Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition.
Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition.
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DOI：
10.1158/1940-6207.capr-10-0030
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Piazza GA
中科院分区：
文献类型：
--
作者：
Tinsley HN;Gary BD;Thaiparambil J;Li N;Lu W;Li Y;Maxuitenko YY;Keeton AB;Piazza GA
在实验研究中，非甾体抗炎药（NSAID）显示出有希望的抗炎活性，但由环氧合酶（考克斯）抑制引起的毒性限制了它们用于化学预防的临床应用。研究表明，该机制可能是考克斯独立的，但替代目标尚未得到很好的定义。在这里，我们表明，非甾体抗炎药，舒林酸硫化物（SS）抑制cGMP磷酸二酯酶（PDE）的活性在结肠肿瘤细胞裂解物的浓度，抑制结肠肿瘤细胞生长在体外和体内。一系列化学性质不同的NSAID在与其抑制结肠肿瘤细胞生长的效力相关的浓度下抑制cGMP水解，而未观察到与考克斯-2抑制的相关性。与其抑制cGMP水解的选择性相一致，与cAMP水解相比，SS抑制cGMP特异性PDE 5同工酶并增加结肠肿瘤细胞中的cGMP水平。在评价的许多PDE同工酶特异性抑制剂中，仅PDE 5选择性抑制剂MY 5445抑制结肠肿瘤细胞生长。SS和MY 5445对细胞生长的影响与抑制β-catenin介导的转录活性有关，从而抑制细胞周期蛋白D和生存素的合成，这两种蛋白分别调节肿瘤细胞的增殖和凋亡。SS对正常结肠细胞中cGMP PDE活性的影响最小，正常结肠细胞显示对SS的敏感性降低，并且不表达PDE 5。与正常结肠粘膜相比，发现PDE 5在结肠肿瘤细胞系以及结肠腺瘤和腺癌中过表达。这些结果表明，PDE 5抑制、cGMP升高和β-连环蛋白转录活性抑制可能有助于某些NSAID的化学预防特性。
In experimental studies, nonsteroidal anti-inflammatory drugs (NSAIDs) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here we show that the NSAID, sulindac sulfide (SS) inhibits cGMP phosphodiesterase (PDE) activity in colon tumor cell lysates at concentrations that inhibit colon tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit colon tumor cell growth, while no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cAMP hydrolysis, SS inhibited the cGMP specific PDE5 isozyme and increased cGMP levels in colon tumor cells. Of numerous PDE isozyme specific inhibitors evaluated, only the PDE5 selective inhibitor MY5445 inhibited colon tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in colon tumor cell lines as well as in colon adenomas and adenocarcinomas compared to normal colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs.