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w w studies have also used EGCG as a major tea bioactive compound. In addition, EGCG-rich green tea polyphenol extract and whole tea have been used in some animal studies.

16.2.1.1 Effects of Tea Polyphenols on Invasion and Metastasis of Melanoma

A series of studies has been conducted to determine the anti-invasion activities in vitro and antimetastasis activities in vivo of tea polyphenols, especially EGCG, in several cancer types. Because of the highly metastatic potential of melanoma cells, the effects of tea polyphenols on melanoma cell invasion and metastasis are among the most extensively studied cancer types. Murine B16 melanoma cell line and its highly metastatic sublines, such as B16-F3m, B16-F10, and B16-BL6 cells, have been used for evaluation. EGCG significantly inhibited B16-F3m cell migration and invasion in vitro;8 tea catechin significantly inhibited the invasion of B16-F10 melanoma cells in vitro.9 On the other hand, EGCG did not inhibit invasion of highly metastatic B16-BL6 cells in vitro.10

Besides the in vitro anti-invasion studies, tea polyphenols have been evaluated for their antimetastasis activities in several animal models. In one animal study,8 the B16-F3m cells were implanted intraperitoneally into the mice to develop metastases, and the mice were treated with EGCG at 2 mg/day, three times/week for 11 weeks. EGCG significantly reduced lung metastases in mice bearing B16-F3m melanomas.8 In another animal study,9 B16-F10 melanoma cells were intravenously inoculated into the mice to develop lung metastases, and tea catechin was administered orally at 200 |jmol/kg body weight for 10 alternate days. The lung metastases were significantly inhibited by catechin treatment.9 Taniguchi and co-workers applied two animal models of metastasis to evaluate the antime-tastasis effects of EGCG.11 In the experimental metastasis model, B16-F10 melanoma cells were inoculated intravenously to develop lung metastases, and in the spontaneous metastasis model, the more metastatic B16-BL6 melanoma cells were inoculated subcutaneously into the mouse footpad to develop primary tumors, followed by removal of the primary tumors to develop lung metastases.11 Per oral administration of EGCG (0.05 and 0.1%) significantly inhibited lung metastasis of both B16-F10 and B16-BL6 melanoma tumors in both lung metastasis animal models.11 However, EGCG did not show inhibitory effect on lung metastasis of B16-BL6 cells in one animal study in which lung metastases were developed by intravenous inoculation of cancer cells.10

16.2.1.2 Effects of Tea Polyphenols on Invasion and Metastasis of Prostate Cancer

Several animal studies have been conducted to determine the effects of tea on prostate tumor metastasis. We studied the effects of green tea and black tea, alone or in combination with soy isoflavone-enriched phytochemical extract, soy phy-tochemical concentrate (SPC), which contains 50% total isoflavones by weight, on the growth and metastasis of androgen-sensitive LNCaP human prostate tumors in an orthotopic tumor model. We found that the combination of tea (1.5% tea infusion) with SPC (0.5% of the diet) significantly inhibited lymph node metastases of LNCaP tumors.12 The transgenic mouse model for prostate tumors, the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, was also used to determine the effect of green tea polyphenols (GTPs) on the growth and metastasis of prostate tumors. Oral infusion of a polyphenolic fraction isolated from green tea at a human achievable dose (0.1% in drinking water, equivalent to 6 cups of green tea per day) significantly inhibited prostate tumor development and increased survival in these mice. GTP infusion resulted in almost complete inhibition of distant site metastases.13 On the other hand, the decaffeinated green tea extract (59% EGCG, 86% total catechins, and 0.5% caffeine) did not inhibit the growth or metastasis of xenografts of TRAMP-C1 cells in mice,14 although EGCG inhibited invasion of TRAMP-C1 cells in vitro.14

16.2.1.3 Effects of Tea Polyphenols on Invasion and Metastasis of Other Types of Cancer

Lewis lung carcinoma is another type of highly metastatic tumor that is used for invasion/metastasis studies. Green tea infusion, EGCG, and black tea polyphenols, theaflavin and theaflavin digallate, significantly inhibited invasion of highly metastatic mouse Lewis lung carcinoma LL2-Lu3 cells in vitro.15,16 The per oral administration of green tea infusion (2%) significantly reduced the number of lung colonies of mouse Lewis lung carcinoma cells in vivo.16

Tea polyphenols (EGCG, theaflavins, or green tea polyphenol extracts) also inhibited invasion of other types of cancer cells in vitro, such as biliary carcinoma cells,17 fibrosarcoma cells,18 gastric cancer cells,19 hepatoma cells,20 medulloblas-toma cells,21 oral carcinoma cells,22 and pancreatic carcinoma cells.23

It is surprising that few studies have investigated the effects of tea polyphenols on invasion and metastasis of breast cancer. On the other hand, in an epidemio-logical study, increased consumption of green tea was closely associated with decreased numbers of axillary lymph node metastases among premenopausal patients with stage I and II breast cancer.24 Further follow-up study showed that increased consumption of green tea was significantly correlated with decreased recurrence of stage I and II breast cancer.24

In summary, available in vitro and animal studies provide promising evidence that tea polyphenols may have potent anticancer metastasis activities. On the other hand, because many in vitro studies used high levels of tea polyphenols, their antimetastasis activities need to be further verified in animal models at appropriate levels of supplementation. In particular, because of the prevalence of breast cancer, more effort should be made to determine the effects of tea polyphenols on breast cancer invasion and metastasis.

16.2.2 Soy Isoflavones and Antimetastasis

Soy isoflavones comprise of genistein, daidzein, and in less content, glycitein. They exist mainly in the glycoside forms in the soybean called genistin, daidzin, and glycitin, respectively. Upon intestinal bacterial action, the glycosides are converted to their biologically active aglycone forms. Genistein is one of the predominant soy isoflavones, and is shown to have variety types of biological functions that are related to its anticarcinogenesis activity.25 Moreover, genistein is also found to be a potent inhibitor of cancer cell metastasis. In this part of the review, the anti-invasion and antimetastasis activities of genistein and other soy isoflavones will be summarized.

16.2.2.1 Effects of Soy Isoflavones on Invasion and Metastasis of Breast Cancer

A series of in vitro studies has been conducted to determine the effects of soy isoflavones, especially genistein, on invasion of breast cancer cells. Genistein inhibited invasion of a highly metastatic subline of BALB/c mammary carcinoma 410.4 cells with an EC50 of approximately 1 ||M, at which genistein showed little effect on cell growth.26 On the other hand, daidzein was much less potent than genistein on inhibiting 410.4 cell invasion, and most of the effect on invasion was apparently due to its effect on growth inhibition.26 Magee and co-workers27 determined the effects of soy isoflavones (genistein, daidzein, glycitein, equol, O-desmethylangolensin) on invasion of a breast cancer cell-line MDA-MB-231 in vitro, and found that soy isoflavones exerted a potent inhibitory effect on cell invasion without affecting cell growth. Genistein inhibited both constitutive as well as epidermal growth factor (EGF)-stimulated invasion of estrogen receptor (ER)-negative human breast carcinoma lines MDA-MB-231 and MDA-MB-468 in vitro.28

Despite the in vitro effects of soy isoflavones on breast cancer cell invasion, their antimetastasis activities on breast cancer cells in vivo have not been reported. On the other hand, one animal study reported possible metastasis-promoting effects of soy isoflavones.29 In the study, a soybean extract enriched in isoflavones was further heated to denature protease inhibitors, and both heated and unheated extracts were determined for their effects on the growth and metastasis of a mammary tumor MAC-33 in mice. Soy isoflavones did not inhibit the tumor growth, and heated soybean extract significantly increased the number of lung metastases.29 Clearly, more in vitro and in vivo studies are urgently required to determine the role of soy isoflavones in metastasis of breast cancer.

16.2.2.2 Effects of Soy Isoflavones on Invasion and Metastasis of Prostate Cancer

Although the effects of soy isoflavones on prostate cancer cell invasion have not been adequately studied, the effects of soy isoflavones on prostate cancer metastasis were determined in two animal studies. We have studied the effects of genistin and an isoflavone-enriched SPC on orthotopic growth and metastasis of LNCaP human prostate tumors.30 SPC at 0.5% of the diet significantly inhibited both lymph node and lung metastases, whereas genistin at the same level as that in the SPC diet did not significantly inhibit lymph node or lung metastases.30 These data suggest that soybean contains bioactive components other than genistein that have significant antimetastasis activity. In another study, a cell line, K1 that was derived from a carcinogen-induced accessory sex gland carcinoma, was used to examine the effects of genistein on tumor growth and metastasis. Genistein (50 mg/kg body weight) significantly inhibited tumor growth, lymph node metastases, and lung metastases, suggesting that genistein may be a useful chemotherapeutic agent to inhibit the growth and metastasis of accessory sex gland cancers, such as those derived from the prostate.31

16.2.2.3 Effects of Soy Isoflavones on Invasion and Metastasis of Melanoma

Several in vitro and in vivo studies have evaluated the effects of genistein on invasion and metastasis of melanoma cells. Genistein significantly inhibited invasion of B16-BL6 mouse melanoma cells in vitro.32,33 In the animal model in which the lung metastasis was developed by intravenous inoculation of B16-BL6 melanoma cells, genistein significantly inhibited the lung metastases.3234 Similarly, B16-F10 melanoma cells were inoculated intravenously to develop lung metastases, and genistein significantly inhibited lung metastases of B16-F10 cells in mice.35 36 On the other hand, the isoflavone daidzein had no significant effect on the reduction of lung metastasis induced by melanoma cells.36

16.2.2.4 Effects of Soy Isoflavones on Invasion and Metastasis of Other Types of Cancer

The effects of genistein on invasion and metastasis of other types of cancer cells were also evaluated. Genistein significantly inhibited invasion of fibrosarcoma cell line HT1080 in vitro,31 highly invasive lung carcinoma LL2 cells in vitro,35 cervical cancer cells in vitro,38 glioblastoma cells in vitro,39 head and neck cancer cells in vitro,40 transformed keratinocytes in vitro,41 and oral squamous cell carcinoma in vitro.42 Both genistein and glycitein also inhibited Jurkat cell invasion at a similar extent in vitro.43

Two animal studies showed that genistein inhibited metastasis of pancreatic cancer and intestinal tumors in vivo. Pancreatic tumors were orthotopically implanted in mice, and intraperitoneal administration of genistein (1.3 mg/mouse/day) significantly inhibited tumor metastasis to liver.44 In an animal study of azoxymethane (AOM)-induced intestinal adenocarcinoma, genistein (5 or 10 mg/kg body weight) significantly inhibited the incidence of metastasis of tumors to peritoneum and significantly reduced lymphatic vessel invasion of adenocarcinomas, without significant inhibition on the growth of intestinal cancer.45 On the other hand, genistein did not inhibit metastasis of oral squamous cell carcinoma in vivo.42

In summary, available evidence from in vitro and animal studies in general supports the antimetastasis role of soy isoflavones. Although genistein is the major bioactive component in soy, soy may contain other antimetastasis components, and the combination of soy bioactive components may have more potent antime-tastasis activities than any single component. More in vivo studies should be conducted to evaluate the effects of soy bioactives combinations on the metastasis of various types of cancer.

16.2.3 Apigenin and Quercetin and Antimetastasis

16.2.3.1 Effects of Apigenin on Invasion and Metastasis of Cancer

Apigenin is a natural plant flavonoid present in the leaves and stems of vascular plants, including fruits and vegetables. Previous studies have suggested that apigenin has cancer chemopreventive activities, which include antimutagenesis,46 inhibition of ornithine decarboxylase,47 COX-2,48 and aromatase,49 increase of gap junction communication,50 and inhibition of cell cycle progression by arresting cancer cells at G2/M phases.51 Its anti-invasion and antimetastasis activities have been investigated in recent years.

Apigenin was shown to significantly inhibit the protease-mediated invasiveness of estrogen-insensitive MDA-MB-231 human breast cancer cells in vitro52 and invasion of B16-BL6 melanoma cells in vitro.10 Two animal studies evaluated the effects of apigenin on tumor metastasis. In one animal study using intravenous inoculation of B16-BL6 melanoma cells to develop lung metastases, apigenin administration at 25 and 50 mg/kg body weight significantly inhibited lung metastasis of B16-BL6 melanoma tumors.10 Another animal study using an AOM-induced and bombesin-enhanced intestinal adenocarcinoma and metastasis rat model, subcutaneous injection of apigenin at 0.75 or 1.5 mg/kg body weight significantly inhibited the incidence of peritoneal metastasis and the incidence of lymphatic vessel invasion of adenocarcinomas in rats.53

16.2.3.2 Effects of Quercetin on Invasion and Metastasis of Cancer

Quercetin is a plant flavonoid found in most edible fruits and vegetables. Daily human consumption has been estimated to be ~25 mg including its glycoside, rutin.54 Quercetin has demonstrated chemopreventive activity in a variety of laboratory animal models, including tumorigenesis induced by AOM in the colon of mice55 and human breast tumor xenografts.56 The possible anti-invasion and antimetastasis of quercetin have been studied recently. Quercetin inhibited the invasion of murine melanoma B16-BL6 cells in vitro.57 Quercetin also significantly inhibited lung metastasis of B16-BL6 melanoma tumors in mice.10 When administered at 200 nmol/kg body weight, quercetin did not inhibit lung metastasis of B16-F10 melanoma cells, but its glycoside rutin at the same dose significantly inhibited lung metastasis by 72%.58

In summary, despite promising in vitro and especially in vivo evidence to suggest that apigenin and quercetin may be potent antimetastasis agents, the evidence is still insufficient and more in vitro and animal studies are required to further evaluate the antimetastasis activities of apigenin and quercetin.

Dieting Dilemma and Skinny Solutions

Dieting Dilemma and Skinny Solutions

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