Anoikis Effect by Quinazolines on Prostate Growth

喹唑啉对前列腺生长的失巢效应

• 批准号: 6874451
• 负责人: Natasha Kyprianou
• 金额: $ 23.96万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874451
• 关键词: angiogenesis; apoptosis; benign prostate hyperplasia; biological signal transduction; cell growth regulation; cell line; coagulation factor VIII; cysteine endopeptidases; enzyme activity; enzyme mechanism; extracellular matrix; focal adhesion kinase; gel mobility shift assay; gene expression profiling; human tissue; immunocytochemistry; integrins; male; microarray technology; prazosin; prostate neoplasms; proteomics; quinazolines; smooth muscle; transforming growth factors; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Loss of apoptotic control in prostate growth disorders involves the altered expression/activation of downstream intracellular effectors of apoptosis signaling pathways. Re-instating functional apoptotic mechanisms, by targeting specific components in this pathway, are of high significance in the regulation of prostate growth. Recent studies documented the ability for quinazoline-based a1-adrenoceptor antagonists, doxazosin and terazosin, to induce apoptosis in human prostate smooth muscle, benign and malignant epithelial cells, via an a1-adrenoceptor independent mechanism and suppress tissue vascularity. Our hypothesis is that quinazoline-based a1-adrenoceptor antagonists suppress prostate growth by inducing apoptosis (via induction of intracellular signaling effectors) and inhibit angiogenesis by promoting anoikis (via interference with extracellular matrix attachments). To test this hypothesis, the following aims are proposed: In Specific Aim 1 we will use DNA microarray analysis and proteomic analysis to identify intracellular signaling effectors of apoptosis induced by quinazoline-based a1-adrenoceptor antagonists in prostate benign and malignant cells. Specific Aim 2 will identify the extracellular matrix components involved in quinazoline-induced anoikis in prostate epithelial and endothelial cells with focus on Fas-Fasligand-caspase-8 activation mechanism and integrin effectors. Specific Aim 3 will establish that the quinazolines, doxazosin and terazosin, suppress prostate vasculature and inhibit tissue angiogenesis in patients after a1 blockade treatment. Immunohistochemical analysis will be performed on tissue specimens from BPH patients treated with a1 blockade (for obstructive symptoms) using antibodies against Factor VIII (microcrossed density), vascular endothelial growth factor (VEGF), and focal ashesion kinase (FAK). The goal of the proposed studies is to determine the early response genes at the intracellular (TGF-beta) and extracellular matrix (integrins) environment underlying the quinazoline-mediated apoptosis, targeted by this pharmacologic intervention in benign and malignant prostate growth. Potential results will establish the apoptotic/anoikis effect by the quinazolines as a significant phenomenon with clinical relevance in development and progression of benign prostatic hyperplasia (BPH) prostate cancer.

描述（由申请人提供）：前列腺生长障碍中凋亡控制的丧失涉及凋亡信号通路下游细胞内效应物的表达/激活的改变。通过靶向该通路中的特定成分，恢复功能性凋亡机制在调节前列腺生长中具有重要意义。最近的研究表明，喹唑啉类a1-肾上腺素受体拮抗剂doxazosin和terazosin能够通过不依赖a1-肾上腺素受体的机制诱导人前列腺平滑肌、良性和恶性上皮细胞凋亡，并抑制组织血管。我们的假设是，喹唑啉类a1-肾上腺素能受体拮抗剂通过诱导细胞凋亡（通过诱导细胞内信号效应）抑制前列腺生长，并通过促进血管增生（通过干扰细胞外基质附着）抑制血管生成。为了验证这一假设，我们提出了以下目标：在Specific Aim 1中，我们将使用DNA微阵列分析和蛋白质组学分析来鉴定基于喹唑啉的a1-肾上腺素能受体拮抗剂诱导前列腺良性和恶性细胞凋亡的细胞内信号效应物。特异性目标2将确定喹唑啉诱导前列腺上皮和内皮细胞损伤的细胞外基质成分，重点关注Fas-Fasligand-caspase-8激活机制和整合素效应物。特异性Aim 3将建立喹唑啉类药物doxazosin和terazosin在a1阻断治疗后抑制前列腺血管并抑制组织血管生成。使用针对因子VIII（微交叉密度）、血管内皮生长因子（VEGF）和局灶连接激酶（FAK）的抗体，对接受a1阻断治疗（用于阻塞性症状）的BPH患者的组织标本进行免疫组织化学分析。这些研究的目标是确定细胞内（tgf - β）和细胞外基质（整合素）环境中的早期反应基因，这些基因是喹唑啉介导的细胞凋亡的基础，通过这种药物干预来靶向良性和恶性前列腺生长。潜在的结果将确定喹唑啉类药物的凋亡/anoikis效应在良性前列腺增生（BPH）前列腺癌的发生和进展中是一种重要的临床现象。