Anoikis Effect by Quinazolines on Prostate Growth

描述（由申请人提供）：前列腺生长障碍中细胞凋亡控制的丧失涉及细胞凋亡信号传导途径下游细胞内效应物的表达/激活改变。 通过靶向该途径中的特定组分，恢复功能性凋亡机制在前列腺生长的调节中具有重要意义。 最近的研究证明了喹唑啉类α 1肾上腺素受体拮抗剂多沙唑嗪和特拉唑嗪通过α 1肾上腺素受体非依赖性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的能力。 我们的假设是，喹唑啉为基础的α 1-肾上腺素受体拮抗剂抑制前列腺生长诱导凋亡（通过诱导细胞内信号效应）和抑制血管生成促进失巢凋亡（通过干扰细胞外基质附着）。 为了验证这一假设，提出了以下目标：在具体目标1中，我们将使用DNA微阵列分析和蛋白质组学分析，以确定细胞内信号转导效应的细胞凋亡诱导的喹唑啉为基础的α 1-肾上腺素受体拮抗剂在前列腺良性和恶性细胞。 具体目标2将确定参与喹唑啉诱导的前列腺上皮细胞和内皮细胞失巢凋亡的细胞外基质成分，重点关注Fas-Fas配体-caspase-8激活机制和整合素效应子。 具体目标3将确定喹唑啉类、多沙唑嗪和特拉唑嗪抑制a1阻断治疗后患者的前列腺血管形成并抑制组织血管生成。将使用抗因子VIII（微交叉密度）、血管内皮生长因子（VEGF）和局灶性粘附激酶（FAK）的抗体，对接受a1阻断（用于阻塞性症状）治疗的BPH患者的组织标本进行免疫组织化学分析。 拟议研究的目标是确定在细胞内（TGF-β）和细胞外基质（整合素）环境下喹唑啉介导的细胞凋亡的早期反应基因，通过这种药物干预良性和恶性前列腺生长。 潜在的结果将确定喹唑啉类的凋亡/失巢凋亡效应是良性前列腺增生（BPH）前列腺癌发展和进展中具有临床相关性的重要现象。

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.