Department of Pharmacology and Toxicology, University of Alabama at Birmingham, USA.
Cancer Prev Res (Phila). 2010 Oct;3(10):1303-13. doi: 10.1158/1940-6207.CAPR-10-0030. Epub 2010 Sep 28.
Nonsteroidal anti-inflammatory drugs (NSAID) 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 cyclic guanosine 3',5'-monophosphate (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 also inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit colon tumor cell growth, whereas no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cyclic AMP 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 with 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.
非甾体抗炎药 (NSAID) 显示出有前景的抗肿瘤活性，但由于环氧化酶 (COX) 抑制导致的毒性限制了它们在化学预防中的临床应用。研究表明，其机制可能与 COX 无关，尽管替代靶点尚未明确。在这里，我们表明 NSAID 舒林酸硫醚 (SS) 在抑制体外和体内结肠肿瘤细胞生长的浓度下抑制结肠肿瘤细胞裂解物中环鸟苷酸 3'，5'-单磷酸 (cGMP) 磷酸二酯酶 (PDE) 活性。一系列化学多样性的 NSAIDs 也在与抑制结肠肿瘤细胞生长的效力相关的浓度下抑制 cGMP 水解，而与 COX-2 抑制没有相关性。与抑制 cGMP 水解的选择性相比，SS 与抑制 cAMP 水解相比，选择性抑制 cGMP 特异性 PDE5 同工酶并增加结肠肿瘤细胞中的 cGMP 水平。在评估的众多 PDE 同工酶特异性抑制剂中，只有 PDE5 选择性抑制剂 MY5445 抑制结肠肿瘤细胞生长。SS 和 MY5445 对细胞生长的影响与抑制 β-连环蛋白介导的转录活性有关，以抑制 cyclin D 和 survivin 的合成，分别调节肿瘤细胞增殖和凋亡。SS 对正常结肠细胞中 cGMP PDE 活性的影响很小，这些细胞对 SS 的敏感性降低，并且不表达 PDE5。与正常结肠黏膜相比，PDE5 在结肠肿瘤细胞系以及结肠腺瘤和腺癌中过度表达。这些结果表明，PDE5 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。
