Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3101, USA.
Cancer Prev Res (Phila). 2010 Sep;3(9):1187-97. doi: 10.1158/1940-6207.CAPR-09-0270. Epub 2010 Aug 17.
Although nonsteroidal anti-inflammatory drugs (NSAID), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer, results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study, we evaluated the effect of sulindac on colon tumorigenesis in the Apc(Min/+) mouse model. Sulindac (180 ppm) given in drinking water for 9 weeks to Apc(Min/+) mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 versus 1.6 tumors per mouse, respectively; P < 0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine, sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 versus 42.0 tumors per mouse, respectively; P < 0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many noncyclooxygenase targets, including p21, beta-catenin, E-cadherin, mitochondrial apoptotic proteins, and peroxisome proliferator-activated receptor-gamma. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear beta-catenin accumulation. Importantly, p21(WAF1/cip1) and peroxisome proliferator-activated receptor-gamma expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies using combinations of agents that target multiple molecular pathways to overcome sulindac resistance.
虽然非甾体抗炎药（NSAIDs），包括舒林酸，已被广泛用作结直肠癌的化学预防剂，但结果并不一致。据报道，NSAIDs，通常是舒林酸，往往不会导致腺瘤完全消退，并且一些患者对 NSAID 治疗产生耐药性。在这项研究中，我们评估了舒林酸对 Apc(Min/+)小鼠模型中结肠癌发生的影响。舒林酸（180ppm）在饮用水中给予 Apc(Min/+)小鼠 9 周，显著降低了结肠肿瘤的大小，但实际上与未治疗的对照组相比，增加了结肠肿瘤的多发性（分别为平均每只小鼠 5.5 个和 1.6 个肿瘤；P<0.0001）。这表明该药物可以抑制结肠肿瘤的进展，但不能抑制其发生。正如预期的那样，在小肠中，舒林酸与未治疗的对照组相比，显著降低了肿瘤的大小和多发性（分别为平均每只小鼠 2.3 个和 42.0 个肿瘤；P<0.0001）。舒林酸处理也可抑制小肠和结肠中前列腺素的生成。舒林酸还通过调节许多非环氧化酶靶标，包括 p21、β-连环蛋白、E-钙黏蛋白、线粒体凋亡蛋白和过氧化物酶体增殖物激活受体-γ，发挥其生长抑制作用。我们发现舒林酸治疗可防止结肠癌中 E-钙黏蛋白的丢失，并伴有核β-连环蛋白积累的抑制。重要的是，在舒林酸治疗的小鼠的结肠肿瘤中，p21(WAF1/cip1)和过氧化物酶体增殖物激活受体-γ的表达缺失，这表明这些蛋白的缺失对于耐药性是必要的。总之，这些观察结果可能适用于设计使用靶向多个分子途径的联合药物的新型临床疗法，以克服舒林酸耐药性。
