Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice.
Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice.
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DOI：
10.1158/1940-6207.capr-17-0015
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Browning DD
中科院分区：
文献类型：
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作者：
Islam BN;Sharman SK;Hou Y;Bridges AE;Singh N;Kim S;Kolhe R;Trillo-Tinoco J;Rodriguez PC;Berger FG;Sridhar S;Browning DD
肠环磷酸鸟苷（cGMP）信号调节上皮细胞的稳态，并已涉及结肠炎和结肠癌的抑制。在这项研究中，我们研究了磷酸二酯酶-5（PDE 5）抑制剂西地那非在氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）炎症驱动的结直肠癌模型中预防疾病的cGMP升高能力。用西地那非治疗小鼠激活结肠粘膜中的cGMP信号传导，并保护其免受DSS诱导的屏障功能障碍。在用AOM/DSS治疗的小鼠中，与未治疗的对照组相比，在整个疾病过程中口服西地那非使息肉多样性减少了50%。在西地那非治疗的小鼠中形成的息肉与来自未治疗的小鼠的息肉相比增殖性更低并且分化更高，但是细胞凋亡不受影响。西地那非治疗小鼠的息肉炎症也较少;与未治疗对照组相比，它们表现出骨髓细胞浸润减少，iNOS、IFNγ和IL-6表达减少。西地那非的大部分保护作用发生在致癌的起始阶段（多重性降低38%）。在后期促进阶段给予西地那非不影响多重性，但对息肉表型有类似的影响，包括增加粘液产生，减少增殖和炎症。总之，结果表明口服西地那非可抑制AOM/DSS治疗小鼠的息肉形成和炎症。PDE 5作为靶点的验证突出了PDE 5抑制剂在预防人类结肠炎驱动的结肠癌方面的潜在治疗价值。
Intestinal cyclic guanosine monophosphate (cGMP) signaling regulates epithelial homeostasis and has been implicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5 (PDE5) inhibitor sildenafil to prevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS) inflammation-driven colorectal cancer model. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against DSS-induced barrier dysfunction. In mice treated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared to untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared to polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cell infiltration, and reduced expression of iNOS, IFNγ, and IL-6 compared to untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38% reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration of sildenafil suppresses polyp formation and inflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans.