Effects of phosphorylation of immunomodulatory agent FTY720 (fingolimod) on antiproliferative activity against breast and colon cancer cells
Effects of phosphorylation of immunomodulatory agent FTY720 (fingolimod) on antiproliferative activity against breast and colon cancer cells
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DOI：
10.1248/bpb.31.1177
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发表时间：
2008-06-01
影响因子：
2
通讯作者：
Uesato, Shinichi
中科院分区：
文献类型：
--
作者：
Nagaoka, Yasuo;Otsuki, Kota;Uesato, Shinichi
FTY 720（芬戈莫德）是一种新型免疫抑制剂，被发现通过磷酸化成FTY 720 -1-磷酸（FTV 720-P）而被生物活化，FTV 720-P是鞘氨醇-1-磷酸（鞘氨醇-1-P）受体的高亲和力激动剂。FTY 720也被报道具有很强的抗肿瘤活性。FTY 720的磷酸化与FTY 720对癌细胞的生长抑制之间的关联仍不完全清楚。在这项研究中，我们研究了FTY 720，鞘氨醇，及其相关化合物对人乳腺癌细胞系（MCF-7，MDA-MB-231和Sk-Br-3）和人结肠癌细胞系（HCT-116和SW 620）的增殖的影响。非磷酸化FTY 720、鞘氨醇和FTY 720衍生物ISP-I-55对这些细胞显示出显著的生长抑制作用，药物处理后48小时的IC 50值为5-20 μ M。我们证实，FTY 720诱导活化的主要丝裂原活化蛋白激酶，JNK，没有激活的p38和磷酸化ERK在MCF-7乳腺癌细胞的下调。相反，磷酸化衍生物FTY 720-P和鞘氨醇-1-P以及膦烷FTY 720衍生物cFTY 720-P在5-50 μ M的浓度范围内不抑制细胞的生长，而FTY 720-P和鞘氨醇-1-P轻微诱导MCF-7细胞的生长。将FTY 720与鞘氨醇激酶抑制剂二甲基鞘氨醇组合，增强FTY 720的抑制作用。这些结果表明FTY 720的抗增殖活性不是由其内源性或外源性磷酸化引起的。
FTY720 (fingolimod), a novel immunosuppressant, was found to become biologically activated by phosphorylation into FTY720-1-phosphate (FTV720-P), which is a high-affinity agonist for sphingosine-1-phosphate (sphingosine-1-P)-receptors. FTY720 has also been reported to have a strong antitumor activity. The association between the phosphorylation of FTY720 and the growth inhibition of FTY720 against cancer cells are still not completely understood. In this study, we investigated the effects of FTY720, sphingosine, and their related compounds on the proliferation of human breast cancer cell lines (MCF-7, MDA-MB-231 and Sk-Br-3) and human colon cancer cell lines (HCT-116 and SW620). Non-phosphorylated FTY720, sphingosine and an FTY720 derivative, ISP-I-55, showed significant growth inhibition against these cells, with IC50 values of 5-20 mu M at 48 h postdrug treatment. We confirmed that FTY720 induces the activation of a major mitogen-activated protein kinase, JNK, without the activation of p38 and down-regulation of phospho-ERK in MCF-7 breast cancer cells. In contrast, the phosphorylated derivatives, FTY720-P and sphingosine-1-P, as well as a phosphinane FTY720 derivative, cFTY720-P, did not inhibit the growth of the cells in the concentration range of 5-50 mu M, whereas FTY720-P and sphingosine-1-P slightly induced the growth of MCF-7 cells. Combining FTY720 with dimethylsphingosine, a sphingosine kinase inhibitor, augmented the inhibitory effect of FTY720. These results indicate that the antiproliferative activity, of FTY720 does not result from its phosphorylation, either endogenous or exogenous.