A water soluble parthenolide analog suppresses in vivo tumor growth of two tobacco-associated cancers, lung and bladder cancer, by targeting NF-κB and generating reactive oxygen species.
A water soluble parthenolide analog suppresses in vivo tumor growth of two tobacco-associated cancers, lung and bladder cancer, by targeting NF-κB and generating reactive oxygen species.
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DOI：
10.1002/ijc.25587
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发表时间：
2011-05-15
影响因子：
6.4
通讯作者：
Sweeney, Christopher J.
中科院分区：
文献类型：
--
作者：
Shanmugam, Rajasubramaniam;Kusumanchi, Praveen;Appaiah, Hitesh;Cheng, Liang;Crooks, Peter;Neelakantan, Sundar;Peat, Tyler;Klaunig, James;Matthews, William;Nakshatri, Harikrishna;Sweeney, Christopher J.
二甲氨基帕索内酯(DMAPT)是一种具有临床前活性的水溶性单烯内酯类似物，可用于治疗血液系统恶性肿瘤。利用非小细胞肺癌细胞系(A549、H522)、永生化人支气管上皮细胞系(BEAS2B)、膀胱癌细胞系(UMUC-3、HT-1197、HT-1376)和膀胱乳头状瘤(RT-4)，研究DMAPT在烟草相关肿瘤中的抗癌活性。流式细胞仪、凝胶电泳法和免疫印迹法检测细胞内活性氧(ROS)的产生、核转录因子κBDNA结合的抑制以及细胞周期分布和凋亡蛋白的变化。DMAPT产生ROS，继而激活JNKDNA，同时也降低了NFκBDNA结合和抗凋亡蛋白TRAF 2和XIAP。DMAPT诱导细胞死亡，改变细胞周期分布，上调p21和p73水平，并呈细胞类型依赖性。DMAPT抑制BEAS2B细胞周期蛋白D1的表达。在烟草致癌物亚硝胺酮-4-(甲基亚硝氨基)-1-(3-吡啶)-1-丁酮存在下，DMAPT保留了NF-κB和细胞周期抑制活性。BrdU蓄积实验显示，5~20μM的DMAPT对所有细胞系的细胞增殖抑制率均在95%以上。口服DMAPT对A549和UMUC-3皮下移植瘤的生长抑制率分别为54%(p=0.015)和63%(p=0.015)，对A549肺转移体积的抑制率为28%(p=0.043)。总而言之，这些数据显示了DMAPT在早期和晚期烟草相关肿瘤中的新的抗癌特性以及它在体内的显着活性。这些数据为TCC和NSCLC的临床试验提供了支持。
Dimethylaminoparthenolide (DMAPT) is a water soluble parthenolide analogue with preclinical activity in hematologic malignancies. Using NSCLC cell lines (A549, H522) and an immortalized human bronchial epithelial cell line (BEAS2B) and TCC cell lines (UMUC-3, HT-1197, HT-1376) and a bladder papilloma (RT-4), we aimed to characterize DMAPT's anti-cancer activity in tobacco associated neoplasms. Flow cytometric, electrophorectic mobility gel shift assays (EMSA), and western blot studies measured generation of reactive oxygen species (ROS), inhibition of NFκB DNA binding, and changes in cell cycle distribution and apoptotic proteins. DMAPT generated ROS with subsequent JNK activation and also decreased NFκB DNA binding and anti-apoptotic proteins, TRAF-2 and XIAP. DMAPT induced apoptotic cell death and altered cell cycle distribution with upregulation of p21 and p73 levels in a cell type dependent manner. DMAPT suppressed cyclin D1 in BEAS2B. DMAPT retained NFκB and cell cycle inhibitory activity in the presence of the tobacco carcinogen nitrosamine ketone, 4(methylnitrosamino)-1-(3–pyridyl)-1-butanone (NNK). Using a BrdU accumulation assay, 5 to 20μM of DMAPT was shown to inhibit cellular proliferation of all cell lines by more than 95%. Oral dosing of DMAPT suppressed in vivo A549 and UMUC-3 subcutaneous xenograft growth by 54% (p=0.015) and 63% (p<0.01) respectively and A549 lung metastatic volume by 28% (p=0.043). In total this data demonstrates DMAPT's novel anti-cancer properties in both early and late stage tobacco associated neoplasms as well as its significant in vivo activity. The data provides support for the conduct of clinical trials in TCC and NSCLC.
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影响因子：
8
作者：
Decesse, JT;Medjkane, S;Crémisi, CE
通讯作者：
Crémisi, CE
影响因子：
20.3
作者：
Hewamana, Saman;Alghazal, Suhair;Pepper, Chris
通讯作者：
Pepper, Chris
影响因子：
4.8
作者：
Helbig, G;Christopherson, KW;Nakshatri, H
通讯作者：
Nakshatri, H
影响因子：
3.5
作者：
Bork, PM;Schmitz, ML;Heinrich, M
通讯作者：
Heinrich, M
影响因子：
5.7
作者：
Gopal, Y. N. Vashisht;Chanchorn, Ekkavvit;Van Dyke, Michael W.
通讯作者：
Van Dyke, Michael W.