Curr. Med. Chem. - Anti-Cancer Agents, 2002, 2, 441-463 441 1568-0118/02 $35.00+.00 © 2002 Bentham Science Publishers Ltd. Green Tea Catechins as Novel Antitumor and Antiangiogenic Compounds Michel Demeule, Jonathan Michaud-Levesque, Borhane Annabi, Denis Gingras, Dominique Boivin, Julie Jodoin, Sylvie Lamy, Yanick Bertrand, and Richard Béliveau* Laboratoire de Médecine Moléculaire, UQAM-Hôpital Sainte-Justine, Montréal, Canada Abstract: The concept of cancer prevention by use of naturally occuring substances that could be included in the diet is under investigation as a practical approach towards reducing cancer incidence, and therefore the mortality and morbidity associated with this disease. Tea, which is the most popularly consumed beverage aside from water, has been particularly associated with decreased risk of various proliferative diseases such as cancer and atherosclerosis in humans. Various studies have provided evidence that polyphenols are the strongest biologically active agents in green tea. Green tea polyphenols (GTPs) mainly consist of catechins (3-flavanols), of which (-)-epigallocatechin gallate is the most abundant and the most extensively studied. Recent observations have raised the possibility that green tea catechins, in addition to their antioxidative properties, also affect the molecular mechanisms involved in angiogenesis, extracellular matrix degradation, regulation of cell death and multidrug resistance. This article will review the effects and the biological activities of green tea catechins in relation to these mechanisms, each of which plays a crucial role in the development of cancer in humans. The extraction of polyphenols from green tea, as well as their bioavailability, are also discussed since these two important parameters affect blood and tissue levels of the GTPs and consequently their biological activities. In addition, general perspectives on the application of dietary GTPs as novel antiangiogenic and antitumor compounds are also presented. INTRODUCTION The benefits of green tea in increasing alertness and staving off disease have been known for centuries. Most historians and botanists now believe that tea plant culture first began in China and was most likely brought to India, Korea, Sri Lanka and Japan; the human use of green tea is believed to have originated more than 5000 years ago [1, 2]. Various legends exist regarding the origins of tea. One of them is the story where the Emperor Sh'eng Nung took the first sip of tea about 2737 B.C. [2]. The legend holds that the emperor was relaxing outdoors under a tree for a royal nap listening to the perky bubbling of a small cauldron of water over a nearby fire. A gentle breeze wafted through the nearby trees, carrying with it a few leaves, which casually dropped into the boiling water. A less curious person would simply have thrown out the leaves or considered them a nuisance, but the emperor was intrigued by the aroma that resulted from this unexpected marriage of leaf and water. Ever game, he scooped a little of the leaf-spotted water into a small cup, and dared a sip… then another and another. Soon he sent his servant to fetch more leaves, and a new beverage was born from the tree we now know as Camellia sinensis. The beneficial detoxification effects of tea leaves was first reported in a Chinese book on pharmaceutical plants written about 200 B.C. [3]. Tea was first considered as a *Address correspondence to these authors at the Laboratoire de Médecine Moléculaire, Université du Québec à Montréal-Hôpital Sainte- Justine, C.P. 8888, Succursale Centre-ville, Montréal, Québec, Canada H3C 3P8; Tel: (514) 987-3000, Ext. 8551; Fax: (514) 987-0246; E-mail: oncomol@nobel.si.uqam.ca medicine until the Tang dynasty (A.D. 618-907), when tea was finally recognized and accepted as a beverage. For centuries, until the Ming dynasty (A.D. 1368-1644), green tea was the only type of tea produced in its homeland. In the early 8 th century, green tea was transferred to Japan from China for medicinal use and historical records cite the existence of a powdered tea called hiki-cha (a very rough powdered tea, similar to the matcha green tea), which was bestowed upon priests summoned to the court of Japanese Emperor Shomu about A.D. 729. Later, in the 15 th century, Japan ennobled tea into a religion of estheticism – teaism [4]. Since then more than twenty schools of tea ceremony or tea cult have been developed, and the ceremonies themselves differ from very simple to hours-long elaborate performances [2]. Already in A.D. 1211, a renowned Zen Buddhist priest and teacher (Eisai, Kitcha Yojoki) said that “tea is a miraculous medicine for the maintenance of health, an extraordinary power to prolong life and anywhere a person cultivates tea, long life will follow” [2]. More recently pharmacologists, chemists, physicians, nutritionists and others in the field of science are recognizing the beneficial properties associated with daily consumption of green tea. Of particular interest are studies reporting that green tea reduces the risk of cancer, one of the major causes of mortality throughout the world [5, 6]. Like other chronic diseases, the main underlying causes of cancer are environmental in nature. Humans are exposed to a variety of carcinogens including tobacco smoke, alcoholic drinks, industrial carcinogens, aflatoxins, heterocyclic amines, N- nitroso compounds and polycyclic aromatic hydrocarbons. Dietary intervention is one way of influencing carcinogen metabolism. A wide variety of bioactive compounds and