22-oxa-1α,25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer
22-oxa-1α,25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer
复制标题
DOI：
10.1093/carcin/bgi049
复制
发表时间：
2005-06-01
期刊：
影响因子：
4.7
通讯作者：
Okano, T
中科院分区：
文献类型：
--
作者：
Nakagawa, K;Sasaki, Y;Okano, T
1α，25-二羟基维生素D-3(1α，25-D-3)在体外对癌细胞具有明显的抗增殖和抗侵袭作用。然而，其体内的钙化作用限制了其治疗应用。在这里，我们报道了22-OXA-1α，25-二羟基维生素D-3(22-OXA-1α，25-D-3)，一种低钙维生素D类似物，静脉注射绿色荧光蛋白转基因Lewis肺癌(LLC-GFP)细胞后对C57BL/6小鼠转移肺癌的疗效。注射肿瘤细胞的小鼠同时植入含有1α、25-D-3、22-oxa-1α、25-D-3或赋形剂的渗透性微泵。1α，25-D-3治疗组有高钙血症，而22-oxa-1α，25-D-3和赋形剂治疗组在实验期间保持正常血钙。1α，25-D-3组和22-oxa-1α，25-D-3组小鼠肺转移瘤总数、肺重量和肺组织GFP mRNA表达均显著减少。在体外实验中，1α，25-D-3和22-oxa-1α，25-D-3降低了LLC-GFP细胞中基质金属蛋白酶2、9、血管内皮生长因子和甲状旁腺激素相关蛋白的表达。此外，在血管生成试验中，1α，25-D-3和22-oxa-1α，25-D-3处理的小鼠的肿瘤细胞或碱性成纤维细胞生长因子诱导的血管生成的数量减少。此外，利用维生素D受体(VDR)缺失突变(VDR-/-)小鼠纠正的低钙血症和高维生素D血症的新实验模型，我们考察了22-OXA-1α，25-D-3在宿主体内诱导的无其他功能的22-OXA-1α，25-D-3的抗癌作用。在VDR-/-小鼠中，22-oxa-1α，25-D-3以剂量依赖的方式直接抑制LLC-GFP细胞的转移活性，而不直接影响宿主体内22-oxa-1α，25-D-3调节的钙化活性或其他作用。这些结果表明，抑制癌细胞的转移和血管生成活性可能是22-OXA-1α，25-D-3抗肿瘤作用的主要机制之一。我们的研究结果表明，22-氧杂-1α，25-D-3对预防肺癌的转移是有益的。
1 alpha,25-Dihydroxyvitamin D-3 (1 alpha,25-D-3) has potent antiproliferative and anti-invasive properties in vitro in cancer cells. However, its calcemic effect in vivo limits its therapeutic applications. Here, we report the efficacy of 22-oxa-1 alpha,25-dihydroxyvitamin D-3 (22-oxa-1 alpha,25-D-3), a low calcemic analog of vitamin D, against the development of metastatic lung carcinoma after an intravenous injection of green fluorescent protein-transfected Lewis lung carcinoma (LLC-GFP) cells in C57BL/6 mice. The mice injected with tumor cells were implanted simultaneously with osmotic minipumps containing either 1 alpha,25-D-3, 22-oxa-1 alpha,25-D-3 or vehicle. The 1 alpha,25-D-3 treatment group had been hypercalcemic, but the 22-oxa-1 alpha,25-D-3 and vehicle treatment groups remained normocalcemic for the duration of the experiment. The total number of lung metastases, lung weight and the expression of GFP mRNA in the lung were markedly decreased in 1 alpha,25-D-3 and 22-oxa-1 alpha,25-D-3-treated mice. In the in vitro experiment, 1 alpha,25-D-3 and 22-oxa-1 alpha,25-D-3 reduced the expression of matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial growth factor and parathyroid hormone-related protein in LLC-GFP cells. Furthermore, in the angiogenesis assay, the number of tumor cells or basic fibroblast growth factor-induced angiogenesis was reduced in 1 alpha,25-D-3 and 22-oxa-1 alpha,25-D-3-treated mice. Moreover, using a new experimental model of vitamin D receptor (VDR) null mutant (VDR-/-) mice with corrected hypocalcemia and hypervitaminosis D, we examine the anti-cancer effect of 22-oxa-1 alpha,25-D-3 without other functions induced by 22-oxa-1 alpha,25-D-3 in the host. In the VDR-/- mice, 22-oxa-1 alpha,25-D-3 directly inhibited the metastatic activity of LLC-GFP cells in a dose-dependent manner without exerting a direct influence on the calcemic activity or other actions regulated by 22-oxa-1 alpha,25-D-3 in the host. These results indicate that the inhibition of metastasis and angiogenesis-inducing activity in cancer cells seemed to be a major mechanism responsible for the anti-cancer effects of 22-oxa-1 alpha,25-D-3. Our findings show that 22-oxa-1 alpha,25-D-3 is beneficial for the prevention of metastasis in lung carcinoma.