Pancreatic cancer prevention with NO-releasing NSAIDs

使用释放 NO 的非甾体抗炎药预防胰腺癌

• 批准号: 6952717
• 负责人: Basil Rigas
• 金额: $ 26.12万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-29 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952717
• 关键词: RNA interference; apoptosis; aspirin; biological signal transduction; cancer prevention; carcinogenesis; cell proliferation; chemoprevention; disease /disorder model; gel mobility shift assay; hamsters; high performance liquid chromatography; isomer; neoplastic cell; nitric oxide; nonsteroidal antiinflammatory agent; nuclear factor kappa beta; pancreas neoplasms; tissue /cell culture

DESCRIPTION (provided by applicant): Chemoprevention can be a major component of the control of pancreatic cancer, one of the deadliest malignancies. Preclinical data indicate that NSAIDs prevent pancreatic cancer, but epidemiological studies are conflicting, perhaps reflecting lack of sufficient efficacy by traditional NSAIDs. Of note, NSAID side effects preclude their large-scale application in cancer prevention. The novel nitric oxide-releasing aspirin (NO-ASA) consists of an ASA molecule and a NO-releasing moiety linked via a chemical spacer. There are three positional isomers of NO-ASA (ortho, meta and para). Two studies have documented its superior safety in humans. We have observed that NO-aspirin (NO-ASA) is 695-fold more potent than ASA in inhibiting the growth of cultured pancreatic cancer cells. Our preliminary study also shows that NO-ASA inhibits pancreatic cancer formation by 89.9% in hamsters treated with the carcinogen BOP. These findings combined with its superior efficacy and safety, make NO-ASA a promising chemopreventive agent and constitute a compelling argument to study its mechanism of action in pancreatic carcinogenesis. We propose to evaluate two hypotheses: a) that NO-ASA is a chemopreventive agent against pancreatic cancer, and b) that NO-ASA inhibits the NF-kappaB pathway in the pancreas and that this effect accounts, to a significant degree, for its ability to prevent pancreatic cancer. NF-kappaB activation is a key event in pancreatic carcinogenesis and our preliminary data indicate that NO-ASA strongly inhibits it. We will study the three positional isomers of NO-ASA. Our specific aims are: 1) Determine in cultured pancreatic cancer cells the effect of NO-ASA on the NF-kappaB pathway. Specifically, we will study the inhibition of NF-kappaB activation by NO-ASA and determine its mechanism; the effect of NO-ASA on pancreatic cancer cell kinetics and determine whether NF-kappaB inhibition is required for this effect; assess the expression of NF-kappaB dependent genes that mediate it; and determine which part of the NO-ASA molecule is critical for its effect on NF-kappaB. Based on the results of this Specific Aim, we will select the most promising NO-ASA positional isomer to: 2) Determine in an animal model of pancreatic cancer the efficacy of NO-ASA against pancreatic carcinogenesis and elucidate its in vivo effect on NF-kappaB. Specifically, we will determine in the pancreas tumor incidence and multiplicity; inhibition of NF-kappaB activation; effects on cell proliferation, apoptosis and relevant NF-kappaB dependent genes that mediate this effect. These studies will provide mechanistic data and a detailed preclinical evaluation, setting the stage for the clinical assessment of NO-ASA against pancreatic cancer.

描述（由申请人提供）：化学预防可以是控制胰腺癌（最致命的恶性肿瘤之一）的主要组成部分。临床前数据表明，非甾体抗炎药可以预防胰腺癌，但流行病学研究相互矛盾，这可能反映出传统非甾体抗炎药缺乏足够的疗效。值得注意的是，非甾体抗炎药的副作用阻碍了其在癌症预防中的大规模应用。新型释放一氧化氮的阿司匹林 (NO-ASA) 由 ASA 分子和通过化学间隔基连接的释放一氧化氮的部分组成。 NO-ASA 存在三种位置异构体（邻位异构体、间位异构体和对位异构体）。两项研究证明了其对人类的卓越安全性。我们观察到，NO-阿司匹林 (NO-ASA) 在抑制培养的胰腺癌细胞生长方面比 ASA 有效 695 倍。我们的初步研究还表明，在接受致癌物质 BOP 治疗的仓鼠中，NO-ASA 可以抑制胰腺癌的形成 89.9%。这些发现与其卓越的功效和安全性相结合，使 NO-ASA 成为一种有前途的化学预防剂，并为研究其在胰腺癌发生中的作用机制提供了令人信服的论据。我们建议评估两个假设：a) NO-ASA 是一种针对胰腺癌的化学预防剂，b) NO-ASA 抑制胰腺中的 NF-kappaB 通路，并且这种效应在很大程度上解释了其预防胰腺癌的能力。 NF-kappaB 激活是胰腺癌发生的关键事件，我们的初步数据表明 NO-ASA 强烈抑制它。 我们将研究 NO-ASA 的三种位置异构体。我们的具体目标是： 1) 在培养的胰腺癌细胞中确定 NO-ASA 对 NF-kappaB 通路的影响。具体来说，我们将研究NO-ASA对NF-kappaB激活的抑制作用并确定其机制； NO-ASA 对胰腺癌细胞动力学的影响，并确定是否需要抑制 NF-kappaB 来实现该效果；评估介导 NF-κB 依赖性基因的表达；并确定 NO-ASA 分子的哪一部分对其对 NF-κB 的影响至关重要。基于该特定目标的结果，我们将选择最有前途的NO-ASA位置异构体来：2)在胰腺癌动物模型中确定NO-ASA抗胰腺癌发生的功效，并阐明其对NF-κB的体内作用。具体来说，我们将确定胰腺肿瘤的发病率和多重性；抑制 NF-κB 激活；对细胞增殖、凋亡以及介导这种作用的相关 NF-κB 依赖性基因的影响。这些研究将提供机制数据和详细的临床前评估，为 NO-ASA 抗胰腺癌的临床评估奠定基础。