LA JOLLA, Calif. , December 3, 2003
Researchers at The Burnham Institute have identified ingredients in green and black teas that are potent inhibitors of a family of proteins implicated in many types of cancer, and discovered how these ingredients, called polyphenols, work to prevent the growth of cancer cells.
Cancer occurs less often among populations that drink tea, the world's second most commonly consumed liquid. This epidemiological evidence has been supported by "in vitro" laboratory studies, which indicate that green tea and certain black teas prevent cancer. The critical question of "how" consumption of green or black tea might prevent cancer has eluded researchers until now.
A collaborative team led by Drs. Maurizio Pellecchia and John C. Reed has discovered that polyphenols act upon certain so-called "anti-death" proteins known as Bcl-2 and Bcl-xL, which are overproduced in most human cancers. They are dubbed anti-death proteins because they disrupt a critical pathway programmed into cells that acts as a culling mechanism to eradicate defective cells and to maintain a balance in cell numbers in the body. Failure of the cell death program is one of the hallmarks of cancer, and explains much of the current difficulty in effectively eliminating cancer cells using available anti-cancer drugs or radiation therapy.
Bcl-2 and Bcl-xL, the subject of intensive investigation in Dr. John C. Reed’s laboratory, offer novel targets for therapeutic intervention: they interfere with tumor cell death induced by chemotherapy and radiation and are highly correlated with tumor resistance to chemotherapy.
Dr. Maurizio Pellecchia, a medicinal chemist, uses sophisticated instrumentation called nuclear magnetic resonance (NMR) in combination with in silico molecular modeling as drug discovery tools. Looking for chemicals in a collection of molecules derived from Chinese herbal medicine, Dr. Pellecchia used NMR and computer animation to determine the 3-dimensional structure of certain tea polyphenols docked into the binding pocket of Bcl-xL.
Drs. Pellecchia and Reed are using the information made available through these studies to design semi-synthetic versions of chemical compounds found in green tea extracts to provide more potent inhibitors of Bcl-2 and Bcl-xL than the naturally occurring chemicals found in tea.
Dr. Reed, inventor of a DNA-based therapy for suppressing Bcl-2 in cancer stated, "this discovery is very exciting because the natural products found in tea are already more potent than other existing anti-Bcl-2 therapies in clinical trials. By using structure-based drug optimization technologies, we can take what Mother Nature has provided and make it better and safer."
How much green tea is required to suppress Bcl-2 and Bcl-xL activity in vitro? "Surprisingly, very low amounts", according to Dr. Pellecchia. "The level required for inhibition of these proteins was very small--in the nanomolar range. Unlike previously proposed mechanisms for similar tea extracts against other protein targets, this tight inhibition correlates with the low concentrations of tea polyphenols present in the bloodstream after tea consumption. We expect that the anti-Bcl-2/xL activity of certain green and black tea extracts could be effective in vivo also after consumption of moderate amounts of tea. We believe this inhibition could play a major role in the cancer prevention properties of tea."
These results, published in the December issue of Cancer Research, the official journal of the American Association for Cancer Research, also point to novel clinical uses of tea extracts as chemo-sensitizers, which could overcome chemoresistance to conventional chemotherapy.
What's next? Dr. Pellecchia points out that "much work needs to be done experimentally in vitro, then in vivo starting with rodents before we move to human clinical trials, but we are very encouraged by these findings."
Maurizio Pellecchia, Ph.D. is an Associate Professor in the Burnham Institute’s Cancer Center.
John C. Reed, M.D., Ph.D. is President and CEO of The Burnham Institute, and Professor in the Institute's Cancer Center.
This research was supported by grants awarded from the National Cancer Institute, The Prostate Cancer Foundation (formerly known as CapCure), and the Hearst Foundation, Inc.