BU-32: a novel proteasome inhibitor for breast cancer.
BU-32: a novel proteasome inhibitor for breast cancer.
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DOI：
10.1186/bcr2411
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Tekmal RR
中科院分区：
文献类型：
--
作者：
Agyin JK;Santhamma B;Nair HB;Roy SS;Tekmal RR
蛋白酶体抑制为癌症治疗提供了一种有吸引力的方法，并可能在乳腺癌的治疗中得到应用。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，作为单一药物使用时活性有限。这强调了寻找新的和更有效的蛋白酶体抑制剂的必要性。在这项研究中，我们通过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）的疗效。我们最近合成了一种新的蛋白酶体抑制剂（BU-32），并通过体外细胞毒性和蛋白酶体抑制实验测试了其对不同乳腺癌细胞的生长抑制作用，包括MCF-7、MDA-MB-231和SKBR3。流式细胞术检测BU32的凋亡电位，分析细胞周期调节蛋白。使用MDA-MB-231-GFP细胞进行了实体瘤和肿瘤转移的体内肿瘤异种移植研究。我们首次报道了BU-32在MDA-MB-231 （IC50 = 5.8 nM）、SKBR3 （IC50 = 5.7 nM）和MCF-7细胞（IC50 = 5.8 nM）中表现出很强的细胞毒性。它下调一系列血管生成标记基因，上调凋亡标记基因，包括Bid和Bax。用BU-32孵育MDA-MB-231细胞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具有显著的效果，可显著减轻骨骼中的肿瘤负荷。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中是有效的。结果表明它在乳腺癌治疗中的潜在益处。
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. 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. 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. 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.
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影响因子：
4.8
作者：
Breitschopf, K;Zeiher, AM;Dimmeler, S
通讯作者：
Dimmeler, S
影响因子：
3.1
作者：
Cardoso, Fatima;Ross, Jeffrey S;Durbecq, Virginie
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Durbecq, Virginie
影响因子：
45.3
作者：
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通讯作者：
Stadler, WM
影响因子：
4.8
作者：
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通讯作者：
Wolf, DH
影响因子：
12.4
作者：
An, B;Goldfarb, RH;Dou, QP
通讯作者：
Dou, QP