新型 TGFβ 受体 1 抑制剂抑制乳腺癌转移。
Inhibition of breast cancer metastases by a novel inhibitor of TGFβ receptor 1.
机构信息
Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Rd, Shanghai, China.
出版信息
J Natl Cancer Inst. 2013 Jan 2;105(1):47-58. doi: 10.1093/jnci/djs485. Epub 2012 Nov 24.
BACKGROUND
Transforming growth factor beta (TGFβ), which is implicated in metastasis to various organs in breast cancer, is a potential target for new antitumor metastasis drugs.
METHODS
To identify specific inhibitors of TGFβ receptor 1 (TGFβR1) in breast cancer metastasis, a virtual library of more than 400000 different compounds was screened by molecular docking modeling and confirmed with Smad-binding element luciferase and TGFβR1 kinase assays. Affymetrix GeneChip expression analysis of mRNA levels and real-time polymerase chain reaction were performed to determine expression changes of TGFβ-mediated, metastasis-associated genes in breast cancer cells after treatment with the small-molecule inhibitor YR-290. YR-290 was also examined for its effects on breast cancer migration, invasion, and metastasis using transwell and epithelial-to-mesenchymal transition (EMT) assays in vitro and three different mouse (BALB/c and NU/NU nude) models (n = 10 per group). Kaplan-Meier analyses were used to assess survival. All statistical tests were two-sided.
RESULTS
YR-290 interacted with the kinase domain of TGFβR1, abrogated kinase activity (half maximal inhibitory concentration = 137nM, 95% confidence interval = 126.4 to 147.6nM) and inhibited the TGFβ-mediated downstream signaling pathway and metastasis-associated genes in breast cancer cells. YR-290 inhibited TGFβ-modulated breast cancer cell migration and invasion. In tumor metastasis mouse models, YR-290 almost completely blocked cancer metastasis. Numbers of lung tumor nodules of mice treated with 1mg/kg and 5mg/kg YR-290 were reduced by 74.93% (95% confidence interval = 61.45% to 88.41%) and 94.93% (95% confidence interval = 82.13% to 100%), respectively, compared with control mice. Treatment with YR-290 also statistically significantly prolonged the survival of tumor-bearing mice.
CONCLUSIONS
YR-290 is a novel inhibitor of tumor metastasis that works by blocking TGFβ signaling pathways.
背景
转化生长因子β（TGFβ）在乳腺癌向各种器官转移中起作用，是一种新的抗肿瘤转移药物的潜在靶点。
方法
为了鉴定乳腺癌转移中 TGFβ 受体 1（TGFβR1）的特异性抑制剂，通过分子对接建模筛选了超过 400000 种不同化合物的虚拟库，并通过 Smad 结合元件荧光素酶和 TGFβR1 激酶测定进行了验证。采用 Affymetrix GeneChip 表达分析测定 mRNA 水平，并采用实时聚合酶链反应检测乳腺癌细胞经小分子抑制剂 YR-290 处理后 TGFβ 介导的、与转移相关基因的表达变化。还通过体外 Transwell 和上皮间质转化（EMT）测定以及三种不同的小鼠（BALB/c 和 NU/NU 裸鼠）模型（每组 10 只）研究了 YR-290 对乳腺癌迁移、侵袭和转移的影响。采用 Kaplan-Meier 分析评估生存情况。所有统计检验均为双侧检验。
结果
YR-290 与 TGFβR1 的激酶结构域相互作用，阻断激酶活性（半最大抑制浓度=137nM，95%置信区间=126.4 至 147.6nM），并抑制乳腺癌细胞中 TGFβ 介导的下游信号通路和与转移相关的基因。YR-290 抑制 TGFβ 调节的乳腺癌细胞迁移和侵袭。在肿瘤转移小鼠模型中，YR-290 几乎完全阻断了癌症转移。与对照组小鼠相比，1mg/kg 和 5mg/kg YR-290 处理的小鼠肺部肿瘤结节数分别减少了 74.93%（95%置信区间=61.45%至 88.41%）和 94.93%（95%置信区间=82.13%至 100%）。YR-290 治疗还显著延长了荷瘤小鼠的生存时间。
结论
YR-290 是一种新型肿瘤转移抑制剂，通过阻断 TGFβ 信号通路发挥作用。
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