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.

抽象的前列腺癌是最常见的癌症，也是第二大常见的癌症原因美国男性的相关死亡。尽管预防和治疗的进展总体上有所改善生存，显然仍然需要有效的、基于机制的方法，以实现长期目标改善前列腺癌的治疗。在众多已建成的信令网络中雷帕霉素的 PTEN/AKT/哺乳动物靶点与前列腺癌的发展有关 (AKT/mTOR) 和 MAPK 途径。值得注意的是，PTEN/AKT/mTOR 和 MAPK 信号通路发挥作用合作促进肿瘤生长和激素难治性疾病的出现。这些观察构成我们提议的基础，即同时靶向 PTEN/Akt/mTOR 和 MAPK 信号传导途径可能是抑制前列腺上皮内瘤变（PIN）发展的有效策略及其转化为癌症。根据这一假设，并在我们追求无毒膳食制剂的过程中在化学预防方面，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物质。属于多酚黄酮类的化学物质。前列腺癌PC3细胞的治疗与非瑟汀一起使用可抑制 mTOR 激酶信号传导。使用独特的人类前列腺上皮家族我们观察到模仿前列腺癌发生过程中多个步骤的细胞系肿瘤发生潜力增加的细胞表现出更高的 mTOR 信号传导和对非瑟酮更高的敏感性诱导细胞死亡。更有趣的是，利用分子模型，我们观察到非瑟酮在物理上相互作用与 mTOR 分子结合并停靠在两个位点，结合能为 -8Kcal/mol。这些观察提供证据表明非瑟酮作为 mTOR 信号复合物的新型抑制剂发挥作用，导致诱导细胞死亡。在此应用中，我们建议利用非瑟酮靶向多种信号传导的能力途径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，并在体内使用基因工程 Nkx3.1/Pten 突变小鼠模型，该模型概括了许多特征人类前列腺癌。与当前研究最相关的是，Nkx3.1/Pten 突变小鼠表现出癌症进展过程中的 AKT/mTOR 和 MAPK 信号传导。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的后果 AKT/mTOR 和 ERK MAPK 信号传导促进前列腺肿瘤发生。在此应用程序中，我们将 1) 建立 PTEN/Akt/mTOR 和 MAPK 信号通路的参与，并确定非瑟酮在独特的人类前列腺上皮细胞系家族，模拟前列腺过程中的多个步骤致癌作用，2) 研究膳食非瑟酮的影响以及 PTEN/Akt/mTOR 和 MAPK 的参与 PIN 和雄激素依赖性腺癌发生过程中的信号通路 Nkx3.1/Pten 前列腺癌小鼠模型和 3) 研究非瑟酮对抗去势的功效在晚期 Nkx3.1/Pten 突变小鼠模型中诱导雄激素非依赖性腺癌前列腺癌。该提案的成功完成可能会导致非瑟酮作为一种新型药物的开发用于预防和可能用于治疗前列腺癌的药剂。