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肿瘤，治疗困难，常规放化疗耐药。几个主要的信号级联反应与胶质瘤的发展有关，包括生长因子及其受体（如EGFR）的过度表达和激活，细胞内信号蛋白（如PI3-K/Akt）的过度表达和激活以及细胞增殖和细胞周期的失调。白藜芦醇（反式3,4'，5-三羟基二苯乙烯）是一种多酚类化合物，富含葡萄、花生、红酒和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，并作为一种癌症化学预防剂，抑制癌变过程的不同步骤，如肿瘤的发生、促进和进展。然而，白藜芦醇介导的信号传导机制在体内尚不明确。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胶质瘤细胞的细胞增殖和诱导凋亡细胞死亡。caspase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。本研究采用裸鼠U251脑胶质瘤模型，研究白藜芦醇对肿瘤生长的抑制作用及其在体内的分子机制。我们假设白藜芦醇通过下调EGFR-和PI3-K/ akt介导的信号通路的表达和/或抑制激活来抑制体内胶质瘤的发展。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，通常很少或没有毒性作用，价格低廉，可口服。使用这些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大有裨益。胶质瘤是一种成人恶性脑肿瘤，治疗困难，对常规放化疗有耐药性。白藜芦醇是一种多酚类化合物，富含葡萄、花生、红酒和各种植物和食物。白藜芦醇具有抗炎和抗氧化的特性，是一种癌症化学预防剂。我们的体外研究表明，白藜芦醇可以抑制胶质瘤细胞的增殖并诱导细胞凋亡。因此，我们试图用一个完善的神经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，本研究将促进天然产物治疗药物的开发，极大地改善脑肿瘤的治疗。

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.