Novel resveratrol analogs and colorectal cancer treatment

新型白藜芦醇类似物和结直肠癌治疗

基本信息

批准号：
8847232
负责人：
CHUNMING LIU
金额：
$ 31.22万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-06 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847232
关键词：
APC gene Accounting Adenomatous Polyposis Coli Adverse effects Affect Anabolism Animal Model Antineoplastic Agents Binding Biological Biological Assay Biological Factors Biological Process CTNNB1 gene Cancer Cell Growth Cancer Etiology Cell Proliferation Cell model Cells Cessation of life Chemoprevention Chemopreventive Agent Colorectal Cancer Development Disclosure Drug Targeting Epigenetic Process Event Family Funding Future Generations Genes Genetic Transcription Genetically Engineered Mouse Goals Grant Grapes Growth Half-Life Human Hypermethylation In Vitro Lead Legal patent Malignant Neoplasms Malignant neoplasm of liver Mediating Metabolism Methionine Modeling Molecular Molecular Target Mus Mutation Neoplasms Nude Mice Organoids Pathway interactions Patients Polyamines Publications Reporting Resveratrol Role S-Adenosylmethionine Signal Pathway Signal Transduction Skin Testing Therapeutic Therapeutic Agents Toxic effect United States Xenograft procedure analog base cancer cell cancer prevention cancer therapy colon carcinogenesis colorectal cancer prevention design drug candidate efficacy testing histone methylation in vivo inhibitor/antagonist methionine adenosyltransferase mortality mouse model novel promoter public health relevance research study trans-resveratrol tumor metabolism tumor progression

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States and accounts for more than 50,000 deaths per year. CRC is initiated by mutations of adenomatous polyposis coli (APC) and b-catenin genes, which result in abnormal activation of the Wnt signaling pathway. Inhibition Wnt signaling is essential for CRC prevention and treatment; however, prior efforts along these lines were not successful because of the side effects displayed by these inhibitors. We hypothesize that natural products and their analogs are ideal therapeutic agents if they target key pathways in CRC and possess minimal toxicity. Recently, we reported that resveratrol, which is found in the skin of red grapes, significantly inhibits Wnt signaling. Resveratrol is reported to have anti-cancer activity and not toxic at concentration (1 gram/day) effective for CRC treatment, but resveratrol has a half-life in vivo that limits its utility as a therapeutic agent. Supported by an R21 grant (RCA139359), we designed and synthesized resveratrol analogs called FlDAS agents that are more potent than resveratrol in cell based assays and possess significantly greater half-lives than reservatrol. One particular compound, FlDAS-4r, inhibits growth of human CRC xenografts in nude mice and is well tolerated in mice. Using a biotinylated, biologically active form of FIDAS-4r, we identified methionine adenosyltransferase 2A (MAT2A) as the direct target for resveratrol analogs. Our central hypothesis is that resveratrol and its analogs inhibit MAT2A and regulate the levels and metabolism of S-adenosylmethionine (SAM), thus inhibiting Wnt signaling and the proliferation of CRC cells. To further define the molecular mechanism of these anti- cancer agents and to develop these agents for CRC treatment and chemoprevention, we will pursue the following three Specific Aims: 1) To define the mechanisms regulating inhibition of MAT2A by FIDAS agents; 2) To delineate the mechanisms of how FIDAS agents inhibit CRC cell growth; and 3) To characterize novel FIDAS agents using in vivo mouse models.

描述（由申请人提供）：大肠癌（CRC）是美国与癌症相关死亡率的第二大原因，每年占50,000多人的死亡。 CRC是由腺瘤性息肉病（APC）和B-catenin基因的突变引发的，这导致Wnt信号通路异常激活。抑制Wnt信号对于预防CRC和治疗至关重要。但是，由于这些抑制剂所表现出的副作用，因此沿这些线路的事先努力并没有成功。我们假设天然产物及其类似物是理想的治疗剂，如果它们靶向CRC中的关键途径并且具有最小的毒性。最近，我们报道了在红葡萄皮肤中发现的白藜芦醇显着抑制Wnt信号传导。据报道，白藜芦醇具有抗癌活性，在浓度（1克/天）的有效性有效的CRC治疗时没有毒性，但是白藜芦醇的体内半衰期限制了其作为治疗剂的效用。由An支持 R21 Grant（RCA139359），我们设计和合成了称为FLDAS药物的白藜芦醇类似物，在基于细胞的测定中比白藜芦醇更有效，并且半衰期比储层大得多。一种特殊的化合物FLDAS-4R抑制了裸鼠人类CRC异种移植物的生长，并且在小鼠中耐受耐受性。我们使用FIDAS-4R的生物素化，生物活性形式，我们将甲二氨酸腺苷转移酶2a（MAT2A）确定为白藜芦醇类似物的直接靶标。我们的中心假设是白藜芦醇及其类似物抑制MAT2A并调节S-腺苷甲氨酸（SAM）的水平和代谢，从而抑制Wnt信号传导和CRC细胞的增殖。为了进一步定义这些抗癌药物的分子机制，并开发了这些用于CRC治疗和化学预防的药物，我们将追求以下三个具体目标：1）定义FIDAS药物抑制MAT2A的机制； 2）描述FIDAS药物如何抑制CRC细胞生长的机制； 3）使用体内小鼠模型来表征新颖的FIDAS剂。