The Proteasome as Molecular Target of Grape Polyphenols

蛋白酶体作为葡萄多酚的分子靶标

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6952307
• 关键词: Bax gene /protein; antineoplastics; antioxidants; apoptosis; athymic mouse; cancer prevention; cell line; chemoprevention; cytotoxicity; drug discovery /isolation; drug screening /evaluation; enzyme activity; flavonoids; fruit; neoplastic cell; nutrition aspect of cancer; nutrition related tag; prostate neoplasms; protease inhibitor; proteasome; quercetin; xenotransplantation

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）：

项目成果

The tumor proteasome as a novel target for gold(III) complexes: implications for breast cancer therapy.

• DOI: 10.1016/j.ccr.2009.01.032
• 发表时间: 2009
• 期刊: Coordination chemistry reviews
• 影响因子: 20.6
• 作者: Milacic V;Dou QP
• 通讯作者: Dou QP

Relationship between the methylation status of dietary flavonoids and their growth-inhibitory and apoptosis-inducing activities in human cancer cells.

• DOI: 10.1002/jcb.21853
• 发表时间: 2008-10-01
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Landis-Piwowar, Kristin R.;Milacic, Vesna;Dou, Q. Ping
• 通讯作者: Dou, Q. Ping

Tea polyphenols and their roles in cancer prevention and chemotherapy.

• DOI: 10.3390/ijms9071196
• 发表时间: 2008-06
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Chen D;Dou QP
• 通讯作者: Dou QP

Withaferin A inhibits the proteasome activity in mesothelioma in vitro and in vivo.

Withaferin A 在体外和体内抑制间皮瘤中的蛋白酶体活性。

• DOI: 10.1371/journal.pone.0041214
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Yang,Huanjie;Wang,Ying;Cheryan,VinoT;Wu,Wenjuan;Cui,CindyQiuzhi;Polin,LisaA;Pass,HarveyI;Dou,QPing;Rishi,ArunK;Wali,Anil
• 通讯作者: Wali,Anil

The challenge of developing green tea polyphenols as therapeutic agents.

• DOI: 10.1007/s10787-008-8031-x
• 发表时间: 2008-10
• 期刊: INFLAMMOPHARMACOLOGY
• 影响因子: 5.8
• 作者: Huo, C.;Wan, S. B.;Lam, W. H.;Li, L.;Wang, Z.;Landis-Piwowar, K. R.;Chen, D.;Dou, Q. P.;Chan, T. H.
• 通讯作者: Chan, T. H.