Brewing up potential anti-cancer drugs from green tea

Drinking green tea has a protective effect against some forms of cancer but drinking large amounts can increase the risk of birth defects such as spina bifida – according to previous epidemiological studies.

Today, scientists have reported that a naturally occurring polyphenol (EGCG) isolated from green tea leaves inhibits the growth of cancer cells, in vitro, when present at the low concentrations found in the blood and other tissues of green tea drinkers. EGCG binds to the enzyme DHFR, an established target for anticancer drugs and also implicated in birth defects. EGCG could provide the starting point for a new family of anti-cancer drugs. The research was conducted by a team of scientists at the University of Murcia (UMU), Spain , in collaboration with the John Innes Centre (JIC) Norwich, UK .

“This is a very exciting discovery” said Professor Roger Thorneley (leader of the JIC team). “For the first time we have a clear scientific explanation of why EGCG inhibits the growth of cancer cells at concentrations which are found in the blood of people who drink 2 or 3 cups of green tea a day. We have identified the enzyme in tumour cells that EGCG targets and understand how it stops this enzyme from making DNA. This means we may be able to develop new anticancer drugs based on the structure of the EGCG molecule”.

Dr José Neptuno Rodríguez-López (Initiator of the project and leader of the UMU team) takes up the story. “We decided to look at EGCG because we recognised that its structure is very similar to that of the successful anti-cancer drug methotrexate. We discovered that EGCG can kill cancer cells in the same way as methotrexate. However, because EGCG binds to the target enzyme less tightly than methotrexate, it should have decreased side effects on healthy cells. We are now using EGCG as the starting point to design and develop effective new anti-cancer drugs that kill tumour cells but inflict less damage on healthy cells.”

A prophylactic effect of green tea drinking on certain forms of cancer has been suggested by epidemiological studies. The structure of EGCG resembles methotrexate which kills cancer cells by binding to, and inactivating, the enzyme dihydrofolate reductase (DHFR). The research team found that EGCG also binds strongly to DHFR and stops it functioning. DHFR is essential to DNA synthesis in both normal and tumour cells. However tumour cells grow and divide more quickly than normal cells, processes requiring more DNA synthesis and therefore higher levels of DHFR activity. A range of therapeutic agents, called antifolates, exploit the difference in DHFR requirement of cancerous and normal cells to selectively kill cancer cells. Importantly, at the concentrations found in green tea drinkers’ blood and other tissues, EGCG also kills cancer cells. New types of antifolate drugs are being developed by pharmaceutical companies because methotrexate and related drugs cause a very significant amount of damage to healthy cells (i.e. adverse side effects) particularly in the liver and bone marrow. EGCG has considerable potential as a “lead compound” for the development of new anticancer drugs.

However, the research team also sound a note of caution. Epidemiological studies have linked high levels of green tea consumption by women, around the time of conception and in pregnancy, to an increased incidence of spina bifida and anencephaly. These are neural tube defects associated with folic acid deficiency. (Folic acid is recommended as a food supplement for women trying to become pregnant and subsequently during pregnancy because it helps to protect against these defects). In green tea drinkers EGCG’s antifolate activity would be expected to significantly decrease folic acid levels and minimise the positive effects of folic acid supplements. Thus this new research provides a possible biochemical explanation for the epidemiological link between heavy green tea drinking and an increased incidence of birth defects.

http://www.jic.ac.uk/