Drug Discovery Research Center, Department of Pharmacology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
Drug Discovery Research Center, Department of Pharmacology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
Drug Discov Today. 2020 Aug;25(8):1521-1527. doi: 10.1016/j.drudis.2020.06.008. Epub 2020 Jun 17.
Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term use because of potentially fatal toxicities from cyclooxygenase (COX) inhibition. Studies suggest the mechanism responsible for the anticancer activity of the NSAID sulindac is unrelated to COX inhibition but instead involves an off-target, phosphodiesterase (PDE). Thus, it might be feasible develop safer and more efficacious drugs for cancer indications by targeting PDE5 and PDE10, which are overexpressed in various tumors and essential for cancer cell growth. In this review, we describe the rationale for using the sulindac scaffold to design-out COX inhibitory activity, while improving potency and selectivity to inhibit PDE5 and PDE10 that activate cGMP/PKG signaling to suppress Wnt/β-catenin transcription, cancer cell growth, and tumor immunity.
尽管有大量报告得出结论认为非甾体抗炎药（NSAIDs）具有抗癌活性，但由于环氧化酶（COX）抑制可能导致潜在致命的毒性，此类常见药物类别不建议长期使用。研究表明，NSAID 舒林酸发挥抗癌作用的机制与 COX 抑制无关，而是涉及非靶向的磷酸二酯酶（PDE）。因此，通过针对在各种肿瘤中过度表达并对癌细胞生长至关重要的 PDE5 和 PDE10，开发用于癌症适应症的更安全、更有效的药物可能是可行的。在这篇综述中，我们描述了使用舒林酸支架来设计消除 COX 抑制活性的原理，同时提高抑制 PDE5 和 PDE10 的效力和选择性，以抑制激活 cGMP/PKG 信号通路的药物，从而抑制 Wnt/β-catenin 转录、癌细胞生长和肿瘤免疫。
