Light & Shadows of Chalandor

Tea Impacts BCl-2 gene: Fresh evidence claimed for how tea protects against cancer

Dec 2003. LA JOLLA, CA. 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 "population based" (epidemiological) evidence has been supported by "in vitro" laboratory studies, which indicate that green tea and certain black teas prevent cancer when applied to cells in a dish.

The critical question of "how" consumption of green or black tea might prevent cancer has eluded researchers until now.

A team led by Drs. Maurizio Pellecchia and distinguished cancer researcher John Reed has discovered that polyphenols act upon certain so-called "anti-death" proteins known as Bcl-2 and Bcl-x_L, which are overproduced in most human cancers. These 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.

Defective cells are supposed to do "apoptosis," i.e. commit cell suicide. Cancer starts to become a threat to the body when defective cells keep right on growing and dividing. So, failure of the cell death program is one of the hallmarks of cancer, and according to Reed explains much of the current difficulty in effectively eliminating cancer cells using available anti-cancer drugs or radiation therapy.

Bcl-2 and Bcl-x_L, the subject of intensive investigation in Reed’s laboratory, make desirable targets for drugs and other therapie: they interfere with tumor cell death induced by chemotherapy and radiation and are highly correlated with tumor resistance to chemotherapy.

Dr. 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-x_L.

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-x_L 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-x_L activity in cells in a dish (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/x_L 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."

Green Tea Kills Prostate Cancer Cells

PSA RisingDecember 14, 1998. New evidence that green tea contains an anti-cancer agent has been reported by Purdue University researchers Dorothy Morre and D. James Morre. They say EGCg, a compound in green tea, inhibits an enzyme called tNOX, which is required for cancer cell growth.
The researchers claim that this is the first scientific finding to explain precisely how this compound works inside a cell to ward off cancer. They say lab tests showed EGCg can kill cultured cancer cells with no ill effect on healthy cells. The results were presented at the 38th annual meeting of the American Society for Cell Biology in San Francisco.
"Our research shows that green tea leaves are rich in this anti-cancer compound, with concentrations high enough to induce anti-cancer effects in the body," says Dorothy Morre, professor of foods and nutrition in Purdue's School of Consumer and Family Sciences. Drinking more than four cups of green tea a day, she says, could provide enough of the active compound to slow and prevent the growth of cancer cells.

Green More Potent Than Black

Tea      Although all teas come from the same botanical source, green tea differs from black tea or other teas because of the way the tea leaves are processed after they are picked. For black tea, freshly picked leaves are "withered" indoors and allowed to oxidize. With green tea, the leaves are not oxidized, but are steamed and parched to better preserve the natural active substances of the leaf.
     Experts who compare patterns of disease frequency around the world have found that people who drink more than four cups a day of green tea seem to have a lower overall risk of cancer. But scientists did not know for sure how the tea produced these effects.
      Morre and her husband, who is the Dow Distinguished Professor of Medicinal Chemistry and Molecular Pharmacology at Purdue, show in their independent study how green tea interacts with an enzyme on the surface of many types of cancer cells including breast, prostate, colon and neuroblastoma. This enzyme, called quinol oxidase, or NOX, helps carry out several functions on the cell surface and is required for growth in both normal and cancerous cells.

Blocks Tumor Cell Growth

      "Normal cells express the NOX enzyme only when they are dividing in response to growth hormone signals," Dorothy Morre says. "In contrast, cancer cells have somehow gained the ability to express NOX activity at all times." This overactive form of NOX, known as tNOX -- for tumor-associated NOX -- has long been assumed to be vital for the growth of cancer cells, because drugs that inhibit tNOX activity also block tumor cell growth in culture.
      After hearing a researcher discuss green tea's anti-cancer potential on a television show, the couple set out to investigate whether tea infusions -- made when the compounds of tea leaves leach into hot water -- would have an effect on tNOX enzyme activity. In studies of cultured cells and isolated membranes of cells, they found that black tea could inhibit tNOX activity at dilutions of one part tea to 100 parts of water. The green tea infusions, however, were 10 to 100 times more potent, inhibiting the activity of tNOX at dilutions ranging from one part tea per 1,000 to 10,000 parts water.
      "This finding suggested that green tea leaves are rich in a compound that inhibits tNOX," Dorothy Morre says. "With concentrations of the active compound at these levels, drinking several cups of green tea per day might inhibit the growth of cancer cells in the body."

New Acronyms to Learn -- EGCg Inhibits tNOX

      To pinpoint the active compound, Morre and her husband tested a number of compounds found in tea. Among them, they tested epigallocatechin gallate, or EGCg, a primary component of green tea already linked to anti-cancer effects. Their studies, done with cultured cells and with purified NOX protein in solutions, found that EGCg was capable of inhibiting the tNOX activity of cancer cells at low doses -- requiring only several cups of green tea per day -- but did not inhibit the NOX activity of healthy cells. The Morres also found that EGCg inhibits the growth of, and kills, cancerous human mammary cells in culture, but does not kill cultured, non-cancerous human mammary cells.
      The Purdue team also determined how the cancer cells died. "In the presence of EGCg, the cancer cells literally failed to grow or enlarge after division," Dorothy Morre says. "Then, presumably because they did not reach the minimum size needed to divide, they underwent programmed cell death, or apoptosis."
      Others who worked on the research are Andrew Bridge, a premed student at Wabash College in Crawfordsville, Ind.; Peichuan Sun, a graduate student supervised by Dorothy Morre; and Lian-Ying Wu, a research technologist at Purdue. Dorothy Morre says that further work is needed to understand how tNOX works in cancer cell growth. "For now, it is sufficient to know that when tNOX activity is inhibited, the cancerous cells eventually die," she says.

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