Celecoxib enhances doxorubicin-induced cytotoxicity in MDA-MB231 cells by NF-κB-mediated increase of intracellular doxorubicin accumulation
Celecoxib enhances doxorubicin-induced cytotoxicity in MDA-MB231 cells by NF-κB-mediated increase of intracellular doxorubicin accumulation
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DOI：
10.1016/j.ejca.2006.09.010
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发表时间：
2007-01-01
影响因子：
8.4
通讯作者：
Lowik, Clemens W. G. M.
中科院分区：
文献类型：
--
作者：
van Wijngaarden, Jens;van Beek, Ermond;Lowik, Clemens W. G. M.
非甾体抗炎药（NSAID）和环氧合酶（考克斯）抑制剂是抗炎剂，也已显示可用于抗癌治疗。在本研究中，我们表明，具体的考克斯-2抑制剂塞来昔布增强阿霉素（dox）对人MDA-MB 231乳腺肿瘤生长在体内和体外的抑制作用。我们还发现，塞来昔布增加细胞内蓄积和保留的阿霉素在体外。由于NSAID吲哚美辛和特异性考克斯-2抑制剂NS 398不影响dox的体外作用，因此这些作用可能是通过COX非依赖性机制介导的。已经表明，一些COX抑制剂可以通过抑制ABC转运蛋白克服多药耐药性来增强细胞抑制剂的作用。然而，我们发现，三个主要的ATP结合盒（ABC）转运蛋白，涉及在dox运输，在MDA-MB 231细胞中是无活性的。因此，P-糖蛋白（P-gp）阻断剂PSC 833也增加dox的细胞蓄积的发现是出乎意料的。为了阐明dox蓄积的分子机制，我们研究了NF-κ B的参与，因为该转录因子与塞来昔布作用以及耐药性有关。我们发现，塞来昔B和PSC 833，而不是吲哚美辛或NS 398，几乎完全抑制基础和dox诱导的NF-κ B基因报告活性和p65亚基核转位。此外，NF-κ B抑制剂PDTC模拟了塞来昔B和PSC 833对细胞生长和细胞内dox积累的作用，表明NF-κ B在功能上参与了这些化合物的作用。总之，我们表明，结构不同的化合物，其中塞来昔B和PSC 833，增加细胞内积累的dox和增强dox诱导的细胞毒性在MDA-MB 231乳腺癌细胞中最有可能通过调节NF-κ B活性。(c)2006爱思唯尔有限公司保留所有权利。
Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase (COX) inhibitors are anti-inflammatory agents that have also shown to be useful in anticancer therapy. In the present study, we show that the specific COX-2 inhibitor celecoxib enhances the inhibitory effect of doxorubicin (dox) on human MDA-MB231 breast tumour growth in vivo and in vitro. We also found that celecoxib increased the intracellular accumulation and retention of dox in vitro. Since the NSAID indomethacin and the specific COX-2 inhibitor NS398 did not affect the in vitro actions of dox, these effects are likely to be mediated via a COX-independent mechanism. It has been suggested that some COX-inhibitors can enhance the actions of cytostatics by overcoming multidrug resistance through the inhibition of ABC-transporter proteins. However, we found that the three main ATP-binding cassette (ABC)-transporter proteins, implicated in dox transport, were inactive in MDA-MB231 cells. Therefore, the finding that the P-glycoprotein (P-gp) blocker PSC833 also increased cellular accumulation of dox was unexpected. In order to unravel the molecular mechanisms involved in dox accumulation, we examined the involvement of NF-kappa B, as this transcription factor has been implicated in celecoxib action as well as in chemoresistance. We found that celecoxib and PSC833, but not indomethacin or NS398, almost completely inhibited basal- and dox induced NF-kappa B gene-reporter activity and p65 subunit nuclear translocation. Furthermore, the NF-kappa B inhibitor PDTC mimicked the actions of celecoxib and PSC833 on cell growth and on intracellular accumulation of dox, suggesting that NF-kappa B is functionally involved in the actions of these compounds., In conclusion, we show that structurally different compounds, among which are celecoxib and PSC833, increase the intracellular accumulation of dox and enhance dox induced cytotoxicity in MDA-MB231 breast cancer cells most likely via the modulation of NF-kappa B activity. (c) 2006 Elsevier Ltd. All rights reserved.