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

描述（由申请方提供）：非甾体抗炎药（NSAID）在实验动物模型中强烈抑制肿瘤发生，但环氧合酶（考克斯）抑制的毒性限制了其在人类癌症化学预防中的应用。以往的研究已经得出结论，COX非依赖性机制是负责他们的活动，这表明它可能是可行的，以开发更安全，更有效的药物，通过靶向这些机制。我们已经发现，某些NSAID如舒林酸硫化物（SS）的肿瘤细胞生长抑制和凋亡诱导特性与cGMP特异性磷酸二酯酶PDE 5的抑制密切相关。SS可以选择性地抑制PDE 5以增加细胞内cGMP水平，并激活蛋白激酶G以磷酸化2-连环蛋白，从而诱导其降解以抑制关键凋亡调节蛋白如生存素的转录。最近，我们已经表明，PDE 5的siRNA敲低可以像SS一样选择性地诱导肿瘤细胞凋亡。拟定的研究将侧重于乳腺癌化学预防，因为PDE 5似乎是乳腺肿瘤细胞中主要的cGMP降解同工酶，也在乳腺癌患者的腺癌中表达。我们假设PDE 5在乳腺肿瘤发生中起着重要作用，可以有针对性地开发安全有效的乳腺癌化学预防药物。为了支持这一假设，我们合成了一系列新型他达拉非衍生物，这些衍生物能够有效地选择性抑制乳腺肿瘤细胞的生长并诱导其凋亡。为了进一步检验这一假设，目标1将确定PDE 5和cGMP信号传导对新型他达拉非衍生物抗癌活性的重要性，并将评价PDE 5在人乳腺肿瘤中的表达;目标2将合成并评价新型他达拉非衍生物的体外抗癌活性，并将鉴定具有最佳药理学特性的候选物用于体内疗效试验;目标3将评价最佳他达拉非衍生物的化学预防功效和安全性，并将确认体内作用机制。这些研究的目的是验证PDE 5作为抗癌靶点，确定其在癌症中的潜在作用，并确定安全有效的他达拉非衍生物用于临床前药物开发。

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.