Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208
Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208
复制标题
瘤内雌激素磺基转移酶诱导有助于二硫代氨基甲酸酯衍生物 TM208 的抗乳腺癌作用
DOI：
10.1038/aps.2015.14
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发表时间：
2015-10-01
影响因子：
8.2
通讯作者：
Lu, Wei
中科院分区：
文献类型：
--
作者：
Ji, Xi-wei;Chen, Guang-ping;Lu, Wei
目的：磺基转移酶催化的硫酸化反应是雌激素失活的重要途径。因此，激活雌激素磺基转移酶（EST）可能是治疗雌激素依赖性乳腺癌的一种替代方法。在这项研究中，我们调查了EST的参与在抗乳腺癌作用的二硫代氨基甲酸酯衍生物TM 208在体外和体内。方法：人乳腺癌MCF-7细胞的生存能力进行了测定，使用SBB法。携带MCF-7细胞的裸鼠经口给予TM 208（50和150 mg· kg-1· d-1）18天。收集异种移植肿瘤和子宫。实时荧光定量PCR检测ESTmRNA的表达。用Western blot、ELISA和免疫组化方法检测EST蛋白的表达。放射性分析用于测量EST活性。结果：TM 208（10、15和20 μmol/L）浓度依赖性地增加MCF-7细胞EST的表达;与三氯生（一种磺化抑制剂）共处理可消除TM 208诱导的MCF-7细胞毒性。TM 208具有明显的抗雌激素活性：它对E2处理的MCF-7细胞具有更强的细胞毒性。在MCF-7裸鼠移植瘤中，TM 208可呈时间依赖性地增加EST的表达和活性，并阻断E2浓度的逐渐升高。此外，TM 208给药阻断了雌激素刺激的子宫增大。结论：TM 208和三苯氧胺的抗乳腺癌作用与其诱导EST表达和降低雌激素水平有关。TM 208可能被开发为治疗雌激素受体阳性乳腺癌的抗癌药物。
Aim:Sulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo.Methods:The viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg· kg− 1· d− 1) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity. Uterotropic bioassay was used to examine the uterine estrogen responses.Results:Treatment with TM208 (10, 15 and 20 μmol/L) concentration-dependently increased EST expression in MCF-7 cells in vitro. Co-treatment with triclosan, an inhibitor of sulfonation, abolished TM208-induced cytotoxicity in MCF-7 cells. TM208 exhibited an apparent anti-estrogenic property: it exerted more potent cytotoxicity in E2-treated MCF-7 cells. In the nude mice bearing MCF-7 cells, TM208 administration time-dependently increased the expression and activity of EST, and blocked the gradual increase of E2 concentration in the xenograft tumors. Furthermore, TM208 administration blocked the estrogens-stimulated uterine enlargement. Tamoxifen, a positive control drug, produced similar effects on the expression and activity of EST in vitro and in vivo.Conclusion:The induction of EST and reduction of estrogen concentration contribute to the anti-breast cancer action of TM208 and tamoxifen. TM208 may be developed as anticancer drug for the treatment of estrogen receptor-positive breast cancer.