Resveratrol-induced apoptotic cell death in glioma

白藜芦醇诱导神经胶质瘤细胞凋亡

基本信息

批准号：
7313929
负责人：
HAO JIANG
金额：
$ 18.13万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7313929
关键词：
1-Phosphatidylinositol 3-Kinase Adult Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Apoptotic Biological Assay Biological Factors Brain Brain Neoplasms Cancer cell line Caspase Cell Cycle Cell Death Cell Proliferation Cells Chemopreventive Agent Cyclin-Dependent Kinase Inhibitor Daily Data Development Dose Down-Regulation Drug Kinetics EGF gene Edible Plants Epidermal Growth Factor Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Experimental Neoplasms Female Glioma Grapes Green Fluorescent Proteins Growth Factor Human Image Immunohistochemistry In Situ Nick-End Labeling In Vitro Inbred BALB C Mice Intracellular Signaling Proteins LY294002 Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of brain Measurement Measures Mediating Modeling Molecular Mus Nude Mice Patients Peanuts - dietary Phosphorylation Phosphotransferases Preventive Procedures Process Property Propylene Glycols Propylene glycol Protein Overexpression Proto-Oncogene Proteins c-akt Publishing Radiation therapy Radiosurgery Rate Rattus Receptor Protein-Tyrosine Kinases Regulation Reporting Resistance Resveratrol Role S-Phase Fraction Signal Pathway Signal Transduction Sirolimus Source Staging Staining method Stains Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Toxic effect U251 Week angiogenesis carcinogenesis caspase-3 chemotherapy cost day human FRAP1 protein human disease implantation improved in vivo inhibitor/antagonist kinase inhibitor mTOR Inhibitor mouse model neoplastic cell prevent receptor red wine research study therapeutic target trans-resveratrol transcription factor tumor tumor growth tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): Glioma is a malignant brain tumor in adults, difficult to treat and resistant to conventional radiotherapy and chemotherapy. Several major signaling cascades have been implicated in the development of gliomas, which include over-expression and activation of growth factors and their receptors (i.e. EGFR), over-expression and activation of intracellular signaling proteins (i.e. PI3-K/Akt) and deregulation of cell proliferation and the cell cycle. Resveratrol (trans-3,4',5-trihydroxystilbene) is a polyphenolic compound highly enriched in grapes, peanuts, red wine and a variety of plant and food sources. Resveratrol has been reported to have anti-inflammatory and antioxidant properties and acts as a cancer chemopreventive agent, inhibiting different steps of the carcinogenesis process, such as tumor initiation, promotion and progression. However, the signaling mechanisms mediated by resveratrol are not well defined in vivo. Our published in vitro studies show that resveratrol suppresses cell proliferation and induces apoptotic cell death in human U251 glioma cells in a dose- and time-dependent manner. Activation of caspases and suppression of phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (Akt)-mediated signaling pathways are involved in this process. In the current study, we investigate the effect of resveratrol on the suppression of tumor growth and its underlying molecular mechanism in vivo using a U251 intracerebral glioma model in nude mice. We hypothesize that resveratrol suppresses the development of glioma in vivo through the down-regulation of expression and/or suppression of the activation of EGFR- and PI3-K/Akt-mediated signaling pathways. Specifically, the effect of resveratrol on the tumor growth will be determined and the regulation of EGFR/PI3-K/Akt-mediated signaling pathways by resveratrol will be examined. Natural products, such as resveratrol, usually have little or no toxic effects, are low cost and can be consumed orally. Development of potential preventive or adjunctive therapies using such products will be of great benefit for the treatment of glioma, as well as other human diseases. Glioma is a malignant brain tumor in adults, which is difficult to treat and resistant to conventional radiotherapy and chemotherapy. Resveratrol is a polyphenolic compound highly enriched in grapes, peanuts, red wine and a variety of plant and food sources. Resveratrol has anti-inflammatory and antioxidant properties and acts as a cancer chemopreventive agent. Our in vitro studies show that resveratrol suppresses cell proliferation and induces apoptotic cell death in glioma cells. Therefore, we seek to test the effect of resveratrol in vivo using a well-established animal model of glioma. By elucidating the molecular mechanisms underlying the therapeutic effects of resveratrol, this study would facilitate the development of therapeutic agents using natural products and greatly improve the treatment of brain tumors.

描述（由申请人提供）：神经胶质瘤是成年人的恶性脑肿瘤，难以治疗并且对常规放疗和化学疗法有抵抗力。几个主要的信号级联反应与神经胶质瘤的发展有关，其中包括生长因子及其受体的过度表达和激活（即EGFR），细胞内信号蛋白（即PI3-K/AKT）的过表达和激活以及细胞繁殖和细胞周期的消失。白藜芦醇（Trans-3,4'，5-Trihydroxystilbene）是一种多酚化合物，高度富含葡萄，花生，红酒以及各种植物和食物来源。据报道，白藜芦醇具有抗炎和抗氧化特性，并充当癌症化学预防剂，抑制了癌变过程的不同步骤，例如肿瘤的启动，促进和进展。然而，白藜芦醇介导的信号传导机制在体内尚未很好地定义。我们发表的体外研究表明，白藜芦醇以剂量和时间依赖性的方式抑制人U251神经胶质瘤细胞中的细胞增殖并诱导凋亡细胞死亡。胱天蛋白酶的激活和抑制磷脂酰肌醇3-激酶（PI3-K）/蛋白激酶B（AKT）介导的信号传导途径参与此过程。在当前的研究中，我们研究白藜芦醇对使用U251在裸鼠中使用U251脑神经胶质瘤模型在体内抑制肿瘤生长及其潜在的分子机制的影响。我们假设白藜芦醇通过下调和/或抑制EGFR-和PI3-K/AKT介导的信号传导途径的激活来抑制体内神经胶质瘤的发展。具体而言，将确定白藜芦醇对肿瘤生长的影响，并将检查白藜芦醇对EGFR/PI3-K/AKT介导的信号传导途径的调节。天然产品（例如白藜芦醇）通常几乎没有有毒作用，是低成本，可以口服食用。使用此类产品开发潜在的预防或辅助疗法将对胶质瘤以及其他人类疾病的治疗有很大的好处。神经胶质瘤是成年人的恶性脑肿瘤，很难治疗和抗对常规放疗和化学疗法的抗性。白藜芦醇是一种多酚化合物，高度富含葡萄，花生，红酒以及各种植物和食物来源。白藜芦醇具有抗炎和抗氧化特性，并充当癌症化学预防剂。我们的体外研究表明，白藜芦醇抑制细胞增殖并诱导神经胶质瘤细胞中的凋亡细胞死亡。因此，我们寻求使用良好的神经胶质瘤动物模型在体内测试白藜芦醇的作用。通过阐明白藜芦醇治疗作用的分子机制，这项研究将促进使用天然产物的治疗剂的发展，并大大改善脑肿瘤的治疗。