Molecular mechanism of chemoprevention by benzylistothiocyanate in pancreatic can

硫氰酸苄酯化学预防胰腺癌的分子机制

基本信息

  • 批准号:
    7686705
  • 负责人:
  • 金额:
    $ 7.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-15 至 2011-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this preclinical research project is to assess the efficacy of benzyl isothiocyanate (BITC), a constituent of many edible cruciferous vegetables for prevention of pancreatic cancer using in vitro cell culture and in vivo animal models. The rationale for these studies stems from recent epidemiological data as well as preliminary results obtained in our laboratory. Several epidemiological studies have supported that frequent intake of cruciferous vegetables is linked to a decreased risk in various type of human cancer including pancreatic carcinoma. Our preliminary studies in vitro led us to a novel hypothesis that BITC induced death receptor as well as phosphorylation of antiapoptotic protein Bcl-xL might be predominant factors to destroy pancreatic cancer cells and prevent its progression. BITC might behave as an agent that is capable of intervening simultaneously at several targets in the carcinogenic process. This type of compound is thought to have selective advantage over other single-target compounds. Specific Aim 1 will systemically determine the role of intrinsic (phosphorylation of Bcl-xL and involvement of mitochondria) and extrinsic (death receptor mediated activation of caspase-8) pathways in BITC mediated apoptosis induction in pancreatic cancer cells. In specific Aim 2, the effect of oral administration of BITC on the progression of Pancreatic Intraepithelial Neoplasia (Pan IN) in a conditional KrasG12D mouse model will be investigated. It is believed that pancreatic ductal adenocarcinoma gradually arises from precursor lesion Pan IN. In that respect conditional KrasG12D mouse model is a valuable tool to investigate Pan IN biology. Biochemical assays will also be deployed to assess whether in vitro studies such as death receptor up regulation or Bcl-xL phosphorylation can be translated in vivo if any delay or prevention of the progression of Pan IN occurs in BITC treated animals. In summary, the studies proposed in this research program never explored before will I) define the mechanism by which BITC inhibits growth of human pancreatic cancer cells that may be helpful to identify mechanism- based biomarkers for future clinical trials and II) assess in vivo efficacy of BITC against pancreatic cancer using established animal model, which is a prerequisite for ensuing any clinical trial with this compound against pancreatic cancer. PUBLIC HEALTH RELEVANCE: Project Narrative At present, pancreatic cancer ranks as the fourth leading cause of cancer mortality in the United States (U.S.). The long-term goal of this preclinical research project is to assess the efficacy of benzyl isothiocyanate (BITC), a constituent of many edible cruciferous vegetables for prevention of pancreatic cancer using in vitro as well as animal models.
描述(由申请人提供):本临床前研究项目的总体目标是使用体外细胞培养和体内动物模型评估异硫氰酸苄酯(BITC)预防胰腺癌的功效,BITC是许多可食用十字花科蔬菜的成分。这些研究的基本原理源于最近的流行病学数据以及我们实验室获得的初步结果。几项流行病学研究表明,经常摄入十字花科蔬菜与降低各种人类癌症(包括胰腺癌)的风险有关。我们的初步体外研究使我们提出了一个新的假设,即BITC诱导的死亡受体以及抗凋亡蛋白Bcl-xL的磷酸化可能是破坏胰腺癌细胞并阻止其进展的主要因素。BITC可能表现为能够同时干预致癌过程中的多个靶点的试剂。这种类型的化合物被认为比其他单一目标化合物具有选择性优势。具体目标1将系统地确定内在(Bcl-xL的磷酸化和线粒体的参与)和外在(死亡受体介导的半胱天冬酶-8活化)途径在胰腺癌细胞中BITC介导的凋亡诱导中的作用。在特定目的2中,将研究BITC经口给药对条件性KrasG 12 D小鼠模型中胰腺上皮内瘤变(Pan IN)进展的影响。一般认为胰腺导管腺癌是由胰腺癌前病变Pan IN逐渐发展而来的。在这方面,条件KrasG 12 D小鼠模型是研究Pan IN生物学的有价值的工具。如果BITC处理的动物中发生Pan IN进展的任何延迟或预防,还将部署生化测定来评估体外研究(如死亡受体上调或Bcl-xL磷酸化)是否可以在体内转化。总之,本研究计划中提出的研究以前从未探索过,I)定义BITC抑制人胰腺癌细胞生长的机制,这可能有助于为未来的临床试验鉴定基于机制的生物标志物,II)使用已建立的动物模型评估BITC对胰腺癌的体内疗效,这是确保使用该化合物进行任何针对胰腺癌的临床试验的先决条件。公共卫生相关性:目前,胰腺癌是美国癌症死亡率的第四大原因。该临床前研究项目的长期目标是评估异硫氰酸苄酯(BITC)的功效,BITC是许多可食用十字花科蔬菜的成分,用于体外和动物模型预防胰腺癌。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Modulation of MicroRNAs by Chemical Carcinogens and Anticancer Drugs in Human Cancer: Potential Inkling to Therapeutic Advantage.
人类癌症中化学致癌物和抗癌药物对 MicroRNA 的调节:治疗优势的潜在暗示。
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ARUNA BASU其他文献

ARUNA BASU的其他文献

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{{ truncateString('ARUNA BASU', 18)}}的其他基金

Molecular mechanism of chemoprevention by benzylistothiocyanate in pancreatic can
硫氰酸苄酯化学预防胰腺癌的分子机制
  • 批准号:
    7573218
  • 财政年份:
    2008
  • 资助金额:
    $ 7.55万
  • 项目类别:

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