[Frontiers in Bioscience 12, 4839-4854, September 1, 2007]

Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential

Sharmila Shankar, Gyanendra Singh, Rakesh K. Srivastava

Department of Biochemistry, University of Texas Health Science Center at Tyler, Tyler, Texas, USA 75703

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Mechanisms of Action
3.1. Regulation of Bcl-2 family members
3.2. Regulation of cell cycle
3.3. Regulation of MAP kinase
3.4. Generation of Reactive Oxygen Species (ROS)
3.5. Regulation of PI3-Kinase / AKT Pathway
3.6. Regulation of Transcription factors
3.7. Regulation of TRAIL - Death receptor pathway
4. Bioavailability and Metabolism of Resveratrol
5. Clinical significance of Resveratrol
5.1. Effects of Resveratrol on cancer
5.2. Effects of Resveratrol on angiogenesis
5.3. Effects of Resveratrol on cardiovascular disease
5.4. Antiviral effects of Resveratrol
5.5. Effects of Resveratrol on inflammation
5.6. Effects of Resveratrol on Diabetes
5.7. Other effects of Resveratrol
6. Combination of Resveratrol with Chemotherapy
7. Combination of Resveratrol with Radiotherapy
8. Conclusions and Future directions
9. Acknowledgements
7. References

1. ABSTRACT

Resveratrol, a polyphenol found in numerous plant species, including mulberries, peanuts and grapes, has shown to possess chemopreventive properties against several cancers, and cardiovascular diseases. Recently, resveratrol has been shown to have positive effects on age longevity, lipid levels and a preventative quality against certain cancers and viral infections. Resveratrol induces apoptosis by up-regulating the expression of Bax, Bak, PUMA, Noxa, Bim, p53, TRAIL, TRAIL-R1/DR4 and TRAIL-R2/DR5 and simultaneously down-regulating the expression of Bcl-2, Bcl-XL, Mcl-1 and survivin. Resveratrol causes growth arrest at G1 and G1/S phases of cell cycle by inducing the expression of CDK inhibitors p21/WAF1/CIP1 and p27/KIP1. Resveratrol has also been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and nuclear factor-кB activity. Modulation of cell signaling pathway by resveratrol explains its diverse bioactivities related with human health. Resveratrol also potentiates the apoptotic effects of cytokines, chemotherapeutic agents and gamma-radiation. Pharmacokinetic and pharmacodynamic studies demonstrated that the main target organs of resveratrol are liver and kidney, and it is metabolized by hydroxylation, glucuronidation, sulfation and hydrogenation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression. There is growing evidence that resveratrol can prevent or delay the onset of various cancers, heart diseases, ischemic and chemically induced injuries, pathological inflammation and viral infections. This review summarizes the molecular mechanisms of resveratrol and its clinical benefits for human diseases.