Resveratrol-induced apoptotic cell death in glioma

描述(申请人提供)：胶质瘤是一种成人恶性脑瘤，难以治疗，对常规放疗和化疗耐药。神经胶质瘤的发生与多种信号转导通路有关，包括生长因子及其受体(即EGFR)的过度表达和激活，细胞内信号蛋白(即PI3-K/Akt)的过度表达和激活，以及对细胞增殖和细胞周期的调控。白藜芦醇(反式-3，4‘，5-三羟基二苯乙烯)是一种多酚化合物，在葡萄、花生、红酒和各种植物和食物来源中高度丰富。白藜芦醇已被报道具有抗炎和抗氧化特性，并作为癌症化学预防药物，抑制肿瘤发生、促进和进展等不同阶段的致癌过程。然而，白藜芦醇在体内介导的信号转导机制还不是很清楚。我们发表的体外研究表明，白藜芦醇以剂量和时间依赖的方式抑制人U251胶质瘤细胞的增殖和诱导细胞凋亡。半胱氨酸氨基转移酶的激活和磷脂酰肌醇3-激酶(PI3-K)/蛋白激酶B(Akt)介导的信号通路的抑制参与了这一过程。在本研究中，我们利用裸鼠U251脑内胶质瘤模型，研究了白藜芦醇对肿瘤生长的抑制作用及其分子机制。我们假设白藜芦醇在体内通过下调和/或抑制EGFR-和PI3-K/Akt介导的信号通路的表达和/或激活来抑制胶质瘤的发展。具体来说，将确定白藜芦醇对肿瘤生长的影响，并研究白藜芦醇对EGFR/PI3-K/Akt介导的信号通路的调节。天然产品，如白藜芦醇，通常毒性很小或没有影响，成本低，可以口服。利用这些产品开发潜在的预防性或辅助疗法将对胶质瘤和其他人类疾病的治疗大有裨益。胶质瘤是一种成人恶性脑瘤，治疗难度大，对常规放疗和化疗耐药。白藜芦醇是一种多酚化合物，高度富含葡萄、花生、红酒和各种植物和食物来源。白藜芦醇具有抗炎和抗氧化特性，是一种癌症化学预防药物。我们的体外研究表明，白藜芦醇抑制胶质瘤细胞的增殖和诱导细胞凋亡。因此，我们试图使用一个成熟的胶质瘤动物模型来测试白藜芦醇在体内的作用。通过阐明白藜芦醇治疗作用的分子机制，本研究将促进利用天然产品开发治疗药物，并极大地提高脑肿瘤的治疗效果。

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.