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Developing Fisetin for the Managment of Prostate Cancer

开发非瑟酮治疗前列腺癌

基本信息

批准号：
8278499
负责人：
Hasan Mukhtar
金额：
$ 30.81万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8278499
关键词：
AKT inhibition Adenocarcinoma Adjuvant Androgens Apple Binding Cancer Etiology Castration Cell Death Cell Death Induction Cell Line Cell Proliferation Cells Cessation of life Chemicals Chemoprevention Complex Cucumber Development Diet Diospyros Docking Dyes Engineering Epithelial Cells Exhibits Family Flavonoids Frequencies Growth Growth Factor Homologous Gene Hormones Human In Vitro Intraepithelial Neoplasia MAP Kinase Gene MAP2K1 gene MAPK Signaling Pathway Pathway Malignant Neoplasms Malignant neoplasm of prostate Molecular Molecular Models Mus Mutant Strains Mice Mutation Onions PTEN gene Pathway interactions Phenotype Phosphotransferases Pre-Clinical Model Predisposition Prevention Process Prostate Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Proto-Oncogene Proteins c-akt Raptors Refractory Refractory Disease Second Primary Cancers Signal Pathway Signal Transduction Site Staging Strawberries TSC2 gene Testing Tumor Suppressor Genes Tumorigenicity base cancer diagnosis cell growth cell transformation combinatorial deprivation fisetin hormone refractory prostate cancer human FRAP1 protein human MAP3K1 protein improved in vivo inhibitor/antagonist inorganic phosphate mTOR Inhibitor mTOR Signaling Pathway mTOR inhibition mTOR protein malignant phenotype member men molecular modeling mouse model mutant mouse model neoplastic cell novel polyphenol prostate carcinogenesis tensin tumor tumor growth tumor progression tumorigenesis tumorigenic

项目摘要

ABSTRACT Prostate cancer is the most commonly diagnosed cancer and the second most common cause of cancer related deaths among men in the US. Although advances in prevention and treatment have improved overall survival, there remains a clear need for effective mechanism-based approaches that can achieve long-term improvements in the management prostate cancer. Among the many signaling networks that have been implicated in the development of prostate cancer are the PTEN/AKT/mammalian target of rapamycin (AKT/mTOR) and MAPK pathways. Notably, the PTEN/AKT/mTOR and MAPK signaling pathways function cooperatively to promote tumor growth and the emergence of hormone-refractory disease. These observations form the basis of our proposal that simultaneous targeting of the PTEN/Akt/mTOR and the MAPK signaling pathways may be an effective strategy for inhibiting the development of prostatic intraepithelial neoplasia (PIN) and its conversion to cancer. In line with this hypothesis and in our pursuit for non-toxic dietary agents for chemoprevention, we recently made some novel and exciting observations with fisetin, a structurally distinct chemical substance that belongs to the flavonoid group of polyphenols. Treatment of prostate cancer PC3 cells with fisetin resulted in inhibition of mTOR kinase signaling. Using a unique family of human prostate epithelial cell lines that mimic multiple steps in the process of prostate carcinogenesis we observed that transformed cells with increased potential for tumorigenesis exhibit higher mTOR signaling and greater sensitivity to fisetin induced cell death. More interestingly, using molecular modeling we observed that fisetin physically interacts with the mTOR molecule and docks at two sites with a binding energy of -8Kcal/mol. These observations provide evidence that fisetin functions as a novel inhibitor of mTOR signaling complex leading to induction of cell death. In this application we propose to take advantage of fisetin's ability to target multiple signaling pathways and investigate its efficacy in vitro using a unique family of six human prostate epithelial cells and in vivo using a genetically engineered Nkx3.1/Pten mutant mouse model that recapitulates many features of human prostate cancer. Most relevant for the current study, Nkx3.1/Pten mutant mice display activation of AKT/mTOR and MAPK signaling during cancer progression. Therefore, we reasoned that these Nkx3.1/Pten mice should provide an excellent preclinical model to test the consequences of simultaneous targeting of AKT/mTOR and ERK MAPK signaling for prostate tumorigenesis. In this application we will 1) establish the involvement of PTEN/Akt/mTOR and the MAPK signaling pathways and determine the efficacy of fisetin in a unique family of human prostate epithelial cell lines that mimic multiple steps in the process of prostate carcinogenesis, 2) investigate the effects of dietary fisetin and involvement of PTEN/Akt/mTOR and the MAPK signaling pathways during the development of PIN and androgen dependent adenocarcinoma in the Nkx3.1/Pten mouse model of prostate cancer and 3) investigate the efficacy of fisetin against castration induced androgen independent adenocarcinoma in the Nkx3.1/Pten mutant mouse model of advanced prostate cancer. A successful completion of this proposal may result in the development of fisetin as a novel agent for prevention and possibly for the treatment of prostate cancer.

摘要