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）：结直肠癌 (CRC) 是美国癌症相关死亡的第二大原因，每年导致超过 50,000 人死亡。 CRC 是由腺瘤性结肠息肉病 (APC) 和 β-catenin 基因突变引发的，导致 Wnt 信号通路异常激活。抑制Wnt信号对于CRC的预防和治疗至关重要；然而，由于这些抑制剂所表现出的副作用，之前的这些努力并未成功。我们假设，如果天然产物及其类似物针对结直肠癌的关键途径并且具有最小的毒性，那么它们就是理想的治疗剂。最近，我们报道了红葡萄皮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，并且在有效治疗 CRC 的浓度（1 克/天）下无毒，但白藜芦醇的体内半衰期限制了其作为治疗剂的用途。由一个支持在 R21 资助 (RCA139359) 的资助下，我们设计并合成了称为 FlDAS 制剂的白藜芦醇类似物，其在基于细胞的测定中比白藜芦醇更有效，并且具有比白藜芦醇显着更长的半衰期。一种特殊的化合物 FIDAS-4r 可抑制裸鼠体内人类 CRC 异种移植物的生长，并且在小鼠中具有良好的耐受性。使用生物素化的生物活性形式的 FIDAS-4r，我们确定甲硫氨酸腺苷转移酶 2A (MAT2A) 是白藜芦醇类似物的直接靶点。我们的中心假设是白藜芦醇及其类似物抑制 MAT2A 并调节 S-腺苷甲硫氨酸 (SAM) 的水平和代谢，从而抑制 Wnt 信号传导和 CRC 细胞的增殖。为了进一步明确这些抗癌药物的分子机制并开发这些药物用于 CRC 治疗和化学预防，我们将追求以下三个具体目标： 1) 明确 FIDAS 药物抑制 MAT2A 的调节机制； 2) 阐明FIDAS药物抑制CRC细胞生长的机制； 3) 使用体内小鼠模型表征新型 FIDAS 试剂。