Chapter 23
Modulation of Mitotic Signal Transduction by Curcumin and Tea Polyphenols and Their Implication for Cancer Chemoprevention Jen-Kun Lin, Yu-Chih Liang, Yu-Li Lin, Yen-Chou Chen, and Shoei-Yn Lin Shiau
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Laboratory for Cancer Research, Institutes of Biochemistry and Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
It has been demonstrated that diets rich in fruits and vegetables are protective aganist cardiovascular diseases and certain forms of cancer. These protective effects have been attributed to the antioxidant present, including vitamin C, Carotenes and phytopolyphenols. The polyphenolic components of higher plants may act as anti-oxidants (sometimes may be as pro-oxidants), or as agents of other mechanisms, contributing to the anti-carcinogenic or cadioprotective action, Curcumin is a widely used dietary pigment (curry), and this polyphenolic compound has been demonstrated to be an inhibitor of tumor promotion in chemical carcinogenesis. Recent studies also indicate that tea polyphenols are active in inhibiting the processes of carcinogenesis induced by various carcinogens. Investigations from this laboratory and others have indicated that modulation of mitotic signal transduction may attribute, in part, to the molecular mechanisms of these cancer chemopreventive agents.
Carcinogenesis is a multiple process comprising initiation, promotion and progression. Multistage models of carcinogenesis have been developed for various tissues and animal species, for mechanistic investigations (7, 2). These animal models have played important roles as in vivo test systems in the identification of exogenous and/or endogenous agents exerting a role in enhancement, or prevention, of various stages of carcinogenesis (2). It has been suggested that intervention of the carcinogenesis process by chemical means, namely cancer chemoprevention, can affect at any of the three stages. However, the promotion stage, because of its reversibility may be a particularly attractive candidate for chemical intervention. Tumor promotion has been described as the clonal expansion or proliferation of an
©1998 American Chemical Society
Shibamoto et al.; Functional Foods for Disease Prevention I ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
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226 initiated cell. Two distinct effects of tumor promoting chemicals have been demonstrated : direct mitogenic effects (proliferation), and the induction of cell lethality (apoptosis). It is apparent that cell proliferation, induced through mitogenic effects may occur directly by interaction of the chemical with a receptor. It may also occur by direct modification of gene expression, or indirectly by the modification of growth factors or hormonal stimulation/inhibition. Meanwhile, tumor promotion may also be induced through partial cytolethal means ; the induction of cell death by a chemical in the target tissue results in a compensatory increase in cell proliferation in the surrounding surviving cells (5). A number of tumor promoters have been shown to produce free oxygen radicals in cells and tissues (Oxygen radicals have been demonstrated to participate in mouse skin tumor promotion) (4). The production of reactive oxygen species (ROS) either extracellularly or intrcellularly, by tumor promoting compounds, has been associated with the tumor promotion stage in several animal model systems (4,5). If the formation of ROS and the resulting damage to cellular proteins, lipids and/or nucleic acids are important in this stage of promotion, then chemopreventive agents that function through anti-oxidant mechanisms may be effective in preventing the transcription of the initiated cell to the neoplastic state. Anti-oxidants are available from both natural and synthetic sources. Chinese herbal medicine such as tumeric and tea are two important plants containing strong antioxidants. Chinese green tea, in particular is composed of several catechin polyphenols. These tea polyphenols have anti-oxidant properties and have been demonstrated to be anticarcinogenic as well as antimutagenic (
