Inhibitory effect of 22-oxa-1,25-dihydroxyvitamin D3, maxacalcitol, on the proliferation of pancreatic cancer cell lines
Inhibitory effect of 22-oxa-1,25-dihydroxyvitamin D3, maxacalcitol, on the proliferation of pancreatic cancer cell lines
复制标题
DOI：
10.1016/j.jsbmb.2005.06.021
复制
发表时间：
2005-10-01
影响因子：
4.1
通讯作者：
Kiyosawa, K
中科院分区：
文献类型：
--
作者：
Kawa, S;Yoshizawa, K;Kiyosawa, K
胰腺癌的有效化疗是迫切需要的。本研究的目的是比较维生素D-3类似物22-oxa-1，25-二羟基维生素D3 maxacalcitol和1，25-二羟基维生素D3 calcitriol对胰腺癌细胞系的抗增殖活性，并分析维生素D受体状态和G（1）期细胞周期调节因子。使用3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四唑溴化物方法并通过测量接种到无胸腺小鼠中的异种移植物的肿瘤大小来比较两种药剂的抗增殖作用。进行维生素D受体含量的Scatchard分析和受体互补DNA的突变分析。通过蛋白质印迹法分析细胞周期蛋白、细胞周期蛋白依赖性激酶和细胞周期蛋白依赖性激酶抑制剂p21和p27的表达水平。在体外，maxacalcitol和calcittiol显着抑制增殖，并导致一个G，期细胞周期阻滞，出现大量的圆顶。在体内，maxacalcitol抑制BxPC-3异种移植物的生长比骨化三醇更显着，不诱导高钙血症。反应细胞具有丰富的功能性维生素D受体。然而，Hs 766 T，显示没有响应任何代理，具有第二高的受体含量，其一级结构没有异常推断的受体互补DNA。在响应细胞中，p21和p27在用两种药剂处理24小时后显著上调。在无反应细胞中，未观察到此类变化。结论：maxacalcitol和骨化三醇作为早期事件上调p21和p27，进而阻断G（1）/S转换并诱导应答细胞的生长抑制，maxacalcitol因其低毒性可能为胰腺癌化疗提供比骨化三醇更有用的工具。(c)2005爱思唯尔有限公司保留所有权利。
Effective chemotherapy for pancreatic cancer is urgently needed. The aim of this study was to compare the anti-proliferative activity on pancreatic cancer cell lines of the vitamin D-3 analog, 22-oxa-1,25-dihydroxyvitamin D3, maxacalcitol, with that of 1,25-dihydroxyvitamin D3, calcitriol, with analysis of vitamin D receptor status and the G(1)-phase cell cycle-regulating factors. Antiproliferative effects of both agents were compared using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method and by measuring the tumor size of xenografts inoculated into athymic mice. Scatchard analysis of vitamin D receptor contents, and mutational analysis of receptor complementary DNA were performed. Levels of expression of cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors, p21 and p27, were analysed by western blotting. In vitro, maxacalcitol and calcittiol markedly inhibited the proliferation and caused a G, phase cell cycle arrest with the appearance of numerous domes. In vivo, maxacalcitol inhibited the growth of BxPC-3 xenografts more significantly than calcitriol, without inducing hypercalcemia. Responsive cells had abundant functional vitamin D receptors. However, Hs 766T, showing no response to either agent, had the second highest receptor contents with no abnormalities in its primary structure deduced by receptor complementary DNA. In the responsive cells, p21 and p27 were markedly up-regulated after 24 h of treatment with both agents. In non-responsive cells, no such changes were observed. In conclusion, maxacalcitol and calcitriol up-regulate p21 and p27 as an early event, which in turn could block the G(1)/S transition and induce growth inhibition in responsive cells, and maxacalcitol may provide a more useful tool for the chemotherapy of pancreatic cancer than calcittiol because of its low toxicity. (c) 2005 Elsevier Ltd. All rights reserved.