流行病學(xué)研究發(fā)現(xiàn)，非甾體抗炎藥(NSAID ),，也即環(huán)氧合酶 (Cyclooxygenasa,，COX) 抑制劑，可以減少發(fā)生結(jié)腸癌的風(fēng)險(xiǎn),，這引起了研究人員對(duì)于NSAID的關(guān)注,。
隨之進(jìn)行的一系列研究表明，服用阿斯匹林或者其他NSAID還可以降低發(fā)生肺癌,、乳腺癌,、前列腺癌、惡性黑色素瘤等腫瘤的危險(xiǎn)性,。為了揭開NSAID減少腫瘤發(fā)生危險(xiǎn)性的作用機(jī)制,，相當(dāng)多的研究從NSAID的作用機(jī)理出發(fā)進(jìn)行了實(shí)驗(yàn),，發(fā)現(xiàn)COX的活性增高和過表達(dá)在腫瘤的發(fā)生和發(fā)展中起著重要作用，提示NSAID的抗腫瘤效果與其抑制COX活性的作用直接相關(guān),，這使得COX成為腫瘤研究領(lǐng)域的一個(gè)新熱點(diǎn),。
雖然環(huán)氧合酶-2（COX-2）抑制劑如后期開發(fā)藥物帕瑞昔布(Apricoxib)，展出良好的抗腫瘤活性,，但COX-2抑制劑的抗腫瘤作用機(jī)制還沒有得到充分的闡述,。最新Carcinogenesis雜志上刊出的一項(xiàng)研究重點(diǎn)考察了Apricoxib對(duì)HT29大腸癌抗腫瘤作用的機(jī)制。
研究發(fā)現(xiàn)在體外細(xì)胞水平上,，Apricoxib對(duì)HT29細(xì)胞呈弱毒性,，但在體內(nèi)卻能明顯抑制大腸癌細(xì)胞HT29的生長(zhǎng)。藥代動(dòng)力學(xué)分析表明,，體內(nèi)藥物濃度能達(dá)到2-4μM的高峰,，但仍不足以完全抑制PGE2的生成，但這一血藥濃度沒有達(dá)到體外對(duì)HT29有細(xì)胞毒性的濃度,。
雖然Apricoxib能顯著抑制腫瘤細(xì)胞增殖和誘導(dǎo)細(xì)胞凋亡,，但同時(shí)不影響血管密度，令人驚訝的是它卻能促進(jìn)血管正?；?。引人注目的是，Apricoxib能誘導(dǎo)上皮-間質(zhì)轉(zhuǎn)化（EMT）,，能上調(diào)E-鈣粘素的表達(dá),，降低波形蛋白以及ZEB1蛋白的表達(dá)。
在體外,，Apricoxib對(duì)發(fā)生EMT的HT29和非小細(xì)胞肺癌細(xì)胞的作用強(qiáng)度提高了50倍,，這表明EMT的發(fā)生，可能依賴對(duì)COX-2的產(chǎn)生有影響,，進(jìn)而結(jié)腸癌和肺癌細(xì)胞對(duì)Apricoxib的敏感性增加,。這些數(shù)據(jù)表明，癌細(xì)胞獲得間充質(zhì)特性后對(duì)Apricoxib敏感性加強(qiáng),，造成Apricoxib具有顯著的抗腫瘤活性,。（生物谷：Bioon.com）
doi:10.1093/carcin/bgs195
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PMID:
Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib
Amanda Robinson Kirane*, Jason Edward Toombs, Jill E Larsen, Katherine T Ostapoff, Katheryn R Meshaw,et al.
Although Cyclooxygenase-2 (COX-2) inhibitors, such as the late stage development drug apricoxib, exhibit antitumor activity, their mechanisms of action have not been fully defined. Here, we characterized the mechanisms of action of apricoxib in HT29 colorectal carcinoma. Apricoxib was weakly cytotoxic towards naive HT29 cells in vitro but inhibited tumor growth markedly in vivo. Pharmacokinetic analyses revealed that in vivo drug levels peaked at 2-4 μM and remained sufficient to completely inhibit PGE2 production, but failed to reach concentrations cytotoxic for HT29 cells in monolayer culture. Despite this, apricoxib significantly inhibited tumor cell proliferation and induced apoptosis without affecting blood vessel density, although it did promote vascular normalization. Strikingly, apricoxib treatment induced a dose-dependent reversal of epithelial-mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and Zeb1 protein expression. In vitro, either anchorage-independent growth conditions or forced EMT sensitized HT29 and NSCLC cells to apricoxib by 50-fold, suggesting the occurrence of EMT may actually increase the dependence of colon and lung carcinoma cells on COX-2. Taken together, these data suggest that acquisition of mesenchymal characteristics sensitizes carcinoma cells to apricoxib resulting in significant single agent antitumor activity.
