文章：

癌症中的维生素D信号通路：抗癌治疗的潜力

Vitamin D signalling pathways in cancer: potential for anticancer therapeutics

原文发布日期：2007-09-01

DOI: 10.1038/nrc2196

类型: Review Article

开放获取: 否

要点：

1. Epidemiological studies point to a relationship between vitamin D deficiency and cancer risk.
2. Alterations in vitamin D receptor expression, and in the synthesis (25-hydroxylase and 1α-hydroxylase) and catabolism (24-hydroxylase) of vitamin D metabolites are involved in the growth regulation of tumours; thus, compromising 1α,25(OH)₂D₃ (also known as calcitriol; the active metabolite of vitamin D signalling) sensitivity and 1α,25(OH)₂D₃ signalling.
3. The antiproliferative effects of 1α,25(OH)₂D₃ have been demonstrated in various tumour types, as determined by preclinical trials.
4. The anti-tumour effects of 1α,25(OH)₂D₃ involve mechanisms that are associated with G0/G1 arrest, differentiation, induction of apoptosis and modulating different signalling pathways in tumour cells, as well as inhibiting tumour angiogenesis.
5. Glucocorticoids potentiate the anti-tumour effects of 1α,25(OH)₂D₃ and decrease 1α,25(OH)₂D₃-induced hypercalcemia. 1α,25(OH)₂D₃ also potentiates the anti-tumour effects of many chemotherapeutic agents such as platinum analogues, taxanes and DNA-intercalating agents.
6. Given that the major vitamin D catabolizing enzyme, CYP24A1 (24-hydroxylase), is often amplified and overexpressed in tumour cells, agents that inhibit this enzyme can potentiate 1α,25(OH)₂D₃ anti-tumour effects.
7. Preclinical data indicate that maximal anti-tumour effects are seen with pharmacological doses of 1α,25(OH)₂D₃, and can be safely achieved in animals using a high-dose, intermittent schedule of administration. Some clinical trial data indicates that 1α,25(OH)₂D₃ is well-tolerated in cancer patients within a proper dosing schedule.
8. Data support the hypothesis that vitamin D compounds may have an important role in cancer therapy and prevention, and merit further investigation.

要点翻译：

1. 流行病学研究表明维生素D缺乏与癌症风险之间存在关联。
2. 维生素D受体表达的改变，以及维生素D代谢物的合成（25-羟化酶和1α-羟化酶）与分解代谢（24-羟化酶）过程参与肿瘤的生长调控，从而影响1α,25-二羟基维生素D3（又称骨化三醇，维生素D信号通路的活性代谢物）的敏感性和信号传导。
3. 临床前试验证实，1α,25-二羟基维生素D3在多种肿瘤类型中均表现出抗增殖效应。
4. 其抗肿瘤作用机制包括：诱导G0/G1期阻滞、促进分化、诱导细胞凋亡、调节肿瘤细胞内的多种信号通路，以及抑制肿瘤血管生成。
5. 糖皮质激素能增强1α,25-二羟基维生素D3的抗肿瘤效果，并减轻其引起的高钙血症。同时，1α,25-二羟基维生素D3也可增强多种化疗药物（如铂类衍生物、紫杉烷类和DNA嵌入剂）的抗肿瘤作用。
6. 由于主要维生素D分解酶CYP24A1（24-羟化酶）在肿瘤细胞中常扩增和过表达，抑制该酶的药物可增强1α,25-二羟基维生素D3的抗肿瘤效应。
7. 临床前数据表明，药理学剂量的1α,25-二羟基维生素D3可产生最大抗肿瘤效果，动物实验通过高剂量间歇给药方案可安全实现该目标。部分临床试验数据证实，在合适给药方案下1α,25-二羟基维生素D3对癌症患者具有良好的耐受性。
8. 现有数据支持维生素D化合物在癌症治疗和预防中可能发挥重要作用的假说，值得进一步深入研究。

英文摘要：

Epidemiological studies indicate that vitamin D insufficiency could have an aetiological role in various human cancers. Preclinical research indicates that the active metabolite of vitamin D, 1α,25(OH)2D3, also known as calcitriol, or vitamin D analogues might have potential as anticancer agents because their administration has antiproliferative effects, can activate apoptotic pathways and inhibit angiogenesis. In addition, 1α,25(OH)2D3 potentiates the anticancer effects of many cytotoxic and antiproliferative anticancer agents. Here, we outline the epidemiological, preclinical and clinical studies that support the development of 1α,25(OH)2D3 and vitamin D analogues as preventative and therapeutic anticancer agents.

摘要翻译： 

流行病学研究表明，维生素D不足可能在多种人类癌症的发病机制中起作用。临床前研究显示，维生素D的活性代谢产物1α,25(OH)₂D₃（也称为骨化三醇）或维生素D类似物具有作为抗癌药物的潜力，因为其给药具有抗增殖效应，可激活凋亡通路并抑制血管生成。此外，1α,25(OH)₂D₃能增强多种细胞毒和抗增殖抗癌药物的抗癌效果。在此，我们概述支持将1α,25(OH)₂D₃和维生素D类似物开发为预防和治疗性抗癌药物的流行病学、临床前及临床研究。

原文链接：

Vitamin D signalling pathways in cancer: potential for anticancer therapeutics