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诊断的癌症，也是癌症相关死亡的第二大常见原因。尽管预防和治疗方面的进步提高了总体生存率，但仍然明显需要有效的基于机制的方法，以实现前列腺癌治疗的长期改善。与前列腺癌发生有关的众多信号网络包括 PTEN/AKT/哺乳动物雷帕霉素靶点 (AKT/mTOR) 和 MAPK 通路。值得注意的是，PTEN/AKT/mTOR 和 MAPK 信号通路协同作用，促进肿瘤生长和激素难治性疾病的出现。这些观察结果构成了我们提议的基础，即同时靶向 PTEN/Akt/mTOR 和 MAPK 信号通路可能是抑制前列腺上皮内瘤变 (PIN) 发展及其转化为癌症的有效策略。根据这一假设，并在我们寻求用于化学预防的无毒饮食剂的过程中，我们最近对非瑟酮进行了一些新颖且令人兴奋的观察，非瑟酮是一种结构独特的化学物质，属于多酚类黄酮类。用非瑟酮处理前列腺癌 PC3 细胞会抑制 mTOR 激酶信号传导。使用模拟前列腺癌发生过程中多个步骤的独特的人类前列腺上皮细胞系家族，我们观察到具有增加的肿瘤发生潜力的转化细胞表现出更高的mTOR信号传导以及对非瑟酮诱导的细胞死亡的更高敏感性。更有趣的是，使用分子模型，我们观察到非瑟酮与 mTOR 分子发生物理相互作用，并以 -8Kcal/mol 的结合能停靠在两个位点。这些观察结果证明非瑟酮作为 mTOR 信号复合物的新型抑制剂发挥作用，导致细胞死亡。在此应用中，我们建议利用非瑟酮靶向多种信号通路的能力，并使用六种人类前列腺上皮细胞的独特家族在体外研究其功效，并使用基因工程 Nkx3.1/Pten 突变小鼠模型在体内研究其功效，该模型概括了许多人类前列腺癌的特征。与当前研究最相关的是，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，我们推断这些 Nkx3.1/Pten 小鼠应该提供一个优秀的临床前模型来测试同时靶向 AKT/mTOR 和 ERK MAPK 信号传导对前列腺肿瘤发生的影响。在此应用中，我们将 1) 建立 PTEN/Akt/mTOR 和 MAPK 信号通路的参与，并确定非瑟酮在模拟前列腺癌发生过程中多个步骤的独特的人前列腺上皮细胞系家族中的功效，2)研究膳食非瑟酮以及 PTEN/Akt/mTOR 和 MAPK 信号通路在 PIN 和雄激素依赖性腺癌发生过程中的影响Nkx3.1/Pten 前列腺癌小鼠模型，3) 在 Nkx3.1/Pten 突变小鼠晚期前列腺癌模型中研究非瑟酮对抗去势诱导的雄激素非依赖性腺癌的功效。该提案的成功完成可能会导致非瑟酮开发为预防前列腺癌并可能用于治疗前列腺癌的新型药物。公共健康相关性：与晚期前列腺癌有关的主要信号网络包括 AKT/哺乳动物雷帕霉素靶点 (AKT/mTOR) 和 MAPK 通路。 AKT/mTOR 和 ERK MAPK 信号通路的组合抑制对于抑制前列腺致瘤性非常有效。我们的研究将提供有关使用无毒膳食成分非瑟酮的信息，该成分可抑制这些信号通路，从而在辅助环境中预防和可能治疗前列腺癌。