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：
8473681
负责人：
Hasan Mukhtar
金额：
$ 28.96万
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/8473681
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 Epithelial Cells Exhibits Family Flavonoids Frequencies Genetic Engineering 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 PC3 cell line 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.

抽象的前列腺癌是最常见的癌症，也是癌症的第二大原因美国男人之间的相关死亡。尽管预防和治疗的进步总体上有所改善生存，仍然需要有效的基于机制的方法，可以实现长期治疗前列腺癌的改善。在众多的信号网络中与前列腺癌发展有关的是雷帕霉素的PTEN/AKT/哺乳动物靶标（AKT/MTOR）和MAPK途径。值得注意的是，PTEN/AKT/MTOR和MAPK信号通路功能合作以促进肿瘤生长和激素难治性疾病的出现。这些观察构成了我们提出的基础，即同时定位PTEN/AKT/MTOR和MAPK信号传导途径可能是抑制前列腺上皮内肿瘤（PIN）发展的有效策略及其转变为癌症。符合这一假设以及我们对无毒饮食剂的追求化学预防，我们最近用Fisetin进行了一些新颖而令人兴奋的观察，这是一种结构上不同的属于类黄酮多酚的化学物质。治疗前列腺癌PC3细胞 fisetin导致MTOR激酶信号传导的抑制作用。使用独特的人类前列腺上皮家族在前列腺致癌过程中模仿多个步骤的细胞系我们观察到了转化肿瘤发生潜力增加的细胞表现出更高的MTOR信号传导和对Fisetin的敏感性更高诱导细胞死亡。更有趣的是，使用分子建模我们观察到fisetin在物理上相互作用用MTOR分子和码头在两个位点，结合能为-8kcal/mol。这些观察提供证据表明，菲塞丁是MTOR信号传导复合物的新型抑制剂，导致诱导细胞死亡。在此应用中，我们建议利用Fisetin靶向多个信号的能力途径并使用六个人类前列腺上皮细胞的独特家族以及在体外研究其功效使用基因设计的NKX3.1/PTEN突变小鼠模型的体内，该模型概括了许多特征人前列腺癌。 NKX3.1/PTEN突变小鼠与当前研究最相关癌症进展过程中Akt/mTOR和MAPK信号传导。因此，我们认为这些NKX3.1/pten 小鼠应提供出色的临床前模型，以测试同时靶向的后果前列腺肿瘤发生的AKT/MTOR和ERK MAPK信号传导。在此应用程序中，我们将建立 PTEN/AKT/MTOR和MAPK信号通路的参与，并确定Fisetin在A中的疗效人类前列腺上皮细胞系的独特家族，它们在前列腺过程中模仿多个步骤致癌作用，2）研究饮食中的fisetin和PTEN/AKT/MTOR和MAPK的影响在销育和雄激素依赖性腺癌开发过程中的信号通路 NKX3.1/前列腺癌的PTEN小鼠模型和3）研究Fisetin对casttration的疗效在晚期NKX3.1/PTEN突变小鼠模型中诱导雄激素独立的腺癌前列腺癌。该提案的成功完成可能会导致Fisetin作为新颖的发展预防药物以及可能治疗前列腺癌的代理。