三醇）在包括卵巢癌在内的几种癌症中具有抗癌活性，但所需的药理剂量可能会导致高钙血症。我们假设新开发的、低钙血症的维生素 D 类似物（an1,25D）可以替代骨化三醇在卵巢癌细胞中作为抗癌药物。
我们使用了两种源自患者的高级别浆液性卵巢癌（HGSOC）细胞系，这些细胞系的基因编码 1,25-二羟维生素 D 24-羟化酶的 mRNA 表达水平较低（13781）和较高（14433），这是骨化三醇的主要靶基因之一。我们测试了骨化三醇和四个结构相关系列的 an1,25D（PRI-1906、PRI-1907、PRI-5201、PRI-5202）对细胞数量、活力、表达和维生素 D 受体（VDR）的影响。
在用所有化合物处理后，mRNA 表达以浓度依赖性方式增加。在两种细胞系中，PRI-5202 是最有效的类似物（在 13781 细胞中：EC=2.98±1.10 nmol/L，在 14433 细胞中：EC=0.92±0.20 nmol/L），而 PRI-1907 是最不活跃的一种（在 13781 细胞中：EC=n/d，在 14433 细胞中：EC=n/d）。在 5 天的治疗后，类似物之间的这种差异消失了。与 14433 细胞相比，13781 细胞对 an1,25D 更敏感。an1,25D 增加了核 VDR 水平并降低了细胞活力，但仅在 13781 细胞系中。
an1,25D 在 HGSOC 细胞系中具有不同的效力，其增加 表达的功效取决于细胞系和化学结构。因此，选择敏感的癌细胞系并进一步优化类似物的结构可能会为卵巢癌的治疗提供新的选择。
