5-LOX-1 and Clinical Chemoprevention of Colon Tumors

5-LOX-1 与结肠肿瘤的临床化学预防

• 批准号: 6920877
• 负责人: Imad Shureiqi
• 金额: $ 29.63万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-02 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6920877
• 关键词: alcohol oxidoreductases; apoptosis; biopsy; blood chemistry; cancer prevention; chemoprevention; clinical research; colon polyp; colorectal neoplasms; cyclooxygenase inhibitors; drug screening /evaluation; endoscopy; gastrointestinal imaging /visualization; gene expression; human subject; immunocytochemistry; immunologic assay /test; lipoxygenase; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; patient oriented research; peroxisome proliferator activated receptor; questionnaires; transcription factor

DESCRIPTION (provided by applicant): NSAIDs are promising chemopreventive agents in colorectal cancers, however their chemopreventive effectiveness is partial. Defining NSAIDs' chemopreventive mechanisms is important to identify molecular targets that can lead to develop better chemopreventive agents. NSAIDs induction of apoptosis is crucial to their antitumorigenic effects. We have found in previous studies that (a) hydroxyoctadecadienoic acid (13-SHODE), a linoleic acid product, and its producing enzyme, 15-lipoxygenase-1 (15-LOX-1), are downregulated in human colorectal cancers; and 13-S-HODE restores apoptosis in colorectal cancer cells, (b) NSAIDs downregulate GATA-6 expression to transcriptionally restore 15-LOX-1 expression that triggers apoptosis in human colorectal cancer cells, and (c) 15-LOX-1 downregulates the peroxisome proliferatoractivated receptor (PPAR)- delta (PPAR-delta) to trigger apoptosis. To test whether these chemopreventive mechanisms of NSAIDs are clinically relevant; our proposal will examine the following hypothesis: NSAIDs downregulate GATA-6 expression to restore 15-LOX-1 expression, which increases 13-S-HODE production to downregulate PPAR-delta expression, thereby inducing apoptosis in human colorectal tumors. This hypothesis will be tested in a clinical study of celecoxib treatment of patients with familial adenomatous polyposis syndrome (FAP) as follows: Specific Aim 1: To determine whether celecoxib downregulates GATA-6 expression to upregulate 15-LOX-1 expression, which in turn downregulates PPAR-d expression to induce apoptosis in human colorecta! polyps, we will measure GATA-6, 15-LOX-1 and PPAR-delta expression, 13-S-HODE levels, and apoptosis rates in colorectal polyps before and after 6 months of treatment with celecoxib in patients with familial adenomatous polyposis syndrome (FAP). Specific Aim 2: To define the relationship between chemopreventive response to celecoxib in patients with FAP' and the effects of celecoxib on 15-LOX-1 in human colorectal polyps, we will measure the response to celecoxib in terms of polyp number before and after 6 months of treatment with celecoxib in patients with FAP and will correlate the chemopreventive response (defined by the changes in mean polyp number) to 13-S-HODE levels before and after celecoxib treatment. If our hypothesis is confirmed, efforts can be directed to develop chemopreventive interventions that specifically target the GATA-6 and 15-LOX-1 signaling pathway.

描述（由申请人提供）：NSAIDS是结直肠癌中有希望的化学预防剂，但是它们的化学预防效果是部分的。定义NSAIDS的化学预防机制对于确定可以导致更好的化学预防剂的分子靶标很重要。 NSAID诱导凋亡对于它们的抗肿瘤作用至关重要。我们在先前的研究中发现，（a）羟基二糖二烯酸（13-shode），一种亚油酸产物及其产生的酶，15-脂氧合酶-1（15-lox-1），在人类结直肠癌中被下调。 （b）NSAID将GATA-6的表达下调以恢复15-LOX-1表达，从而恢复了15-LOX-1的表达，从而恢复了结直肠癌细胞中的凋亡，从而恢复了人类大肠癌细胞中凋亡，（c）15-LOX-15-lox-1下调了过氧化物分析的受体（pPare）-Delta（pare）-Delta（ppara）（ppara）（ppar）（ppara）（ppar）（ppar）。测试NSAID的这些化学预防机制是否在临床上相关；我们的建议将检查以下假设：NSAIDS下调GATA-6表达以恢复15-LOX-1表达，从而增加了13-S-HODE的产生以下调PPAR-delta的表达，从而诱导人类结直肠肿瘤的凋亡。该假设将在一项临床研究中对塞雷克毒素治疗的临床研究，对家族性腺瘤性息肉病综合征（FAP）的患者如下：特定目的1：确定塞来氧化是否下调GATA-6是否在上调15-LOX-1表达中表达15-lox-1表达，在下调pPAR-d-d-decke降低了PPAR表达以诱导人类Colorecta中的凋亡！息肉，我们将测量在家庭腺瘤息肉病综合征（FAP）患者接受Celecoxib治疗6个月之前和之后的结直肠息肉前后，结直肠息肉的GATA-6，15-LOX-1和PPAR-DELTA表达，13-S-大声的水平以及凋亡率。具体目的2：定义FAP患者的化学预防反应与塞氏菌对Celecoxib的关系与塞来昔布对人类结直肠息肉的15-LOX-1对15-LOX-1的影响，我们将根据FAP患者的治疗和celecoxib的治疗，在FAP和CELECOXIB的治疗中对Celecoxib进行6个月的治疗，在FAP和FAP患者中的priperate prientation prientation the Chemoptrate（在plyecoxib的治疗方面）的临时（将临时性均与化学反应相关联）（临时）对celecoxib的响应（将其定义为13）。塞来昔布治疗。如果确认我们的假设，则可以努力开发专门针对GATA-6和15-LOX-1信号通路的化学预防干预措施。