Chemoprevention of familial adenomatous polyposis by low doses of atorvastatin and celecoxib given individually and in combination to APCmin mice
Chemoprevention of familial adenomatous polyposis by low doses of atorvastatin and celecoxib given individually and in combination to APCmin mice
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DOI：
10.1158/0008-5472.can-05-4619
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发表时间：
2006-07-15
期刊：
影响因子：
11.2
通讯作者：
Rao, Chinthalapally V.
中科院分区：
文献类型：
--
作者：
Swamy, Malisetty V.;Patlolla, Jagan M. R.;Rao, Chinthalapally V.
临床前和临床研究已证实，环氧合酶-2（考克斯-2）抑制剂和他汀类药物[羟基-3-甲基戊二酰CoA还原酶（HMGR）抑制剂]可抑制结肠癌的发生。长期使用高剂量的考克斯-2抑制剂可能会引起副作用，联合低剂量的药物可能是增加其疗效并使副作用最小化的有效方法。我们评估了阿托伐他汀（立普妥）和塞来昔布单独或联合在家族性腺瘤性息肉病动物模型中的化学预防效果。给6周龄雄性C57 BL/6 J-APC（min/+）小鼠喂食含0或100 ppm阿托伐他汀或300 ppm塞来昔布或两者组合的饲料，持续约80天。处死小鼠，并对它们的肠道进行肿瘤评分。收集表面正常的粘膜和肠肿瘤，并测定细胞凋亡（末端脱氧核苷酸转移酶介导的缺口末端标记）和HMGR和考克斯-2蛋白表达和活性。我们观察到100 ppm阿托伐他汀显著抑制肠息肉形成（P < 0.002）。正如预期，300 ppm塞来昔布可使肠息肉形成率降低约70%（P < 0.0001）。重要的是，与对照组相比，饮食中100 ppm阿托伐他汀和300 ppm塞来昔布的组合完全抑制结肠息肉和小肠息肉> 86%（P < 0.0001）。阿托伐他汀和塞来昔布联合用药对肿瘤形成的抑制作用与塞来昔布单独用药相比有显著性差异（P < 0.005）。此外，在喂食阿托伐他汀和塞来昔布的动物中观察到肠肿瘤中细胞凋亡率增加（P < 0.01-0.0001），并且在联合使用时更是如此。喂食阿托伐他汀的动物的肿瘤显示HMGR-R活性显著降低。同样，接触塞来昔布的小鼠肿瘤显示考克斯-2活性水平显著降低。这些观察结果表明，阿托伐他汀抑制肠道肿瘤发生，重要的是，当与低剂量塞来昔布一起给药时，它显著增加了APC（min）小鼠的化学预防功效。
Preclinical and clinical studies have established evidence that cyclooxygenase-2 (COX-2) inhibitors and statins [hydroxy-3-methylglutaryl CoA reductase (HMGR) inhibitors] inhibit colon carcinogenesis. Chronic use of high doses of COX-2 inhibitors may induce side effects, and combining the low doses of agents may be an effective way to increase their efficacy and minimize the side effects. We assessed the chemopreventive efficacy of atorvastatin (Lipitor) and celecoxib individually or in combination in an animal model of familial adenomatous polyposis. Six-week-old male C57BL/6J-APC(min/+) mice were either fed diets containing 0 or 100 ppm atorvastatin or 300 ppm celecoxib, or a combination of both for similar to 80 days. Mice were sacrificed, and their intestines were scored for tumors. Normal-seeming mucosa and intestinal tumors were harvested and assayed for apoptosis (terminal deoxynucleotidyl transferase-mediated nick-end labeling) and HMGR and COX-2 protein expression and activity. We observed that 100 ppm atorvastatin significantly (P < 0.002) suppressed intestinal polyp formation. As anticipated, 300 ppm celecoxib decreased the rate of formation of intestinal polyps by similar to 70% (P < 0.0001). Importantly, the combination of 100 ppm atorvastatin and 300 ppm celecoxib in the diet suppressed the colon polyps completely and small intestinal polyps by > 86% (P < 0.0001) compared with the control group. The inhibition of tumor formation by the atorvastatin and celecoxib combination was significant (P < 0.005) when compared with tumor inhibition by celecoxib alone. In addition, increased rates of apoptosis in intestinal tumors (P < 0.01-0.0001) were observed in animals fed with atorvastatin and celecoxib and more so with the combinations. Tumors of animals fed atorvastatin showed a significant decrease in HMGR-R activity. Similarly, tumors of mice exposed to celecoxib showed significantly lower levels of COX-2 activity. These observations show that atorvastatin inhibits intestinal tumorigenesis and that, importantly, when given together with low doses of celecoxib, it significantly increases the chemopreventive efficacy in an APC(min) mice.