Brewing up potential anti-cancer drugs from green tea
Contact:
JIC Press Office 01603 450000
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 [1], in collaboration with
the John Innes Centre (JIC) Norwich, UK [2].
“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 [3] 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.
The research was funded by the European Union [4].
The research is published in the International Journal ‘Cancer Research’
[5].
The inventors (J.N. Rodríguez-López, J. Cabezas-Herrera, and E. Navarro-Perán)
and the patent holder (UMU) have assigned the intellectual property
rights associated with this discovery to the British company Plant Bioscience
ltd. [6]
Notes for editors:
- The University of Murcia (UMU) is an institution devoted to providing
higher education to the public. Among its main objectives are the
creation, development and research into science, technology and culture
through study and research and the transmission of such knowledge
through education. UMU has over 30000 students and almost 2000 staff.
The work presented here was carried out in the Department of Biochemistry
and Molecular Biology A which possesses facilities for the study of
enzymology, protein structure, and cell culture applied to cancer
research.
- The John Innes Centre (JIC), Norwich , UK is an independent, world-leading
research centre in plant and microbial sciences. The JIC has over
850 staff and students. JIC carries out high quality fundamental,
strategic and applied research to understand how plants and microbes
work at the molecular, cellular and genetic levels. The JIC also trains
scientists and students, collaborates with many other research laboratories
and communicates its science to end-users and the general public.
The JIC is grant-aided by the Biotechnology and Biological Sciences
Research Council.
- The gallated polyphenol (-)-epigallocatechin gallate (EGCG), is
an inhibitor of dihydrofolate reductase (DHFR) activity in vitro at
concentrations found in the serum and tissues of green tea drinkers
(0.1 - 1.0 µM). EGCG binding to bovine liver DHFR had kinetics characteristic
of a slow, tight-binding inhibitor of DHF reduction (K I = 0.109 µM),
but of a classical, reversible, competitive inhibitor of chicken liver
DHFR (K I = 10.3 µM).
Polyphenols lacking the ester bonded gallate moiety ( i.e. EGC
and EC), did not inhibit bovine DHFR activity. These results indicate
that the ester bonded gallate moiety is essential for potent inhibition
of bovine liver DHFR. A green tea extract containing significant
amounts of EGCG strongly inhibited the DHFR activity of both the
bovine and chicken liver enzymes.
Responses of cultured lymphoma cells to EGCG and known antifolates
were similar i.e. a dose dependent inhibition of cell growth (IC
50 = 20 µM for EGCG), G0/G1 phase arrest of the cell cycle, and
induction of apoptosis. Folate depletion increased the sensitivity
of cell lines to antifolates and EGCG. These effects were attenuated
by growing cells in a medium containing hypoxanthine-thymidine,
consistent with DHFR being the site of action for EGCG.
- European Union INTAS Program, Project INTAS00-0727.
- Cancer Research can be contacted at: CANCER RESEARCH Editorial Office
615 Chestnut St., 17th Floor, Philadelphia , PA 19106 , voice: (215)440-9300,
fax: (215)440-9354 E-mail address: cancerres@aacr.org
- PBL is a for-profit technology transfer and intellectual property
management company specializing in plant and microbial science and
is the intellectual property management company of the John Innes
Centre and the Sainsbury Laboratory. All enquiries regarding the commercial
exploitation of this IPR should be addressed to PBL (www.pbltechnology.com)
who may be contacted on 01603 456500.
