BU-32：一种新型的乳腺癌蛋白酶体抑制剂。,Breast Cancer Research

当前位置： X-MOL 学术 › Breast Cancer Res. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

BU-32：一种新型的乳腺癌蛋白酶体抑制剂。
Breast Cancer Research ( IF 6.1 ) Pub Date : 2009-01-01 , DOI: 10.1186/bcr2411
Joseph K Agyin ₁ , Bindu Santhamma , Hareesh B Nair , Sudipa S Roy , Rajeshwar R Tekmal

Affiliation

介绍蛋白酶体抑制为癌症治疗提供了一种有吸引力的方法，并可能应用于乳腺癌的治疗。然而，最近评估蛋白酶体抑制剂硼替佐米（Velcade，也称为 PS-341）在转移性乳腺癌患者中的作用的临床试验结果显示，当作为单一药物使用时，其活性有限。这强调需要寻找新的和更有效的蛋白酶体抑制剂。在这项研究中，我们使用体外和体内乳腺癌模型评估了新型蛋白酶体抑制剂 BU-32 (NSC D750499-S) 的功效。方法我们最近合成了一种新型蛋白酶体抑制剂 (BU-32)，并通过体外细胞毒性和蛋白酶体抑制试验测试了其对不同乳腺癌细胞（包括 MCF-7、MDA-MB-231 和 SKBR3）的生长抑制作用。使用流式细胞术和分析细胞周期调节蛋白来测试 BU32 的凋亡潜力。使用 MDA-MB-231-GFP 细胞进行实体瘤和肿瘤转移的体内肿瘤异种移植研究。结果我们首次报告 BU-32 在一组细胞系中表现出强烈的细胞毒性：MDA-MB-231 (IC50 = 5.8 nM)、SKBR3 (IC50 = 5.7 nM) 和 MCF-7 细胞 (IC50 = 5.8 nM) ）。它下调多种血管生成标记基因并上调凋亡标记，包括 Bid 和 Bax。MDA-MB-231 细胞与 BU-32 一起孵育会导致细胞周期抑制蛋白 p21 和 p27 的积累以及肿瘤抑制蛋白 p53 的稳定。体内实体瘤和转移模型的研究表明，0. 06 mg/kg 剂量的 BU-32 显着减少骨骼中的肿瘤负荷。结论我们已经证明 BU-32 在培养的乳腺癌细胞和乳腺癌异种移植物中是有效的。结果表明其在乳腺癌治疗中的潜在益处。

"点击查看英文标题和摘要"

BU-32: a novel proteasome inhibitor for breast cancer.

INTRODUCTION Proteasome inhibition provides an attractive approach to cancer therapy and may have application in the treatment of breast cancer. However, results of recent clinical trials to evaluate the effect of the proteasome inhibitor Bortezomib (Velcade, also called PS-341) in metastatic breast cancer patients have shown limited activity when used as a single agent. This underscores the need to find new and more efficacious proteasome inhibitors. In this study, we evaluate the efficacy of the novel proteasome inhibitor BU-32 (NSC D750499-S) using in vitro and in vivo breast cancer models. METHODS We have recently synthesized a novel proteasome inhibitor (BU-32) and tested its growth inhibitory effects in different breast cancer cells including MCF-7, MDA-MB-231, and SKBR3 by in vitro cytotoxicity and proteasomal inhibition assays. The apoptotic potential of BU32 was tested using flow cytometry and analyzing cell cycle regulatory proteins. In vivo tumor xenograft studies for solid tumor as well as tumor metastasis were conducted using MDA-MB-231-GFP cells. RESULTS We report for the first time that BU-32 exhibits strong cytotoxicity in a panel of cell lines: MDA-MB-231 (IC50 = 5.8 nM), SKBR3 (IC50 = 5.7 nM) and MCF-7 cells (IC50 = 5.8 nM). It downregulates a wide array of angiogenic marker genes and upregulates apoptotic markers, including Bid and Bax. Incubation of MDA-MB-231 cells with BU-32 results in the accumulation of cell cycle inhibitor proteins p21 and p27 and stabilization of the tumor suppressor protein p53. Studies in in vivo solid tumor and metastasis models show significant effect with a 0.06 mg/kg dose of BU-32 and marked reduction in tumor burden in the skeleton. CONCLUSIONS We have shown that BU-32 is effective in cultured breast cancer cells and in breast cancer xenografts. The results suggest its potential benefit in breast cancer treatment.

更新日期：2019-11-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南