Phosphodiesterase 5: A Novel Target and Inhibitor for Breast Cancer Chemopreventi

描述(由申请人提供)：非类固醇抗炎药(NSAIDs)在实验动物模型中强烈抑制肿瘤形成，但环氧合酶(COX)抑制的毒性限制了它们在人类中用于癌症化学预防的使用。以前的研究已经得出结论，COX非依赖性机制是其抗肿瘤活性的原因，这表明通过靶向这种机制来开发更安全、更有效的药物可能是可行的。我们发现，某些非甾体抗炎药如舒林酸硫化物(SS)的抑制肿瘤细胞生长和诱导细胞凋亡的特性与抑制cGMP特异性磷酸二酯酶PDE5密切相关。SS可以选择性地抑制PDE5升高细胞内cGMP水平，并激活蛋白激酶G使2-连环蛋白磷酸化，从而诱导其降解，从而抑制Survivin等关键的细胞凋亡调控蛋白的转录。最近，我们发现PDE5的siRNA敲除可以选择性地诱导肿瘤细胞的凋亡，SS也是如此。拟议的研究将集中在乳腺癌的化学预防上，因为PDE5似乎是乳腺肿瘤细胞中主要的cGMP降解同工酶，在乳腺癌患者的腺癌中也有表达。我们推测PDE5在乳腺癌的发生发展中起着重要的作用，可以作为开发安全有效的乳腺癌化学预防药物的靶点。为了支持这一假设，我们合成了一系列新型的他达拉非衍生物，它们能够有效和选择性地抑制乳腺肿瘤细胞的生长并诱导其凋亡。为了进一步验证这一假说，Aim 1将确定PDE5和cGMP信号转导对于新型他达拉非衍生物抗癌活性的重要性，并将评估PDE5在人类乳腺肿瘤中的表达；Aim 2将合成和评估体外抗癌活性的新型他达拉非衍生物，并将确定具有最佳药理特性的候选化合物用于体内疗效测试；以及Aim 3将评估最佳他达拉非衍生物的化学预防效力和安全性并确认体内的作用机制。这些研究的目标是验证PDE5作为抗癌靶点，确定其在癌症中的潜在作用，并确定用于临床前药物开发的安全有效的他达拉非衍生物。

DESCRIPTION (provided by applicant): Nonsteroidal anti-inflammatory drugs (NSAIDs) strongly inhibit tumorigenesis in experimental animal models, but toxicity from cyclooxygenase (COX) inhibition limits their use in humans for cancer chemoprevention. Previous studies have concluded that a COX-independent mechanism is responsible their antineoplastic activities, which suggests that it may be feasible to develop safer and more efficacious drugs by targeting such mechanisms. We have found that the tumor cell growth inhibitory and apoptosis inducing properties of certain NSAIDs such as sulindac sulfide (SS) are closely associated with inhibition of the cGMP-specific phosphodiesterase, PDE5. SS can selectively inhibit PDE5 to increase intracellular cGMP levels and activate protein kinase G to phosphorylate 2-catenin, thereby inducing its degradation to suppress the transcription of key apoptosis regulatory proteins such as survivin. Recently, we have shown that siRNA knockdown of PDE5 can selectively induce apoptosis of tumor cells as does SS. The proposed studies will focus on breast cancer chemoprevention since PDE5 appears to be the predominant cGMP degrading isozyme in breast tumor cells that is also expressed in adenocarcinomas from breast cancer patients. We hypothesize that PDE5 plays an important role in breast tumorigenesis that can be targeted to develop safe and efficacious drugs for breast cancer chemoprevention. In support of this hypothesis, we have synthesized a series of novel tadalafil derivatives that potently and selectively inhibit the growth and induce apoptosis of breast tumor cells. To further test this hypothesis, Aim 1 will determine the importance of PDE5 and cGMP signaling for the anticancer activity of novel tadalafil derivatives and will evaluate PDE5 expression in human breast tumors; Aim 2 will synthesize and evaluate novel tadalafil derivatives for in vitro anticancer activity and will identify candidates with optimal pharmacological properties for in vivo efficacy testing; and Aim 3 will evaluate chemopreventive efficacy and safety of an optimal tadalafil derivative and will confirm mechanism of action in vivo. The goals of these studies are to validate PDE5 as an anticancer target, determine its potential role in cancer, and identify a safe and effective tadalafil derivative for preclinical drug development.