The Proteasome as Molecular Target of Grape Polyphenols

蛋白酶体作为葡萄多酚的分子靶标

基本信息

批准号：
6952307
负责人：
QING PING DOU
金额：
$ 7.55万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-30 至 2007-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Our long-term objective is to discover novel potent, specific cancer preventative and anticancer agents with no cytotoxicity. Recent results from in vitro, in vivo and clinical trials have supported the use of proteasome inhibitors as potential novel anticancer drugs. We have found that natural and synthetic green tea polyphenols with an ester bond are potent and specific proteasomal chymotrypsin-like inhibitors, while those without an ester bond are inactive. Most recently, we have reported that grape extract inhibits the proteasomal chymotrypsin-like activity in leukemia Jurkat T cell extract and intact Jurkat T cells, associated with apoptosis induction. Furthermore, grape extract induces the appearance of spherical cells preferentially in prostate cancer PC-3 over normal NIH 3T3 cell line. Our findings suggest that the proteasome is a cancer related molecular target for grape antioxidant components. Based on these results, we hypothesize that inhibition of the proteasome activity by some antioxidant polyphenolic compounds contributes to the prostate cancer-preventative activities of grapes. To address this hypothesis, we propose the following Three Specific Aims. Specific Aim 1 is to evaluate potency and selectivity of several grape polyphenolic compounds to inhibit the proteasome activity using purified 20S proteasome, prostate cancer cell extracts, and intact prostate cancer cells. Specific Aim 2 is to evaluate the apoptosis-inducing potency of these polyphenolic compounds in human prostate cancer and normal cells. Specific Aim 3 is to determine whether the abilities of these grape antioxidant polyphenolic compounds to inhibit the proteasome activity and to induce apoptosis correlate with their cancer-preventative activity in vivo using nude mice bearing human prostate cancer cells. These studies should help develop a fundamental understanding about how consumption of grapes and other fruits and vegetables prevents cancer, and discover potent, specific and stable polyphenol proteasome inhibitors with no or little toxicity for the prevention of prostate and other cancers.

描述（由申请人提供）：我们的长期目标是发现新型有效的、特异性的、无细胞毒性的癌症预防和抗癌药物。最近的体外、体内和临床试验结果支持使用蛋白酶体抑制剂作为潜在的新型抗癌药物。我们发现，具有酯键的天然和合成绿茶多酚是有效且特异性的蛋白酶体胰凝乳蛋白酶样抑制剂，而那些没有酯键的绿茶多酚则无活性。最近，我们报道了葡萄提取物抑制白血病 Jurkat T 细胞提取物和完整 Jurkat T 细胞中的蛋白酶体胰凝乳蛋白酶样活性，与细胞凋亡诱导相关。此外，与正常 NIH 3T3 细胞系相比，葡萄提取物优先诱导前列腺癌 PC-3 中球形细胞的出现。我们的研究结果表明，蛋白酶体是葡萄抗氧化成分的癌症相关分子靶标。基于这些结果，我们假设一些抗氧化多酚化合物对蛋白酶体活性的抑制有助于葡萄的前列腺癌预防活性。为了解决这一假设，我们提出以下三个具体目标。具体目标 1 是使用纯化的 20S 蛋白酶体、前列腺癌细胞提取物和完整前列腺癌细胞来评估几种葡萄多酚化合物抑制蛋白酶体活性的效力和选择性。具体目标 2 是评估这些多酚化合物在人前列腺癌和正常细胞中诱导细胞凋亡的效力。具体目标 3 是使用携带人类前列腺癌细胞的裸鼠来确定这些葡萄抗氧化剂多酚化合物抑制蛋白酶体活性和诱导细胞凋亡的能力是否与其体内癌症预防活性相关。这些研究应该有助于对食用葡萄和其他水果和蔬菜如何预防癌症有一个基本的了解，并发现有效、特异性和稳定的多酚蛋白酶体抑制剂，无毒或毒性很小，可以预防前列腺癌和其他癌症。