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

磷酸二酯酶 5：乳腺癌的新靶点和抑制剂

基本信息

批准号：
8712192
负责人：
Gary A Piazza
金额：
$ 40.6万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-16 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8712192
关键词：
Adenocarcinoma Antineoplastic Agents Apoptosis Apoptotic Aromatase Inhibitors Award Binding Biological Markers Breast Breast Epithelial Cells Bromodeoxyuridine Cancer Patient Cell Cycle Progression Cell Line Cessation of life Characteristics Chemoprevention Chemopreventive Agent Classification Clinical Collaborations Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cyclin D1 Death Rate Department of Defense Development Diagnosis Disease Drug Kinetics Drug Targeting Economics Estrogen Receptors Experimental Animal Model Funding Genetic Transcription German population Goals Growth Human Hydrolysis Immunohistochemistry In Vitro Inhibitory Concentration 50 International Isoenzymes Lead Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Measures Mediating Medical Membrane Transport Proteins Metabolic Molecular Target Mouse Mammary Tumor Virus Mus Non-Steroidal Anti-Inflammatory Agents Oral Administration Outcome Pathway interactions Patients Pharmaceutical Preparations Play Preclinical Drug Development Premalignant Prodrugs Proliferation Marker Property Prostaglandin-Endoperoxide Synthase Public Health Relative (related person)Reporting Role Safety Series Signal Transduction Small Interfering RNA Solubility Specimen Sulindac Sulfide Synthesis Chemistry Testing Tissues Toxic effect Transgenic Mice Universities Woman Xenograft procedure analog anticancer activity base breast tumorigenesis cancer chemoprevention caspase-3 cell growth dimethylbenzanthracene dosage efficacy testing genetic regulatory protein improved in vitro testing in vivo inhibitor/antagonist malignant breast neoplasm mouse model neoplastic cell novel phosphodiesterase V phosphoric diester hydrolase screening survivin tadalafil treatment effect tumor tumorigenesis vasodilator-stimulated phosphoprotein

项目摘要

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.

描述（由申请人提供）：非甾体类抗炎药（NSAIDS）在实验动物模型中强烈抑制肿瘤发生，但是环氧酶（COX）抑制的毒性限制了它们在人类对癌症化学抑制的使用。先前的研究得出的结论是，与Cox无关的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，肿瘤细胞的生长抑制和凋亡诱导某些NSAID（例如硫酸硫酸硫酸硫磺（SS））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以增加细胞内CGMP水平并激活蛋白激酶G至磷酸化2-catenin，从而诱导其降解以抑制关键凋亡调节性调节蛋白的转录，例如Survivin。最近，我们已经表明，PDE5的siRNA敲低可以像SS一样有选择地诱导肿瘤细胞的凋亡。提出的研究将重点放在乳腺癌化学预防上，因为PDE5似乎是乳腺癌细胞中的主要CGMP降解同工酶，这也是乳腺癌患者腺癌中表达的。我们假设PDE5在乳腺肿瘤发生中起着重要作用，该作用可用于开发安全有效的药物进行乳腺癌化学预防。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，这些衍生物有效，有选择地抑制生长并诱导乳腺肿瘤细胞的凋亡。为了进一步检验这一假设，AIM 1将确定PDE5和CGMP信号传导对新型达拉非衍生物的抗癌活性的重要性，并将评估人类乳腺肿瘤中PDE5的表达。 AIM 2将综合并评估新的他达拉非衍生物的体外抗癌活性，并将鉴定具有最佳药理特性的候选者，以进行体内功效测试； AIM 3将评估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理。这些研究的目标是验证PDE5作为抗癌靶标，确定其在癌症中的潜在作用，并确定临床前药物开发的安全有效的他达拉非衍生物。