van Wijngaarden Jens, van Beek Ermond, van Rossum Gerda, van der Bent Chris, Hoekman Klaas, van der Pluijm Gabri, van der Pol Marjolein A, Broxterman Henk J, van Hinsbergh Victor W M, Löwik Clemens W G M
Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Eur J Cancer. 2007 Jan;43(2):433-42. doi: 10.1016/j.ejca.2006.09.010. Epub 2006 Nov 9.
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-kappaB, 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-kappaB gene-reporter activity and p65 subunit nuclear translocation. Furthermore, the NF-kappaB inhibitor PDTC mimicked the actions of celecoxib and PSC833 on cell growth and on intracellular accumulation of dox, suggesting that NF-kappaB 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-kappaB activity.
非甾体抗炎药（NSAIDs）和环氧化酶（COX）抑制剂是抗炎药物，它们在抗癌治疗中也显示出有用性。在本研究中，我们表明特异性COX-2抑制剂塞来昔布增强了阿霉素（dox）在体内和体外对人MDA-MB231乳腺肿瘤生长的抑制作用。我们还发现塞来昔布在体外增加了dox的细胞内蓄积和滞留。由于非甾体抗炎药吲哚美辛和特异性COX-2抑制剂NS398不影响dox的体外作用，这些作用可能通过不依赖COX的机制介导。有人提出一些COX抑制剂可通过抑制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，我们发现参与dox转运的三种主要ATP结合盒（ABC）转运蛋白在MDA-MB231细胞中无活性。因此，P-糖蛋白（P-gp）阻滞剂PSC833也增加dox的细胞蓄积这一发现出乎意料。为了阐明参与dox蓄积的分子机制，我们研究了NF-κB的参与情况，因为该转录因子与塞来昔布的作用以及化疗耐药性有关。我们发现塞来昔布和PSC833，但不是吲哚美辛或NS398，几乎完全抑制基础和dox诱导的NF-κB基因报告活性和p65亚基核转位。此外，NF-κB抑制剂PDTC模拟了塞来昔布和PSC833对细胞生长和dox细胞内蓄积的作用，表明NF-κB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，其中包括塞来昔布和PSC833，增加了dox的细胞内蓄积，并最有可能通过调节NF-κB活性增强dox在MDA-MB231乳腺癌细胞中诱导的细胞毒性。
