Green Tea Constituent and Induction of Apoptosis in Human Carcinoma Cells
The term “Chemoprevention” is coined for cancer prevention and cancer control by use of naturally occurring and/or synthetic compounds. The occurrence of the disease may be completely prevented, blocked, or reversed. This approach is promising because chemotherapy and surgery have not been fully effective against the high incidence or low survival rate of most of the cancers. In this regard, the naturally occurring antioxidants present in the diet and beverages consumed by humans are receiving increasing attention.
Tea consumption in the world is very high and ranks second to water consumption. Most tea consumed in the world can be classified in two forms, green tea (approximately 20 percent) and black tea (approximately 80 percent). Extensive studies from laboratories over the last 10 years have verified cancer chemopreventive effects of a polyphenol mixture derived from green tea against many animal tumor bioassay systems. In these studies, oral consumption or topical application of green tea polyphenols or its major constituent, epigallocatechin-3-gallate, has been shown to offer protection against all stages of multistage carcinogenesis that include initiation, promotion, and progression. A 1992 study by Wang et al. has also shown that green tea consumption can inhibit the growth of established skin papillomas in mice. Epidemiologic studies have not provided conclusive results but tend to suggest that green tea may reduce the risk associated with cancers of the bladder, prostate, esophagus, and stomach.
Deciphering the molecular mechanism by which green tea imparts the protective effects is important because it may provide opportunities to interfere with cancer development through administration of purified polyphenolic derivatives. Green tea appears to be potentially an ideal agent for chemoprevention because it has the following characteristics:
High efficacy against multiple sites;
Effectiveness at achievable dose levels;
Capability for oral consumption;
A known mechanism of action;
History of use by the human population; and
General human acceptance.
Cancer chemopreventive agents may alter the regulation of cell cycle. Treatment with such agents may result in cell cycle arrest, thereby reducing the growth and proliferation of cancerous cells, and may also affect the malignant transformation. It has been suggested that tumor growth depends on evasion of normal control mechanisms that operate through a programmed deletion of cells (i.e., apoptosis).
To further explore this theory, in 1997 N. Ahmad, D. K. Feyes, R. Agarwal, H. Muktar, and A. L. Nieminen of the School of Medicine, Case Western Reserve University in Cleveland, OH set up an in vitro study to investigate if green tea polyphenols and the major constituent, epigallocatechin-3-gallate, induced apoptosis and perturbed cell cycle progression in carcinoma cells. Since epigallocatechin-3-gallate is the major constituent present in green tea polyphenols (approximately 50 percent, wt/wt), they performed all the subsequent experiments with epigallocatechin-3-gallate.
As part of their ongoing large-scale program on cancer chemoprevention through diatary constituents, the main aim of the study was to elucidate the mechanism of antitumorigenic effect of epigallocatechin-3-gallate, the major polyphenolic agent present in green tea, and to determine if it directly affects the cell cycle regulation and apoptosis. Apoptosis in recent years has become an important issue in biomedical research. The life spans of both normal and cancer cells within a living system are regarded to be substantially affected by the rate of apoptosis. In addition, apoptosis is a discrete way of cell death different from necrotic cell death and regarded to be an ideal way of cell elimination. Thus, the chemopreventive agents which can modulate apoptosis may be able to affect the steady-state cell population that are often useful targets in the management and therapy for cancer.
In their study, Ahmad et al. demonstrated that green tea polyphenols and their constituents resulted in an induction of apoptosis in A431 cells. Important to note was the fact that epigallocatechin-3-gallate resulted in the induction of apoptosis in all carcinoma cells but not in the normal cells they examined. This selectivity, if it can be observed in vivo at the desirable doses, will be of great therapeutic importance. A vast variety of the chemotherapeutic agents currently used in cancer therapy are thought to kill the cells by the mechanisms other than apoptosis. This may not always be a preferable way of cancer management. Ahmad et al.‘s results showing the induction of apoptosis by epigallocatechin-3-gallate is of importance because its treatment of A431 cells did not cause any necrosis as evident from the confocal microscopy. Moreover, the four different carcinoma cells used in their study had origins from different body sites. This showed that epigallocatechin-3-gallate may be useful against many, if not all, types of cancers. The demonstration of induction of apoptosis by epigallocatechin-3-gallate is also important because green tea is a well-consumed beverage worldwide and has shown promising cancer chemopreventive effects in both laboratory experiments and human epidemiologic studies.
The effect of epigallocatechin-3-gallate in arresting the A431 cells in some phases of the cell cycle suggests the possibility that green tea may also be useful for the control of cancer growth. Based on their findings and on the extensive amount of laboratory and epidemiology data available, Ahmad et al. suggested that clinical trials with epigallocatechin-3-gallate are needed in a population with high cancer risk.
Vol. 89, No. 24, December 17, 1997