MS-275 Sensitizes TRAIL-Resistant Breast Cancer Cells, Inhibits Angiogenesis and Metastasis, and Reverses Epithelial-Mesenchymal Transition In vivo
MS-275 Sensitizes TRAIL-Resistant Breast Cancer Cells, Inhibits Angiogenesis and Metastasis, and Reverses Epithelial-Mesenchymal Transition In vivo
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DOI：
10.1158/1535-7163.mct-10-0582
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发表时间：
2010-12-01
影响因子：
5.7
通讯作者：
Shankar, Sharmila
中科院分区：
文献类型：
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作者：
Srivastava, Rakesh K.;Kurzrock, Razelle;Shankar, Sharmila
组蛋白脱乙酰酶 (HDAC) 抑制剂和肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 显示出治疗癌症的前景。本研究的目的是探讨 HDAC 抑制剂 MS-275 在体内使 TRAIL 耐药乳腺癌细胞敏化、抑制血管生成和转移以及逆转上皮间质转化 (EMT) 的分子机制。 BALB/c 裸鼠原位植入 TRAIL 抗性侵袭性乳腺癌 MDA-MB-468 细胞，并用 MS-275、TRAIL 或 MS-275 随后 TRAIL 静脉注射治疗，前 3 周共 4 次。单独用 TRAIL 治疗小鼠对肿瘤生长、转移、血管生成和 EMT 没有影响。相比之下，MS-275 通过诱导细胞凋亡、抑制肿瘤细胞增殖、血管生成、转移和逆转 EMT 来敏化 TRAIL 耐药异种移植物。用 MS-275 处理裸鼠，导致肿瘤细胞中 NF-kappa B 及其基因产物（细胞周期蛋白 D1、Bcl-2、Bcl-XL、VEGF、HIF-1 α、IL-6、IL-8、MMP-2 和 MMP-9）下调，以及 DR4、DR5、Bax、Bak 和 p21/(CIP1) 上调。此外，与对照小鼠相比，MS-275治疗的小鼠的肿瘤生长显着减少，循环血管VEGFR2阳性内皮细胞、CD31阳性或冯维勒布兰德因子阳性血管以及肺转移减少。有趣的是，MS-275 引起“钙粘蛋白转换”并逆转 EMT，如 E-钙粘蛋白的上调和 N-钙粘蛋白和转录因子 Snail、Slug 和 ZEB1 的下调所示。总之，用 MS-275 和 TRAIL 连续治疗小鼠可能会靶向多种途径来逆转 EMT，并抑制肿瘤进展、血管生成和转移，并代表一种治疗癌症的新治疗方法。 9(12)；3254-66。(C)2010 AACR。
Histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) show promise for the treatment of cancers. The purpose of this study was to examine the molecular mechanisms by which HDAC inhibitor MS-275 sensitizes TRAIL-resistant breast cancer cells in vivo, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition (EMT). BALB/c nude mice were orthotopically implanted with TRAIL-resistant invasive breast cancer MDA-MB-468 cells and treated intravenously with MS-275, TRAIL, or MS-275 followed by TRAIL, 4 times during first 3 weeks. Treatment of mice with TRAIL alone had no effect on tumor growth, metastasis, angiogenesis, and EMT. In comparison, MS-275 sensitized TRAIL-resistant xenografts by inducing apoptosis, inhibiting tumor cell proliferation, angiogenesis, metastasis, and reversing EMT. Treatment of nude mice with MS-275 resulted in downregulation of NF-kappa B and its gene products (cyclin D1, Bcl-2, Bcl-XL, VEGF, HIF-1 alpha, IL-6, IL-8, MMP-2, and MMP-9) and upregulation of DR4, DR5, Bax, Bak, and p21/(CIP1) in tumor cells. Furthermore, MS-275-treated mice showed significantly reduced tumor growth and decreased circulating vascular VEGFR2-positive endothelial cells, CD31-positive or von Willebrand factor-positive blood vessels, and lung metastasis compared with control mice. Interestingly, MS-275 caused "cadherin switch'' and reversed EMT as shown by the upregulation of E-cadherin and downregulation of N-cadherin and transcription factors Snail, Slug, and ZEB1. In conclusion, sequential treatments of mice with MS-275 followed by TRAIL may target multiple pathways to reverse EMT and inhibit tumor progression, angiogenesis, and metastasis and represent a novel therapeutic approach to treat cancer. Mol Cancer Ther; 9(12); 3254-66. (C) 2010 AACR.