Evans Haley, Greenhough Alexander, Perry Laura, Lasanta Gonzalo, Gonzalez Carmen M, Mourino Antonio, Mansell Jason P
School of Applied Sciences, College of Health, Science and Society, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, UK.
Ignacio Ribas Research Laboratory, Department of Organic Chemistry, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Int J Mol Sci. 2025 Jan 3;26(1):365. doi: 10.3390/ijms26010365.
The active metabolite of vitamin D3, calcitriol (1,25D), is widely recognised for its direct anti-proliferative and pro-differentiation effects. However, 1,25D is calcaemic, which restricts its clinical use for cancer treatment. Non-calcaemic agonists of the vitamin D receptor (VDR) could be better candidates for cancer treatment. In this study, we examined the influence of the hydroxylated lithocholic acid derivative CAR-R on osteosarcoma (OS) cell (MG63) growth and differentiation. Treatment of MG63 cells with CAR-R inhibited growth under conventional and hypoxic conditions. Co-treating cells with CAR-R and a lysophosphatidic acid (LPA) analogue resulted in their differentiation, as supported by synergistic increases in alkaline phosphatase (ALP) activity. Under hypoxic conditions, however, this differentiation response was attenuated. The importance of observed increases in hypoxia inducible factors (HIFs) were investigated through targeted disruption using pharmacological and genetic approaches. Disruption elicited a reduction in ALP activity, suggesting an important role for HIFs in OS differentiation. Finally, we examined the expression of the VDR protein. Hypoxic MG63s expressed less VDR, with the levels increasing with CAR-R exposure. Whilst these findings are encouraging, future studies aimed at bolstering the pro-differentiating effect of CAR-R under hypoxic conditions are warranted if this agent is to gain traction in the treatment of OS.
维生素D3的活性代谢产物骨化三醇（1,25D）因其直接的抗增殖和促分化作用而被广泛认可。然而，1,25D会升高血钙水平，这限制了其在癌症治疗中的临床应用。维生素D受体（VDR）的非血钙升高激动剂可能是癌症治疗的更好选择。在本研究中，我们研究了羟基化石胆酸衍生物CAR-R对骨肉瘤（OS）细胞（MG63）生长和分化的影响。用CAR-R处理MG63细胞可在常规和低氧条件下抑制其生长。将CAR-R与溶血磷脂酸（LPA）类似物共同处理细胞会导致其分化，碱性磷酸酶（ALP）活性的协同增加支持了这一点。然而，在低氧条件下，这种分化反应减弱。通过药理学和遗传学方法进行靶向破坏，研究了观察到的缺氧诱导因子（HIFs）增加的重要性。破坏导致ALP活性降低，表明HIFs在OS分化中起重要作用。最后，我们检测了VDR蛋白的表达。低氧MG63细胞表达的VDR较少，随着CAR-R的暴露，其水平升高。虽然这些发现令人鼓舞，但如果这种药物要在OS治疗中获得认可，未来旨在增强CAR-R在低氧条件下促分化作用的研究是必要的。
