Background
Calcitriol, as the most biologically active metabolite derived from the secosteroid hormone vitamin D, the inhibition of calcitriol caused decreased effects of anticancer drugs.[1]
In vitro efficacy test it shown that weekly oral administration of calcitriol allowed reach the peak serum calcitriol concentrations well above 1 nM, a concentration that inhibition more than 50% of prostate cancer proliferation. [2] With 10 nM calcitriol remarkably decreased RAGE protein expression and increased sRAGE concentrations in HL-1 cardiomyocytes compared with control cells.[3] Calcitriol exhibited antiproliferative effects against T47D, MCF-7, and MDA-MB-231 with IC50 values in the range of 0.05-0.25 μM.[4] In addition, calcitriol inhibits melanoma cell proliferation with an IC?? of 0.24 μM.[5] BT-474 cells were dose-dependently growth-inhibited by calcitriol with IC50 of 2.9 nM. With 1 nM Calcitriol synergistically improved AZD4547 antiproliferative effects, allowing a 2-fold AZD4547 dose-reduction. [6]
In vivo test it demonstrated that calcitriol (0.03 μg/kg) 5 times/wk intraperitoneally for 10 wk in UNX ApoE-/- mice caused significant vascular calcification and elevated expression of related proteins (BMP2, RANKL, and Runx2).[8] With 0.5 ug/day calcitriol orally improved insulin resistance and HOMA-β after 6 months in ND patients, however, only improved HOMA-β in the dialysis patients, with no obvious effect on insulin resistance.[7]
参考文献:
[1]Ma J, et al. The mechanism of calcitriol in cancer prevention and treatment. Curr Med Chem. 2013;20(33):4121-30.?
[2]Beer TM. Development of weekly high-dose calcitriol based therapy for prostate cancer. Urol Oncol. 2003 Sep-Oct;21(5):399-405.?
[3]Lee TW, et al. ADAM10 modulates calcitriol-regulated RAGE in cardiomyocytes. Eur J Clin Invest. 2017 Sep;47(9):675-683.
[4]Aljunidee KA, et al. Combination therapy of calcitriol inhibits the proliferation of breast cancer cells: new concept of nonclassical function of calcitriol. Horm Mol Biol Clin Investig. 2021 Nov 15.?
[5]Sutedja EK, et al. Calcitriol Inhibits Proliferation and Potentially Induces Apoptosis in B16-F10 Cells. Med Sci Monit Basic Res. 2022 May 5;28:e935139.
? [6]Morales-Guadarrama G, et al. AZD4547 and calcitriol synergistically inhibited BT-474 cell proliferation while modified stemness and tumorsphere formation. J Steroid Biochem Mol Biol. 2022 May 31;223:106132.
[7]Lu Y, et al. Effects of active vitamin D on insulin resistance and islet β-cell function in non-diabetic chronic kidney disease patients: a randomized controlled study. Int Urol Nephrol. 2022 Jul;54(7):1725-1732.
[8]Becker LE, et al. Effect of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized ApoE knockout mice. Am J Physiol Renal Physiol. 2011 Mar;300(3):F772-82.
骨化三醇作为类固醇激素维生素 D 的最具生物活性的代谢产物，抑制骨化三醇会导致抗癌药物的作用降低。[1]
体外功效测试表明，每周口服骨化三醇可使血清骨化三醇浓度达到峰值，远高于 1 nM，该浓度可抑制超过 50% 的前列腺癌增殖。 [2] 与对照细胞相比，10 nM 骨化三醇可显着降低 HL-1 心肌细胞中 RAGE 蛋白的表达并增加 sRAGE 浓度。[3] 骨化三醇对 T47D、 MCF-7 和 MDA-MB-231 的 IC50 值在 0.05-0.25 μM 范围内。 [4]此外，骨化三醇抑制黑色素瘤细胞增殖，IC50 为 0.24 μM。[5] BT-474 细胞的生长受到剂量依赖性抑制，IC50 为 2.9 nM。与 1 nM 骨化三醇协同改善 AZD4547 的抗增殖作用，使 AZD4547 剂量减少 2 倍。 [6]
体内试验表明，在 UNX ApoE-/- 小鼠中，骨化三醇 (0.03 μg/kg) 腹腔注射 5 次/周，持续 10 周，导致显着的血管钙化和相关蛋白（BMP2、RANKL 和 Runx2）的表达升高。 [8] ND患者口服0.5 ug/天骨化三醇6个月后可改善胰岛素抵抗和HOMA-β，但仅改善透析患者的HOMA-β，对胰岛素抵抗无明显影响.[7]
Protocol
| Cell experiment [1]: |
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Cell lines
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HL-1 cells
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Preparation Method
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Calcitriol (1 and 10 nM) was used to treat HL-1 cells for 48 h to determine the initial dose-response effect. To study the functional relevance of FGFR1 modulation, recombinant mouse FGF-2 (25 ng/mL) was administrated (for 0.5 or 48 h) in control and calcitriol-treated HL-1 cells.
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Reaction Conditions
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1 and 10 nM; 48 h
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Applications
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Compared to control cells, as shown in Fig. 1a, calcitriol (1 and 10 nM) dose-dependently reduced FGFR1 protein expression in HL-1 cells by 31 and 62%, respectively. Similarly, calcitriol (10 nM)-treated HL-1 cells had lower FGFR1 mRNA expression than did control HL-1 cells.
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| Animal experiment [2]: |
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Animal models
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Male C57BL/6J mice aged 4–5 weeks and weighing ~21–27 g
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Preparation Method
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Four groups of mice (n = 11 each) were maintained on either low-fat diet (LFD) or high-fat diet (HFD) with and without 150 IU/kg/day calcitriol orally for 16 weeks.
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Dosage form
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150 IU/kg/day; orally
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Applications
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A significant gradual decrease in weight was observed in HFD-fed mice treated with calcitriol compared with a steady increase in controls. Furthermore, calcitriol treatment reduced concentrations of various inflammatory markers including TNF-α, CRP and IL-6.
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参考文献:
[1]. Lee TW, et al. Calcitriol downregulates fibroblast growth factor receptor 1 through histone deacetylase activation in HL-1 atrial myocytes. J Biomed Sci. 2018 May 18;25(1):42.?
[2]. Alkharfy KM, et al. Calcitriol attenuates weight-related systemic inflammation and ultrastructural changes in the liver in a rodent model. Basic Clin Pharmacol Toxicol. 2013 Jan;112(1):42-9.?
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