Non-steroidal anti-inflammatory drugs (NSAIDs) are promising colorectal cancer (CRC) chemopreventive drugs; however, to overcome NSAIDs’ associated side effects, there is a need to develop safer and efficacious approaches. The present study was designed to evaluate (i) the efficacy of nitric-oxide releasing (NO)-Sulindac as compared to Sulindac; (ii) whether NO-Sulindac is superior to Sulindac in enhancing low-dose difluoromethylornithine (DFMO)-induced chemopreventive efficacy, and (iii) assessing the key biomarkers associated with colon tumor inhibition by these combinations. In F344 rats, colonic tumors were induced by azoxymethane (AOM). At the adenoma stage (13 weeks post AOM), groups of rats were fed the experimental diets containing 0 ppm, 500 ppm DFMO, 150 ppm Sulindac, and 200 ppm NO-Sulindac, individually or in combinations, for 36 weeks. Colon tumors were evaluated histopathologically and assayed for expression levels of proliferative, apoptotic, and inflammatory markers. Results suggest that (except for NO-Sulindac alone), DFMO, Sulindac individually, and DFMO combined with Sulindac or NO-Sulindac significantly suppressed AOM-induced adenocarcinoma incidence and multiplicities. DFMO and Sulindac suppressed adenocarcinoma multiplicity by 63% (p< 0.0001) and 51% (p< 0.0011), respectively, whereas NO-Sulindac had a modest effect (22.8%,p= 0.09). Combinations of DFMO plus Sulindac or NO-Sulindac suppressed adenocarcinoma incidence (60%,p< 0.0001; 50%p< 0.0004), and multiplicity (81%,p< 0.0001; 62%,p< 0.0001). Rats that were fed the combination of DFMO plus Sulindac showed significant inhibition of tumor cell proliferation and induction of apoptosis. In addition, enhancement of p21, Bax, and caspases; downregulation of Ki-67, VEGF, and β-catenin; and modulation of iNOS, COX-2, and ODC activities in colonic tumors were observed. These observations show that a lower-dose of DFMO and Sulindac significantly enhanced CRC chemopreventive efficacy when compared to NO-Sulindac alone, and the combination of DFMO and NO-Sulindac was modestly efficacious as compared to DFMO alone.
非甾体抗炎药（NSAIDs）是前景广阔的结直肠癌（CRC）化学预防药物；然而，为克服NSAIDs的相关副作用，有必要开发更安全有效的给药策略。本研究旨在评估：（1）释放一氧化氮的舒林酸（NO-Sulindac）与普通舒林酸的效能差异；（2）在增强低剂量二氟甲基鸟氨酸（DFMO）诱导的化学预防效果方面，NO-舒林酸是否优于普通舒林酸；（3）评估这些联合方案抑制结肠肿瘤的关键生物标志物。研究使用氧化偶氮甲烷（AOM）诱导F344大鼠结肠肿瘤。在腺瘤阶段（AOM注射后13周），将大鼠分组饲喂含0 ppm、500 ppm DFMO、150 ppm舒林酸及200 ppm NO-舒林酸的实验饲料（单独或联合用药），持续36周。通过组织病理学评估结肠肿瘤，并检测增殖、凋亡和炎症标志物的表达水平。结果显示（除单独使用NO-舒林酸外），DFMO、舒林酸单独使用，以及DFMO联合舒林酸或NO-舒林酸均能显著抑制AOM诱导的腺癌发生率和数量。DFMO和舒林酸分别使腺癌数量降低63%（p<0.0001）和51%（p<0.0011），而NO-舒林酸效果有限（22.8%，p=0.09）。DFMO联合舒林酸或NO-舒林酸可显著降低腺癌发生率（60%，p<0.0001；50%，p<0.0004）及数量（81%，p<0.0001；62%，p<0.0001）。饲喂DFMO联合舒林酸的大鼠显示出肿瘤细胞增殖显著抑制和细胞凋亡诱导。此外，观察到结肠肿瘤中p21、Bax和半胱天冬酶表达增强；Ki-67、VEGF和β-连环蛋白下调；以及iNOS、COX-2和ODC活性调节。这些结果表明，与单独使用NO-舒林酸相比，低剂量DFMO联合舒林酸能显著增强CRC化学预防效能；而DFMO联合NO-舒林酸的方案相较于单独使用DFMO仅显示中等疗效。
肿瘤(癌症)患者之家