Department of Pharmacology, Toxicology and Therapeutics, and Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Mol Cancer Ther. 2010 Dec;9(12):3254-66. doi: 10.1158/1535-7163.MCT-10-0582. Epub 2010 Nov 1.
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-κB and its gene products (cyclin D1, Bcl-2, Bcl-X(L), VEGF, HIF-1α, 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.
组蛋白去乙酰化酶 (HDAC) 抑制剂和肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 显示出治疗癌症的潜力。本研究旨在探讨 HDAC 抑制剂 MS-275 在体内增强 TRAIL 耐药乳腺癌细胞敏感性、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 耐药侵袭性乳腺癌 MDA-MB-468 细胞，在第 1 至 3 周内静脉内给予 MS-275、TRAIL 或 MS-275 后给予 TRAIL，共 4 次。单独给予 TRAIL 治疗对肿瘤生长、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 来增强 TRAIL 耐药异种移植物的敏感性。给予裸鼠 MS-275 治疗导致 NF-κB 及其基因产物（cyclin D1、Bcl-2、Bcl-X(L)、VEGF、HIF-1α、IL-6、IL-8、MMP-2 和 MMP-9）下调，以及 DR4、DR5、Bax、Bak 和 p21(/CIP1) 在肿瘤细胞中上调。此外，与对照组相比，MS-275 治疗的小鼠肿瘤生长明显减少，循环血管中 VEGFR2 阳性内皮细胞、CD31 阳性或血管性血友病因子阳性血管以及肺转移减少。有趣的是，MS-275 导致“钙黏蛋白转换”，并通过上调 E-钙黏蛋白和下调 N-钙黏蛋白以及转录因子 Snail、Slug 和 ZEB1 逆转 EMT。总之，MS-275 序贯治疗联合 TRAIL 可能靶向多种途径逆转 EMT 并抑制肿瘤进展、血管生成和转移，为治疗癌症提供了一种新的治疗方法。
