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：
8160855
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/8160855
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 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Among the major signaling networks that have been implicated in advanced prostate cancer are the AKT/mammalian target of rapamycin (AKT/mTOR) and MAPK pathways. Combinatorial inhibition of the AKT/mTOR and ERK MAPK signaling pathways is highly effective for inhibition of prostate tumorigenicity. Our studies will provide information on the use of a non-toxic dietary ingredient fisetin which inhibits these signaling pathways for the prevention and possible treatment of prostate cancer in an adjuvant setting.

描述（由申请人提供）：前列腺癌是美国男性中最常见的癌症，是癌症与癌症相关的第二大原因。尽管预防和治疗方面的进步提高了总体生存率，但仍然需要对有效的基于机制的方法进行长期改善前列腺癌的有效方法。在与前列腺癌发展有关的许多信号网络中，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信号通路协同起作用，可促进肿瘤生长和激素难治性疾病的出现。这些观察结果是我们提出的基础，即PTEN/AKT/MTOR和MAPK信号通路的同时靶向可能是抑制前列腺上皮内肿瘤（PIN）及其转化为癌症的有效策略。根据这一假设以及我们对化学预防的无毒饮食剂的追求，我们最近用Fisetin进行了一些新颖而令人兴奋的观察结果，Fisetin是一种属于类黄酮的多酚群的结构上不同的化学物质。用Fisetin治疗前列腺癌PC3细胞可抑制mTOR激酶信号传导。使用独特的人类前列腺上皮细胞系，在前列腺癌变过程中模仿多个步骤，我们观察到，转化的细胞具有肿瘤发生的潜力增加的MTOR信号传导较高，并且对Fisetetin诱导的细胞死亡的敏感性更高。更有趣的是，使用分子建模，我们观察到fisetin在两个位点的结合能与-8kcal/mol的两个位点与MTOR分子进行物理相互作用。这些观察结果提供了证据，表明Fisetin是MTOR信号传导复合物的新型抑制剂，导致细胞死亡的诱导。在此应用中，我们建议利用Fisetin靶向多个信号通路的能力，并使用六个人类前列腺上皮细胞的独特家族在体外研究其在体外的功效，并使用基因工程的NKX3.1/PTEN突变体模型在体内进行体内，以重新调整许多人的模型人类前列腺癌的特征。 NKX3.1/PTEN突变小鼠在癌症进展过程中表现出AKT/MTOR和MAPK信号传导的激活。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AKT/MTOR和ERK MAPK信号对前列腺肿瘤发生的同时靶向的后果。在此应用中，我们将1）建立PTEN/AKT/MTOR和MAPK信号通路的参与，并确定Fisetin在独特的人类前列腺上皮细胞系中的疗效，这些细胞系在前列腺癌变过程中模仿多个步骤，2）在NKX3.1/PTEN小鼠模型中，研究饮食中的fisetin以及PTEN/AKT/MTOR和MAPK信号通路的参与以及MAPK信号通路的影响在晚期前列腺癌的NKX3.1/PTEN突变小鼠模型中诱导雄激素独立的腺癌。该提案的成功完成可能会导致Fisetin作为预防和治疗前列腺癌的新药物的发展。公共卫生相关性：在与晚期前列腺癌有关的主要信号网络中，雷帕霉素（AKT/MTOR）和MAPK途径的AKT/哺乳动物靶标。组合抑制AKT/MTOR和ERK MAPK信号通路对抑制前列腺肿瘤性非常有效。我们的研究将提供有关使用无毒饮食成分Fisetin的信息，该饮食成分菲塞蛋白抑制这些信号通路，以预防和可能在辅助环境中治疗前列腺癌。