Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Cancer Prev Res (Phila). 2011 Dec;4(12):2015-26. doi: 10.1158/1940-6207.CAPR-11-0233. Epub 2011 Sep 1.
Preclinical and clinical studies suggest that 5-lipoxygenase (5-LOX), such as 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 {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid}, in APC(Min/+) mouse intestinal tumorigenesis. Six-week-old male and female APC(Min/+) mice (n = 10 per group) were fed with control American Institute of Nutrition-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 more than 83% (P < 0.0001) tumor inhibition in both genders of mice. One hundred and fifty and 300 ppm licofelone resulted in 86% to 97% inhibition of polyps having size greater than 2 mm. One hundred and fifty and 300 ppm licofelone caused more than 72% and 100% inhibition of colonic tumors, respectively. Importantly, in mice fed with licofelone, tumors showed significantly reduced proliferating cell nuclear antigen expression (70%, P < 0.0001), increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells (75%, P < 0.0001), and there was dose-dependent suppression of serum triglycerides (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 show that a novel dual 5-LOX/COX inhibitor dramatically suppresses small intestinal and colonic tumor formation in APC(Min/+) mice.
临床前和临床研究表明，5-脂氧合酶（5-LOX），如 COX-2，是抑制结肠癌的潜在靶点，部分原因是与 COX-2 抑制剂相关的心血管副作用。实验旨在评估新型双重 5-LOX/COX 抑制剂 licofelone [（6-（4-氯苯基）-2,2-二甲基-7-苯基-2,3-二氢-1H-吡咯嗪-5-基）乙酸]在 APC（Min/+）小鼠肠道肿瘤发生中的化学预防作用。将 6 周龄雄性和雌性 APC（Min/+）小鼠（每组 10 只）分别用对照美国营养学会-76A 饮食或含 150 或 300 ppm licofelone 的饮食喂养 14 周（约 100 天），并评估肠道肿瘤的多发性和大小。licofelone 以剂量依赖性方式显著抑制总肠道肿瘤多发性和大小（P < 0.0001；雄性小鼠中 0、150 和 300 ppm 的平均肿瘤数分别为 48.8、17 和 8，雌性小鼠中分别为 34.3、8.8 和 5.5）。高剂量的 licofelone 在雌雄小鼠中均显示出超过 83%（P < 0.0001）的肿瘤抑制作用。150 和 300 ppm licofelone 导致大于 2mm 的息肉大小的抑制率分别为 86%至 97%。150 和 300 ppm licofelone 分别导致结肠肿瘤的抑制率大于 72%和 100%。重要的是，在喂食 licofelone 的小鼠中，肿瘤增殖细胞核抗原表达明显减少（70%，P < 0.0001），末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记阳性细胞增加（75%，P < 0.0001），血清甘油三酯呈剂量依赖性抑制（71%-83%，P < 0.0001），炎症细胞因子减少；COX 和 5-LOX 活性降低（57%-64%，P < 0.0001）。此外，与 300 ppm celecoxib 相比，300 ppm licofelone 能更好地抑制肿瘤生长。这些观察结果表明，新型双重 5-LOX/COX 抑制剂可显著抑制 APC（Min/+）小鼠的小肠和结肠肿瘤形成。
