Abstract
Simple SummaryDeveloping new therapeutic strategies is necessary for leukemias and lymphomas treatment. Therefore, the study aimed to determine the use of an active form of vitamin D3 calcitriol and its analog tacalcitol as an anticancer drug. Most of all, selecting the molecular factor responsible for the cell’s sensitivity to the tested agents. A biomarker that could be use in the future to select patients for therapy and improve survival outcomes. We examined nine cell lines and evaluated the proteins involved in the biological activity of calcitriol and tacalcitol: the classical vitamin D receptor and 1,25D3-MARRS, as well as polymorphism in the VDR gene receptor. Results showed that VDR polymorphism may predispose to response to calcitriol and tacalcitol anticancer therapy.The active forms of vitamin D3 (calcitriol and tacalcitol) coupled to the vitamin D receptor (VDR) are known to exhibit anti-cancer properties. However, not all cancer cells are sensitive to the active forms of vitamin D3 and its analogs. The study aimed to determine whether polymorphism of VDR is responsible for the sensitivity of human leukemia and lymphoma cells to calcitriol and tacalcitol. The impact of calcitriol and tacalcitol on the proliferation and morphology of nine different leukemia and lymphoma cell lines was determined. Only MV-4-11, Thp-1, and HL-60 cell lines sensitive to proliferation inhibition by calcitriol and tacalcitol showed morphology changes. Subsequently, the levels of the VDR and 1,25D3-MARRS proteins of calcitriol and tacalcitol binding receptors and the VDR receptor polymorphism in human leukemia and lymphoma cells were ascertained. Contrary to the current understanding, higher levels of VDR are not responsible for the greater sensitivity of cells to calcitriol and tacalcitol. Importantly, we first showed that sensitivity to calcitriol and tacalcitol in leukemias and lymphomas could be determined by the VDR polymorphism. The FokI polymorphism and the presence of the “bat” haplotype were observed only in the sensitive cells.
Highlights
Leukemia and lymphoma rank among the top 10 most common cancers with high mortality [1]
The results showed that myeloid cancer cells were significantly more sensitive to calcitriol and tacalcitol compared to lymphoid cancer cells (Figure 1a–d)
The analysis showed that cells sensitive to calcitriol and tacalcitol: MV-4-11, Thp-1, HL-60 cell lines, and insensitive Jurkat cell line were positive for the presence of the f allele at the translation initiation site of the vitamin D receptor (VDR) gene
Summary
Leukemia and lymphoma rank among the top 10 most common cancers with high mortality [1]. Attempts are being made to use the active form of vitamin D3, calcitriol, and its derivatives (VDAs, vitamin D analogs) in patients with myeloid tumors. We have shown early in our studies [6], that the oral administration of the active forms of vitamin D to mice increased the calcium level by 78% for calcitriol and only to 47% over the control for tacalcitol. It is necessary to identify biomarkers that would enable the selection of patients for cell differentiation therapy with vitamin D compounds. Calcitriol has a high affinity for the 1,25D3 -MARRS (1,25-dihydroxyvitamin D3 -membrane-associated rapid response to steroids) receptor. This protein is located mainly in the endoplasmic reticulum, cell membrane, cytoplasm, and the internal nuclear matrix [12–14]. The change of nucleotide from T (ATG) to C (ACG)
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