A novel NSAID derivative, phospho-ibuprofen, prevents AOM-induced colon cancer in rats.
A novel NSAID derivative, phospho-ibuprofen, prevents AOM-induced colon cancer in rats.
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DOI：
10.3892/ijo.2012.1756
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发表时间：
2013-02
影响因子：
5.2
通讯作者：
Williams JL
中科院分区：
文献类型：
--
作者：
Ouyang N;Ji P;Williams JL
布洛芬的癌症化学预防特性和胃肠道毒性已得到充分证明。对现有NSAID的修饰改善了该药剂的化学预防功效并降低了其毒性。在这项研究中，布洛芬和修饰的衍生物（磷酸修饰的布洛芬或p-布洛芬）用于化学诱导的结肠癌模型。Fisher 344大鼠注射氧化偶氮甲烷，然后用布洛芬（500 ppm）或对布洛芬（900 ppm）治疗20周以观察异常隐窝病灶（ACF）或40周以评价肿瘤发生率和多样性。免疫荧光法检测结肠组织中β-catenin和p65的表达。将等摩尔剂量的布洛芬（75和670 mg/kg）和对布洛芬（135和1，215 mg/kg）给予大鼠7天，以评估急性毒性。体外实验检测对布洛芬对巨噬细胞RAW 264.7和结肠癌细胞HCT 116的考克斯-2和PGE 2合成、β-catenin表达和NF-κB活性的影响。在第20周，与对照组相比，p-布洛芬和布洛芬显著降低了ACF的多样性（p<0.05）;分别为31.2%和37.9%。在第40周，与对照组相比，p-布洛芬和布洛芬分别使结肠肿瘤的多样性降低了47.2%和56.6%（p<0.01）。等摩尔浓度的布洛芬（670 mg/kg）和对布洛芬（1，215 mg/kg）分别导致85.7%（7只中的6只）和14.3%（7只中的1只）的大鼠发生胃溃疡，p<0.01。免疫荧光染色和western blot分析表明，布洛芬和对布洛芬均能抑制结肠癌细胞中β-catenin的核转位。此外，p-布洛芬而不是布洛芬抑制结肠癌细胞中的NF-κB活化。总的来说，这些结果表明对布洛芬是一种长期用于结肠癌预防的潜在有效新药。
The cancer chemopreventive properties and gastrointestinal toxicity of ibuprofen are well documented. Modification of existing NSAIDs has improved on the chemopreventive efficacy of this agent and reduced its toxicity. In this study, ibuprofen and a modified derivative (phospho-modified ibuprofen or p-ibuprofen) were used in a chemically induced model of colon cancer. Fisher 344 rats were injected with azoxymethane then treated with either ibuprofen (500 ppm) or p-ibuprofen (900 ppm) for 20 weeks to observe aberrant crypt foci (ACF) or 40 weeks to evaluate tumor incidence and multiplicity. β-catenin and p65 were measured in colonic tissues by immunofluorescence staining. Equal molar doses of ibuprofen (75 and 670 mg/kg) and p-ibuprofen (135 and 1,215 mg/kg) were administered to rats for 7 days to assess acute toxicity. The in vitro effect of p-ibuprofen on COX-2 and PGE2 synthesis, β-catenin expression and NF-κB activity were examined in RAW 264.7 macrophage and HCT 116 colon cancer cells. At week 20, p-ibuprofen and ibuprofen significantly reduced the multiplicity of ACF compared with control (p<0.05); 31.2 and 37.9%, respectively. At week 40, p-ibuprofen and ibuprofen reduced the multiplicity of colon tumors compared with control (p<0.01) by 47.2 and 56.6%, respectively. Equal molar concentrations of ibuprofen (670 mg/kg) and p-ibuprofen (1,215 mg/kg) resulted in stomach ulceration in 85.7% (6 out of 7) and 14.3% (1 out of 7) of rats, respectively, with p<0.01. Immunofluoresence staining and western blot analysis demonstrated that both ibuprofen and p-ibuprofen suppressed β-catenin nuclear translocation in colon cancer cells. In addition, p-ibuprofen but not ibuprofen inhibited NF-κB activation in colon cancer cells. Collectively, these results suggest that p-ibuprofen is a potential effective novel drug for long-term use in colon cancer prevention.
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