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Abstract
Grant Number: 5R21AT003463-02 Project Title: Resveratrol-induced apoptotic cell death in glioma
PI Information: Name Title JIANG, HAO hjiang1@hfhs.org Abstract: 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.
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Institution: HENRY FORD HEALTH SYSTEM CFP046 DETROIT, MI 48202 Fiscal Year: 2008 Department: Project Start: 01-AUG-2007 Project End: 31-JUL-2009 ICD: NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE IRG: ZAT1