Chemoprevention of colon and small intestinal tumorigenesis in APC(Min/+) mice by licofelone, a novel dual 5-LOX/COX inhibitor: potential implications for human colon cancer prevention.
Chemoprevention of colon and small intestinal tumorigenesis in APC(Min/+) mice by licofelone, a novel dual 5-LOX/COX inhibitor: potential implications for human colon cancer prevention.
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DOI：
10.1158/1940-6207.capr-11-0233
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发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Rao CV
中科院分区：
文献类型：
--
作者：
Mohammed A;Janakiram NB;Li Q;Choi CI;Zhang Y;Steele VE;Rao CV
临床前和临床研究表明，5-脂氧合酶(5-LOX)和环氧合酶-2(COX-2)一样，是抑制结肠癌的潜在靶点，并在一定程度上与COX-2抑制剂相关的心血管副作用有关。本实验旨在评价新型5-LOX/COX双重抑制剂--利可酮对APCMin/+小鼠肠道肿瘤的化学预防作用。6周龄APCMin/+雄性和雌性APCMin/+小鼠(每组10只)分别饲喂对照AIN-76A饲料或含150或300ppm地塞罗酮的饲料14周(~100天)，观察肿瘤的多发性和肿瘤大小。利可酮以剂量依赖的方式显著抑制全肠道肿瘤的多样性和大小(p<；0.0001；0、150和300ppm的平均肿瘤：雄性小鼠分别为48.8ppm、17ppm和8；雌性小鼠分别为34.38.8ppm、8.8ppm和5.5ppm)。高剂量的利可酮对两性小鼠的肿瘤抑制率均为83%(p<；0.0001)。150和300ppm的利福酮对息肉的抑制率为86%-97%。150和300ppm的利福酮对结肠肿瘤的抑制率分别为72%和100%。重要的是，服用利福酮的小鼠肿瘤细胞增殖细胞核抗原表达显著降低(70%，P<；0.0001)，TUNEL阳性细胞显著增加(75%，P<；0.0001)，血清甘油三酯呈剂量依赖性抑制(71-83%，P<；0.0001)，炎性细胞因子减少，COX和5-LOX活性降低(57-%，P<；0.0001)。此外，与300ppm的塞来昔布相比，300ppm的利洛酮在抑制肿瘤生长方面提供了更好的疗效。这些观察表明，一种新的双重5-LOX/COX抑制剂显著抑制APCMin/+小鼠小肠和结肠肿瘤的形成。
Preclinical and clinical studies suggest that 5-lipoxygenase (5-LOX), like cyclo-oxygenase-2 (COX-2), is a potential target for colon cancer inhibition and, in part, contributes to cardiovascular side effects associated with COX-2 inhibitors. Experiments were designed to assess the chemopreventive effects of a novel dual 5-LOX/COX inhibitor, Licofelone, in APCMin/+ mouse intestinal tumorigenesis. Six week-old male and female APCMin/+ mice (n=10 per group) were fed control AIN-76A diet or diets containing 150 or 300 ppm licofelone for 14 weeks (~100 days), and intestinal tumors were evaluated for tumor multiplicity and size. Licofelone significantly inhibited total intestinal tumor multiplicity and size in a dose-dependent manner (p<0.0001; mean tumors for 0, 150 and 300 ppm: 48.8, 17, and 8, respectively, in male mice; and 34.3, 8.8, and 5.5, respectively, in female mice). Licofelone at high-dose showed >83% (p<0.0001) tumor inhibition in both genders of mice. 150 and 300 ppm licofelone resulted 86%–97% inhibition of polyps>2-mm. 150 and 300 ppm licofelone caused >72% and 100% inhibition of colonic tumors, respectively. Importantly, in mice fed licofelone, tumors showed significantly reduced PCNA expression (70%, P<0.0001), increased TUNEL positive cells (75%, p<0.0001), and there was dose-dependent suppression of serum triglycerids (71–83%, p<0.0001), decreased inflammatory cytokines; and decreased COX and 5-LOX activities (57–64%, p<0.0001). Also, compared with 300 ppm celecoxib, 300 ppm licofelone provided better efficacy in suppressing tumor growth. These observations demonstrate that a novel dual 5-LOX/COX inhibitor dramatically suppresses small intestinal and colonic tumor formation in APCMin/+ mice.