Anticarcinogenic Effects of Dietary Phytoestrogens and Their Chemopreventive Mechanisms

Hwang K-A, Choi K-C. Nutrition and Cancer. 9 Apr 2015 DOI:10.1080/01635581.2015.1040516

Phytoestrogens are phenolic compounds derived from plants and exert an estrogenic as well as an anti-estrogenic effect and also various biological efficacies. Chemopreventive properties of phytoestrogens has emerged from epidemiological observations indicating that the incidence of some cancers including breast and prostate cancers is much lower in Asian people, who consume significantly higher amounts of phytoestrogens than Western people. There are 4 main classes of phytoestrogens: isoflavones, stilbenes, coumestans, and lignans.

Currently, resveratrol is recognized as another major phytoestrogen present in grape and red wine and has been studied in many biological studies. Phytoestrogens have biologically diverse profitability’s and advantages such as low cytotoxicity to patients, lack of side effects in clinical trials, and pronounced benefits in a combined therapy. Hwang & Cho (2015) highlight the effects of genistein, daidzein, and resveratrol in relation with their anti-carcinogenic activity.

Besides well-known mechanisms such as antioxidant property and apoptosis, newly elucidated anti-carcinogenic modes of action including epigenetic modifications and topoisomerase inhibition have been provided to examine the possibility of phytoestrogens as promising reagents for cancer chemoprevention and/or treatment and to suggest the importance of plant-based diet of phytoestrogens.

Resveratrol

Although the wide-ranging benefits of Resveratrol per se, have only fully emerged recently, the proanthocyanidin class of compounds has actually been extensively studied beginning in the 1970's, for their powerful vascular wall strengthening properties and free radical scavenging activity. Proanthocyanidins are a highly specialized group of bioflavonoids and are one of the most potent free radical scavengers known, possessing an antioxidant effect up to 50 times more potent then vitamin E and up to 20 times more powerful then vitamin C. Proanthocyanidins have been well understood for their cell membrane building capability, providing nutritional support to reduce capillary permeability and fragility. In the vascular system the anthocyanidins supports the integrity of vascular walls by increasing vitamin C levels within cells, decreasing the permeabilizing effect of proteolytic/lysosomal enzymes, stimulating the synthesis of collagen and connective tissue, and stabilizing cell membranes.

Resveratrol is also a member of a group of compounds called phytoalexins that are produced by plants during times of environmental stress such as adverse weather, pathogenic attack, insect attack or lack of nutrients. Resveratrol has been identified in more than 70 species of plants, including grapes, cranberries, mulberries, peanuts, and. Polygonum.

Resveratrol is also classified as a Phytoestrogen. Phytoestrogens are substances in plants that mimic the beneficial effects of o estrogen in the human body but without the potential harmful effects associated with estrogen REPLACE ment therapy. In fact phytoestrogens are known for their ability to protect against estrogen related cancers such as breast cancer in women and prostate cancer in men. As men age, testosterone increasingly breaks down into estrogen, a well-known carcinogen. By occupying estrogen receptor sites, phytoestrogens prevent estrogen-associated cancer in both sexes.

Mechanism of Action

Resveratrol is a polyphenolic compound that exists in nature as cis- and trans- stereoisomers. Resveratrol is primarily found in red wine, red grape skins, purple grape juice, mulberries, and in smaller amounts in peanuts. Other sources include eucalyptus (Eucalyptus wandoo, Eucalyptus sideroxylon), spruce (Picea excelsa), and Bauhinia racemosa. Polygonum cuspidatum, the roots of which are used in Chinese and Japanese traditional medicine, is considered to be one of the richest sources of trans-resveratrol.

The trans-resveratrol content of wine is highly dependent on grape type, climate, and practices used to make the wine. White wines have very low trans-resveratrol concentrations. Pinot Noir consistently has the highest concentrations of trans-resveratrol, regardless of climate. Other red wines, including Cabernet Sauvignon, produced in cold, humid climates, such as Bordeaux and Canada, have higher trans-resveratrol content than those produced in hot, dry climates. Unfermented grape juice does not contain resveratrol. Resveratrol is not found in significant quantities in fermented grape beverages that are stored in oak barrels, such as cognac.

Resveratrol is rapidly absorbed with peak concentrations occurring within 30 minutes. Resveratrol is conjugated in the intestine and absorbed as the conjugated form. In plasma, resveratrol is found primarily as glucuronide or sulfate form. In vitro research has been done with unconjugated resveratrol. It is questionable whether free resveratrol absorption is sufficient to exert a pharmacologic effect. Research in humans suggests that quercetin taken orally doesn't reach serum concentrations at which in vitro activity has been seen.

Resveratrol is a weak phytoestrogen. It binds to both alpha and beta estrogen receptors, but its affinity for these receptors is about 7,000 times less than estrogen.

Resveratrol decreases the activity of inflammatory cytokines, which suggests a mechanism for reducing mortality in cardiovascular diseases and cancer. Early research suggests resveratrol might reduce the risk of cancer. Biological activity in humans has not yet been described. Preliminary evidence suggests that trans-resveratrol has antioxidant and anti-mutagenic activity. It may also inhibit tumor growth and promote apoptosis. Preliminary evidence suggests that trans-resveratrol interferes with blood coagulation by inhibiting cyclooxygenases 1 and 2 (COX-1 and COX-2), hydroperoxidases, 5-lipoxygenase, and platelet aggregation. It also causes blood vessel dilation.

The anti-inflammatory effects of resveratrol also suggest potential usefulness for inflammatory diseases such as arthritis. Preliminary evidence suggests resveratrol is a more potent anti-inflammatory agent than either aspirin or ibuprofen; resveratrol seems to inhibit COX-1 and COX-2.

Resveratrol inhibits formation of cholesterol in certain strains of bacteria, but it is not known if this contributes significantly to cholesterol lowering in humans. In human colon cancer cells, resveratrol inhibits cell division and function of RNA and DNA. These effects are reversible and cell growth resumes 40 hours after exposure. Preliminary data suggest that resveratrol may prevent liver cancer cells from invading local tissues. Resveratrol inhibits the replication of herpes simplex virus. Although the mechanism of this action is not fully known, exposure to resveratrol within one hour of cellular infection appears to be most effective in arresting viral growth. This suggests that resveratrol reduces production of proteins needed to regulate viral proliferation.

Resveratrol (trans-3,5,4'-trihydroxystilbene), a compound found largely in the skins of red grapes, is a component of Ko-jo-kon, an oriental medicine used to treat diseases of the blood vessels, heart (Celotti et al., 1996) and liver (Soleas et al., 1997). It came to scientific attention only four years ago, however, as a possible explanation for the "French Paradox" -- the low incidence of heart disease among the French people, who eat a relatively high-fat diet (Kopp, 1998). 

Sources

While present in other plants, such as eucalyptus, spruce, and lily, and in other foods such as mulberries and peanuts, resveratrol's most abundant natural sources are Vitis vinifera, labrusca, and muscadine grapes, which are used to make wines. It occurs in the vines, roots, seeds, and stalks, but its highest concentration is in the skin (Celotti et al., 1996), which contains 50-100 micrograms (ug) per gram (Jang et al., 1997). Resveratrol is a phytoalexin, a class of antibiotic compounds produced as a part of a plant's defense system against disease (Celotti et al., 1996). For example, in response to an invading fungus, resveratrol is synthesized from p-coumaroyl CoA and malonyl CoA (Soleas et al., 1997). Since fungal infections are more common in cooler climates, grapes grown in cooler climates have a higher concentration (Kopp, 1998).

The resveratrol content of wine is related to the length of time the grape skins are present during the fermentation process. Thus the concentration is significantly higher in red wine than in white wine, because the skins are removed earlier during white-wine production, lessening the amount that is extracted (Kopp, 1998). Grape juice, which is not a fermented beverage, is not a significant source of resveratrol. A fluid ounce of red wine averages 160 ug of resveratrol, compared to peanuts, which average 73 ug per ounce (Sanders & McMichael, 1998). Since wine is the most notable dietary source, it is the object of much speculation and research.

Cardiovascular Effects

Many studies suggest that consuming alcohol (especially red wine) may reduce the incidence of coronary heart disease (CHD). Several studies have demonstrated that resveratrol is an effective antioxidant (Chanvitayapongs et al., 1997; Belguendouz et al., 1998; Rotondo et al., 1998; Frankel et al., 1993). It inhibits lipid peroxidation of low-density lipoprotein (LDL) (Chanvitayapongs et al., 1997; Belguendouz et al., 1998), prevents the cytotoxicity of oxidized LDL, and protects cells against lipid peroxidation (Chanvitayapongs et al., 1997). It is thought that because it contains highly hydrophilic and lipophilic properties, it can provide more effective protection than other well-known antioxidants, such as vitamins C and E (Chanvitayapongs et al., 1997). On the other hand, it is less effective than the antioxidants quercetin and epicatechin found in red wine (Soleas et al., 1997). Reduced platelet aggregation has also been demonstrated in studies on resveratrol, further contributing to its prevention of atherosclerosis (Soleas et al., 1997; Rotondo et al., 1998). To date, most of the research on resveratrol's antioxidant and anti-platelet properties has been done in vitro (in an artificial environment using test-tube or tissue-culture preparations). Further studies in animals and humans are necessary to determine whether resveratrol supplementation makes sense.

Cancer-Related Effects

Resveratrol is being studied to see how it affects the initiation, promotion, and progression of cancer. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation, and as an anti-mutagen in rat models (Jang et al., 1997). Resveratrol appears to decrease tumor promotion activity by inhibiting cyclooxygenase-1 (COX-1) (Jang et al., 1997; Frankel et al., 1993; Clement et al., 1998), an enzyme that converts arachidonic acid to pro-inflammatory substances that stimulate tumor-cell growth (Kopp, 1998). Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation (Jang et al., 1997) and inhibited ribonucleotide reductase, an enzyme needed for DNA synthesis in proliferating cells (Fontecave et al., 1998). One appealing characteristic of resveratrol's anti-cancer potential is its minimal toxicity to blood-forming cells (Clement et al., 1998).

Cancer and Resveratrol

Cancer is, perhaps, the most dynamic area of resveratrol research. Resveratrol is the first natural medicinal to have solid evidence behind it showing that it blocks or stops many stages of cancer. Resveratrol not only prevents cancer, it's being proposed as an additional treatment (Cal et al., 2003; Pervaiz, 2001; Ding et al., 2002).

The number of studies has exploded in the past three years, with the depth of knowledge about this polyphenol increasing with each report. Resveratrol is a broad-spectrum agent that stops cancer in many diverse ways, from blocking estrogen and androgens to modulating genes (Gusman et al., 2001; Lu et al., 1999; Serrero et al., 2001; Mitchell et al., 1999).

Some of the latest information about it shows that resveratrol causes a unique type of cell death (Cal et al., 2003), and kills cancer cells whether they do or do not have the tumor suppressor gene, p53. [21] It also works whether cancer cells are of estrogen receptor-positive or negative (Lu, R. et al., 1999; Pozo-Guisado et al., 2002).

In addition to these findings, researchers are beginning to uncover the ability of resveratrol to augment other chemotherapies. For example, vitamin D3 converts to a steroid that inhibits the growth of breast cancer cells. Researchers at the University of Notre Dame have shown that resveratrol increases the effects of vitamin D (Wietzke et al., 2003). Other research shows that it causes drug-resistant non-Hodgkin's lymphoma cancer cells to become susceptible to chemotherapeutic drugs (Gemcetabine, Navelbine, cisplatinum, Paclitaxel, and TRIAL) (Cal et al., 2003).

Researchers in Austria have done elaborate studies showing that resveratrol blocks the ability of cancer cells to metastasize to bone (30-71%) (Ulsperger et al., 1999). The highest results were for pancreas, breast, and renal cancer. Prostate and colon cancers were also inhibited, but not as much. Resveratrol also acts against a component of the Western diet that promotes cancer cell growth: linoleic acid. Linoleic acid is converted to arachidonic, which is converted to hormone-like substances (such as prostaglandin E2 and leukotriene B4) that can promote inflammatory processes that stimulate cancer cell growth, among other things. It has been demonstrated that the Western diet can cause colon cancer in rodents without any other chemical or factor being necessary (Lipkin et al., 1999). In a study from Japan, resveratrol in an amount easily obtained by supplementation, inhibited the growth of breast cancer cells, and blocked the growth-promoting effects of linoleic acid from the Western diet (Nakagawa et al., 2001).

Researchers in Austria have done elaborate studies showing that resveratrol blocks the ability of cancer cells to metastasize to bone (30-71%) (Ulsperger et al., 1999 ). The highest results were for pancreas, breast, and renal cancer. Prostate and colon cancers were also inhibited, but not as much. Resveratrol also acts against a component of the Western diet that promotes cancer cell growth: linoleic acid. Linoleic acid is converted to arachidonic, which is converted to hormone-like substances (such as prostaglandin E2 and leukotriene B4) that can promote inflammatory processes that stimulate cancer cell growth, among other things. It has been demonstrated that the Western diet can cause colon cancer in rodents without any other chemical or factor being necessary (Lipkin et al., 1999). In a study from Japan, resveratrol in an amount easily obtained by supplementation, inhibited the growth of breast cancer cells, and blocked the growth-promoting effects of linoleic acid from the Western diet (Nakagawa et al., 2001). 

Resveratrol works against a wide range of cancers, both at the preventive and treatment stages. Its ability to stop cancer is connected to its capability, first, to distinguish a cancer cell from a normal cell. Unlike chemotherapeutic drugs that affect normal as well as cancer cells, resveratrol does not damage healthy cells. Not only is it not harmful to normal cells, it protects them (Zhuang et al., 2003; Floreani et al., 2003). Second, resveratrol is sophisticated in its actions. It doesn't just scavenge free radicals; it activates and deactivates critical enzymes and genes, hormones and chemicals (Ferguson, 2001; Casper, R.F. et al., 1999; Hsieh et al., 1999).

Resveratrol, the Anti-Cancer Agent

The field of cancer study is one of the most dynamic areas of Resveratrol research. Resveratrol is the first natural medicinal compound with extensive evidence that it blocks or stops many different stages and types of cancer. It is effective at all three phases of the cancer process: initiation, promotion and progression. The results have been so promising that many researchers now propose that Resveratrol be used not only as a cancer preventative agent, but also as a non-toxic chemotherapeutic treatment. The number of Resveratrol related cancer studies have exploded in the past several years. Resveratrol turns out to be a wide spectrum effective agent that fights cancer in a multitude of ways, ranging from blocking estrogenic tumor promoting activity to differentially initiating apoptosis (programmed cell death) on DNA-damaged cells while promoting the health and repair of normal cells. How is it that Resveratrol works against such a wide variety of cancers, both at the preventive and treatment levels? The answer in a nutshell is that Resveratrol is very smart. It appears that this capability is connected to its ability, to distinguish a cancer cell from a normal cell. Unlike dumb chemotherapy drugs that indiscriminately affect both cancerous and normal cells, Resveratrol not only properly discriminates between the types of cells, but also actually protects them, and helps them to repair and regenerate. Once a cell is identified as friend or foe, Resveratrol's mode of operation appears to be very sophisticated and diverse depending on the conditions. Scavenging and destroying harmful free radicals is only the first step in Resveratrol's formidable arsenal of operations. It also activates or deactivates critical genes, enzymes, hormones and other chemicals selectively as the need and circumstances arise and change.

Pezzuto and colleagues reported that resveratrol holds great promise for future development as a chemo preventive agent that may be useful for several disorders. They found Resveratrol to be effective during all stages of the disease. Resveratrol was first shown to act as an antioxidant and anti-mutagenic agent, thus acting as an anti-initiation agent, and also increased levels of the phase II drug-metabolizing enzyme quinone reductase, an enzyme capable of metabolically detoxifying carcinogens, thereby ridding them from the body. All three of these physiological effects are indicative of Resveratrol preventing cancer initiation, the initial, irreversible stage of the cancer process. They also demonstrated Resveratrol's anti-inflammatory effects and inhibition of activity of the cyclooxygenase and hydroperoxidase enzymes, thus conferring anti-promotion activity. The researchers also demonstrated that resveratrol effectively promoted the differentiation of human promyelocytic leukemia cells, indicative of inhibition of the progression phase of cancer. Resveratrol also inhibited the development of preneoplastic lesions in mouse mammary glands treated with a carcinogen in vitro and inhibited tumor formation in mice. No toxic effects were observed in any of these experiments.

Other research has shows that Resveratrol initiates a special type of apoptosis, killing cancer cells regardless of whether they have the tumor suppressor gene p53, or whether the cancer cells are estrogen receptor positive. Resveratrol has been shown to effectively enhance other chemotherapies. Researchers at the University of Notre Dame demonstrated that Resveratrol increases the cancer inhibiting effects of vitamin D3 on breast cancer. Austrian researchers have shown how Resveratrol blocks the capability of cancer cells to metastasize to bone tissue. Researchers in Japan report, "Thus, resveratrol could be a promising anticancer agent for both hormone-dependent and hormone-independent breast cancers, and may mitigate the growth stimulatory effect of linoleic acid in the Western-style diet."

A study presented by Dr Alberts at the Frontiers in Cancer Prevention Research meeting (abstract 1489) examined the effect of Resveratrol, on UVB-related skin damage. The researchers reported, "We're pleased to see that Resveratrol is able to modulate multiple signaling in the cells, which actually protects the skin cells from damages that may lead to the development of cancer," said Dr Nihal Ahmad, of the University of Wisconsin, and lead author of the study. "Further study should continue to support the argument to incorporate this agent into skin care products and regular diets, through the moderate consumption of grapes and red wine." Resveratrol significantly inhibited UVB-mediated increases in skin thickness and edema; epidermal cyclooxygenase (COX-2); ornithine decarboxylase (ODC) enzyme and protein levels; and protein levels of proliferating cell nuclear antigen (PCNA), all of which are established markers of tumor promotion. Resveratrol also further stimulated an UVB-mediated increase in p53 protein levels and was found to inhibit UVB exposure-mediated increases in cell cycle promoting signals including the activation of cell division. The researchers noted the need for promotion of such research. "The incidence of skin cancer is rising faster than any other solid tumor in the United States. It is critical that we develop novel approaches to both primary and secondary prevention of what appears to be becoming an epidemic."

In a review study of cancer chemoprevention by resveratrol: by Aziz MH, Kumar R and N Ahmad, the authors comment on the failure of conventional chemotherapy and aptly summarize the great promise offered by resveratrol: in the years to come.

Cancer, next only to heart diseases, is the second leading cause of deaths in the United States of America and many other nations in the world. The prognosis for a patient with metastatic carcinoma of the lung, colon, breast, or prostate (four of the most common and lethal forms of cancer, which together account for more than half of all deaths from cancer in the USA), remains dismal. Conventional therapeutic and surgical approaches have not been able to control the incidence of most of the cancer types. Therefore, there is an urgent need to develop mechanism-based approaches for the management of cancer. Chemoprevention via non-toxic agents could be one such approach. Many naturally occurring agents have shown cancer chemo preventive potential in a variety of bioassay systems and animal models, having relevance to human disease. It is appreciated that an effective and acceptable chemo preventive agent should have certain properties: (a), little or no toxic effects in normal and healthy cells; (b), high efficacy against multiple sites; (c), capability of oral consumption; (d), known mechanism of action; (e), low cost; and (f), acceptance by human population. Resveratrol is one such agent. A naturally occurring polyphenolic antioxidant compound present in grapes, berries, peanuts and red wine. In some bioassay systems resveratrol has been shown to afford protection against several cancer types.

Resveratrol's Anti-inflammatory Activity

Inflammation is a part of the body's immune response to injury or other life threatening conditions. If kept in check it can serve to help rid the body of invading bacteria or help protect against a variety of other adverse conditions. But in many chronic conditions inflammation causes much more harm than good. For example in autoimmune diseases, the immune system attacks the body's own tissues because it cannot distinguish between the legitimate cells and foreign intruders. In this case inflammation goes awry and the body attacks itself. Many pathological conditions including coronary heart disease, Alzheimer's, stroke, and cancer are exasperated by and in some cases caused by chronic inflammation. The gambit of inflammation-associated conditions is much wider than was once thought. It is now known that low level chronic inflammation plays a major role in many debilitating neurological disorders such as Alzheimer's and Huntington's disease. It is now believed by many researchers in the field of aging, that early long term intervention to reduce or prevent extended mild neurological inflammation may offer protection and possibly prevent many forms of age related dementia. Although memory failure and cognitive decline have long been accepted as a natural part of aging process, recent evidence suggests that much of this inflammation related decline might well be preventable.

Researchers in China recently demonstrated the efficacy of Resveratrol in the treatment of inflammation caused by spinal cord injury. When injected immediately after injury. Resveratrol reversed the inflammatory response as much as anti-inflammatory drugs but with the added benefit of improved energy compensation as well as providing free radical protection. The Resveratrol apparently inhibited specific enzymes that change the way individual cells over respond to the injury causing harmful inflammation.

British researchers reported that Resveratrol tested in vitro was able to dampen the inflammatory process in chronic obstructive pulmonary disease, an irreversible and progressive lung condition that eventually prevents breathing. The inflammatory process in this disease, include macrophages, cells that produce potent immune stimulating chemicals, such as interleukins. At the same time they produce chemicals to prolong cell life, but free radicals and inflammation are generated in the process. The researchers isolated macrophages from the lung fluid samples taken from fifteen smokers and fifteen other patients with COPD. The macrophages were then spurred into action by introducing interleukin or cigarette smoke. The result as expected was the production of interleukin 8, which was around five times as great in patients with COPD as it was in smokers. When Resveratrol was introduced the production of interleukin 8 was almost completely eliminated; by 94 per cent in smokers macrophages and by 88 per cent in COPD macrophages. The researchers concluded that Resveratrol inhibits inflammatory cytokine release from alveolar macrophages in COPD and may be an effective therapy for macrophage pathophysiology in the treatment of chronic obstructive pulmonary disease.

In a preliminary study, Draczynska-Lusiak et el at the University of Missouri showed that resveratrol protected the central nervous system from oxidative stress and stopped oxidation of lipoprotein particles. The researchers suggested that oxidized lipoproteins serve as an oxidative stressor, which initiates the neuronal cell death leading to long term neurological inflammation and the possible manifestation of Alzheimer disease. They showed that Resveratrol employs a "novel mechanism" for scavenging free radicals implicated in the process and suggested that resveratrol especially in combination with vitamins C and E can help inhibit this inflammatory process.

Researchers at the Department of Experimental Pathology and Microbiology, Pathology at Policlinico University in Italy concluded that a small regular dose of resveratrol confirms a protective role against some pathological processes such as inflammation, coronary heart disease, and cancer.

Researchers at Peking Union Medical College, in Beijing found that the inhibition of MMP-9 expression may be one of the anti-inflammatory mechanisms of resveratrol.

The research reference links below include more recent evidence of the anti-inflammatory activity of Resveratrol.

Stilbene compounds: from the grapevine to wine.

Bavaresco L, Fregoni C, Cantù E, Trevisan M. Drugs Exp Clin Res. 1999;25(2-3):57-63.

Stilbenes are natural compounds occurring in a number of plant families, including Vitaceae and (within this family) Vitis vinifera L., which is the most important species grown worldwide for grape and wine production. Stilbenes (resveratrol and viniferins) are present in grapevine as constitutive compounds of the woody organs (roots, canes, stems) and as induced substances (in leaves and fruit) acting as phytoalexins in the mechanisms of grape resistance against certain pathogens. Resveratrol (3, 5, 4'-trihydroxystilbene) was also detected in wine and it was thought to be the active principle of red wines that were shown to reduce heart diseases. This paper reviews data, obtained by the Viticulture Institute of the Catholic University at Piacenza and taken from the literature, on some aspects of stilbene physiology in grapevine and on their relation to resveratrol wine levels. Constitutive stilbene contents of woody organs are reported, as well as the possible role of cluster stems as a source of resveratrol for wine. The accumulation of stilbenes in grape berries infected by grey mold (Botrytis cinerea Pers.) has been investigated and the effects of environmental factors on resveratrol grape and wine levels will be discussed. An unidentified new hydroxystilbene was detected in wine.

Resveratrol analog, 3,5,2′,4′-tetramethoxy- trans -stilbene, potentiates the inhibition of cell growth and induces apoptosis in human cancer cells

Kyung Ae Nam, Sanghee Kim, Yoen Hoi Heo and Sang Kook Lee.

Journal Archives of Pharmacal Research, Publisher Pharmaceutical Society of Korea ISSN0253-6269 (Print) 1976-3786 (Online). Issue Volume 24, Number 5 / October, 2001 Category Research, Article DOI10.1007/BF02975192 Pages441-445

Resveratrol, a trihydroxystilbene found in grapes and several plants, has been shown to be active in inhibiting multistage carcinogenic process. Using resveratrol as the prototype, we synthesized several analogs and evaluated their growth inhibitory effect using cultured human cancer cells. In the present report we show that one of the resveratrol analogs, 3, 5,2’,4’-tetramethoxy-trans-stilbene, potentiated the inhibition of cancer cell growth. Prompted by the strong growth inhibitory activity of the compound (IC50; 0.8 μg/ml) compared to resveratrol (IC50; 18.7 μg/ml) in cultured human colon cancer cells (Col2), we performed an action mechanism study using the compound. The compound induced the accumulation of cellular DNA contents in the sub-G0 phase DNA contents of the cell cycle by in a time dependent manner. The morphological changes were also consistent with an apoptotic process. This result indicated that the compound induced apoptosis of cancer cells, and may be a candidate for use in the development of potential cancer chemotherapeutic or cancer chemopreventive agents.

Key words 3,5,2’,4’-Tetramethoxy-trans-stilbene - Growth inhibition of cancer cells - Apoptosis - Cancer chemoprevention

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