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腾讯登录Carcinogenesis：COX-2抑制剂对肿瘤EMT后更有效
| 导读 | 流行病学研究发现，非甾体抗炎药(NSAID )，也即环氧合酶 (Cyclooxygenasa，COX) 抑制剂，可以减少发生结肠癌的风险，这引起了研究人员对于NSAID的关注。
随之进行的一系列研究表明，服用阿斯匹林或者其他NSAID还可以降低发生肺癌、乳腺癌、前列腺癌、恶性黑色素瘤等肿瘤的危险性。为了揭开NSAID减少肿瘤发生危险性的作用机制，相当多的研究从NSAID的作用机理出发进行了实... |
流行病学研究发现，非甾体抗炎药(NSAID )，也即环氧合酶 (Cyclooxygenasa，COX) 抑制剂，可以减少发生结肠癌的风险，这引起了研究人员对于NSAID的关注。
随之进行的一系列研究表明，服用阿斯匹林或者其他NSAID还可以降低发生肺癌、乳腺癌、前列腺癌、恶性黑色素瘤等肿瘤的危险性。为了揭开NSAID减少肿瘤发生危险性的作用机制，相当多的研究从NSAID的作用机理出发进行了实验，发现COX的活性增高和过表达在肿瘤的发生和发展中起着重要作用，提示NSAID的抗肿瘤效果与其抑制COX活性的作用直接相关，这使得COX成为肿瘤研究领域的一个新热点。
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虽然环氧合酶-2（COX-2）抑制剂如后期开发药物帕瑞昔布(Apricoxib)，展出良好的抗肿瘤活性，但COX-2抑制剂的抗肿瘤作用机制还没有得到充分的阐述。最新<em>Carcinogenesis</em>杂志上刊出的一项研究重点考察了Apricoxib对HT29大肠癌抗肿瘤作用的机制。
<p align="center"><img src="http://www.bioon.com/biology/UploadFiles/201206/2012062709551419.gif" alt="" width="380" height="512" border="0" /></p>
研究发现在体外细胞水平上，Apricoxib对HT29细胞呈弱毒性，但在体内却能明显抑制大肠癌细胞HT29的生长。药代动力学分析表明，体内药物浓度能达到2-4μM的高峰，但仍不足以完全抑制PGE2的生成，但这一血药浓度没有达到体外对HT29有细胞毒性的浓度。
虽然Apricoxib能显著抑制肿瘤细胞增殖和诱导细胞凋亡，但同时不影响血管密度，令人惊讶的是它却能促进血管正常化。引人注目的是，Apricoxib能诱导上皮-间质转化（EMT），能上调E-钙粘素的表达，降低波形蛋白以及ZEB1蛋白的表达。
在体外，Apricoxib对发生EMT的HT29和非小细胞肺癌细胞的作用强度提高了50倍，这表明EMT的发生，可能依赖对COX-2的产生有影响，进而结肠癌和肺癌细胞对Apricoxib的敏感性增加。这些数据表明，癌细胞获得间充质特性后对Apricoxib敏感性加强，造成Apricoxib具有显著的抗肿瘤活性。
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<img src="http://www.bioon.com/biology/UploadFiles/201206/2012062709525840.gif" alt="" width="115" height="150" border="0" />
<a title="" href="http://dx.doi.org/10.1093/carcin/bgs195" target="_blank">doi:10.1093/carcin/bgs195</a>
PMC:
PMID:
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<br/><strong>Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib
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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.
<br/>来源：生物谷
</div>
</div>
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随之进行的一系列研究表明，服用阿斯匹林或者其他NSAID还可以降低发生肺癌、乳腺癌、前列腺癌、恶性黑色素瘤等肿瘤的危险性。为了揭开NSAID减少肿瘤发生危险性的作用机制，相当多的研究从NSAID的作用机理出发进行了实验，发现COX的活性增高和过表达在肿瘤的发生和发展中起着重要作用，提示NSAID的抗肿瘤效果与其抑制COX活性的作用直接相关，这使得COX成为肿瘤研究领域的一个新热点。
<!--more-->
虽然环氧合酶-2（COX-2）抑制剂如后期开发药物帕瑞昔布(Apricoxib)，展出良好的抗肿瘤活性，但COX-2抑制剂的抗肿瘤作用机制还没有得到充分的阐述。最新<em>Carcinogenesis</em>杂志上刊出的一项研究重点考察了Apricoxib对HT29大肠癌抗肿瘤作用的机制。
<p align="center"><img src="http://www.bioon.com/biology/UploadFiles/201206/2012062709551419.gif" alt="" width="380" height="512" border="0" /></p>
研究发现在体外细胞水平上，Apricoxib对HT29细胞呈弱毒性，但在体内却能明显抑制大肠癌细胞HT29的生长。药代动力学分析表明，体内药物浓度能达到2-4μM的高峰，但仍不足以完全抑制PGE2的生成，但这一血药浓度没有达到体外对HT29有细胞毒性的浓度。
虽然Apricoxib能显著抑制肿瘤细胞增殖和诱导细胞凋亡，但同时不影响血管密度，令人惊讶的是它却能促进血管正常化。引人注目的是，Apricoxib能诱导上皮-间质转化（EMT），能上调E-钙粘素的表达，降低波形蛋白以及ZEB1蛋白的表达。
在体外，Apricoxib对发生EMT的HT29和非小细胞肺癌细胞的作用强度提高了50倍，这表明EMT的发生，可能依赖对COX-2的产生有影响，进而结肠癌和肺癌细胞对Apricoxib的敏感性增加。这些数据表明，癌细胞获得间充质特性后对Apricoxib敏感性加强，造成Apricoxib具有显著的抗肿瘤活性。
<div id="ztload">
<div>
<div>
<img src="http://www.bioon.com/biology/UploadFiles/201206/2012062709525840.gif" alt="" width="115" height="150" border="0" />
<a title="" href="http://dx.doi.org/10.1093/carcin/bgs195" target="_blank">doi:10.1093/carcin/bgs195</a>
PMC:
PMID:
</div>
<div>
<br/><strong>Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib
</strong><br/>
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.
<br/>来源：生物谷
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