It is estimated that nearly one-third of all cancer deaths in the United States could be prevented through appropriate dietary modification. Various dietary antioxidants have shown considerable promise as effective agents for cancer prevention by reducing oxidative stress which has been implicated in the development of many diseases, including cancer. Therefore, for reducing the incidence of cancer, modifications in dietary habits, especially by increasing consumption of fruits and vegetables rich in antioxidants, are increasingly advocated. Accumulating research evidence suggests that many dietary factors may be used alone or in combination with traditional chemotherapeutic agents to prevent the occurrence of cancer, their metastatic spread, or even to treat cancer. The reduced cancer risk and lack of toxicity associated with high intake of fruits and vegetables suggest that specific concentrations of antioxidant agents from these dietary sources may produce cancer chemopreventive effects without causing...

Cancer chemoprevention through dietary antioxidants: progress and promise.

Background: High intake of soy foods has been proposed to contribute to the low breast cancer risk in Asian countries. However, results of epidemiologic studies of this association are highly variable, and experimental data suggest that soy constituents can be estrogenic and potentially risk enhancing. Thus, rigorous evaluation of available epidemiologic data is necessary before appropriate recommendations can be made, especially for women at high risk of breast cancer or those who have survived the disease. Methods: We performed a meta-analysis of 18 epidemiologic studies (12 case – control and six cohort or nested case – control) published from 1978 through 2004 that examined soy exposure and breast cancer risk. Pooled relative risk estimates were based on either the original soy exposure measure defi ned in each study or on an estimate of daily soy protein intake. Results: Risk estimates, levels and measures of soy exposure, and control for confounding factors varied considerably across studies. In a pooled analysis, among all women, high soy intake was modestly associated with reduced breast cancer risk (odds ratio [OR] = 0.86, 95% confi dence interval [CI] = 0.75 to 0.99); the association was not statistically signifi cant among women in Asian countries (OR = 0.89, 95% CI = 0.71 to 1.12). Among the 10 studies that stratifi ed by menopausal status the inverse association between soy exposure and breast cancer risk was somewhat stronger in premenopausal women (OR = 0.70, 95% CI = 0.58 to 0.85) than in postmenopausal women (OR = 0.77, 95% CI = 0.60 to 0.98); however, eight studies did not provide menopausespecifi c results, six of which did not support an association. When exposure was analyzed by soy protein intake in grams per day, a statistically signifi cant association with breast cancer risk was seen only among premenopausal women (OR = 0.94, 95% CI = 0.92 to 0.97). Conclusions: Soy intake may be associated with a small reduction in breast cancer risk. However, this result should be interpreted with caution due to potential exposure misclassifi cation, confounding, and lack of a dose response. Given these caveats and results of some experimental studies that suggest adverse effects from soy constituents, recommendations for high- dose isofl avone supplementation to prevent breast cancer or prevent its recurrence are premature. [J Natl Cancer Inst 2006;98:459 – 71]

Meta-Analysis of Soy Intake and Breast Cancer Risk

In this report, we have designed a simple and efficient green chemistry approach for the synthesis of colloidal silver nanoparticles (b-AgNPs) that is formed by the reduction of silver nitrate (AgNO3) solution using Olax scandens leaf extract. The colloidal b-AgNPs, characterized by various physico-chemical techniques exhibit multifunctional biological activities (4-in-1 system). Firstly, bio-synthesized silver nanoparticles (b-AgNPs) shows enhanced antibacterial activity compared to chemically synthesize silver nanoparticles (c-AgNPs). Secondly, b-AgNPs show anti-cancer activities to different cancer cells (A549: human lung cancer cell lines, B16: mouse melanoma cell line & MCF7: human breast cancer cells) (anti-cancer). Thirdly, these nanoparticles are biocompatible to rat cardiomyoblast normal cell line (H9C2), human umbilical vein endothelial cells (HUVEC) and Chinese hamster ovary cells (CHO) which indicates the future application of b-AgNPs as drug delivery vehicle. Finally, the bio-synthesized AgNPs show bright red fluorescence inside the cells that could be utilized to detect the localization of drug molecules inside the cancer cells (a diagnostic approach). All results together demonstrate the multifunctional biological activities of bio-synthesized AgNPs (4-in-1 system) that could be applied as (i) anti-bacterial & (ii) anti-cancer agent, (iii) drug delivery vehicle, and (iv) imaging facilitator. To the best of our knowledge, there is not a single report of biosynthesized AgNPs that demonstrates the versatile applications (4-in-1 system) towards various biomedical applications. Additionally, a plausible mechanistic approach has been explored for the synthesis of b-AgNPs and its anti-bacterial as well as anti-cancer activity. We strongly believe that bio-synthesized AgNPs will open a new direction towards various biomedical applications in near future.

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Potential Theranostics Application of Bio-Synthesized Silver Nanoparticles (4-in-1 System)

Phytosterol and stanol (or phytosterols) consumption reduces intestinal cholesterol absorption, leading to decreased blood LDL-cholesterol levels and lowered cardiovascular disease risk. However, other biological roles for plant sterols and stanols have also been proposed. The objective of this review is to critically examine results from recent research regarding the potential effects and mechanisms of action of phytosterols on forms of cancer. Considerable emerging evidence supports the inhibitory actions of phytosterols on lung, stomach, as well as ovarian and breast cancer. Phytosterols seem to act through multiple mechanisms of action, including inhibition of carcinogen production, cancer-cell growth, angiogenesis, invasion and metastasis, and through the promotion of apoptosis of cancerous cells. Phytosterol consumption may also increase the activity of antioxidant enzymes and thereby reduce oxidative stress. In addition to altering cell-membrane structure and function, phytosterols probably promote apoptosis by lowering blood cholesterol levels. Moreover, consumption of phytosterols by healthy humans at the recommended level of 2 g per day does not cause any major health risks. In summary, mounting evidence supports a role for phytosterols in protecting against cancer development. Hence, phytosterols could be incorporated in diet not only to lower the cardiovascular disease risk, but also to potentially prevent cancer development.

Anticancer effects of phytosterols

The impact of soyfood intake on breast cancer risk has been investigated extensively. Much of this focus can be attributed to the soybean being a dietary source that is uniquely rich in isoflavones. The chemical structure of isoflavones is similar to that of estrogen, and isoflavones bind to both estrogen receptors (ER alpha and ER beta) (although they preferentially bind to and activate ER beta) and exert estrogen-like effects under some experimental conditions. Isoflavones also possess nonhormonal properties that are associated with the inhibition of cancer cell growth. Thus, there are several possible mechanisms by which soy may reduce the risk of breast cancer. However, the role of isoflavones in breast cancer has become controversial because, in contrast to the possible beneficial effects, some data from in vitro and animal studies suggest that isoflavones, especially genistein, the aglycone of the main soybean isoflavone genistin, may stimulate the growth of estrogen-sensitive tumors. Limited human data directly address the tumor-promoting effects of isoflavones and soy. Because the use of soyfoods and isoflavone supplements is increasing, it is important from a public health perspective to understand the impact of these products on breast cancer risk in women at high risk of the disease and on the survival of breast cancer patients. To this end, a workshop was held in November 2005 to review the existing literature and to make research recommendations. This paper summarizes the workshop findings and recommendations. The primary research recommendation is that the impact of isoflavones on breast tissue needs to be evaluated at the cellular level in women at high risk for breast cancer.

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Addressing the Soy and Breast Cancer Relationship: Review, Commentary, and Workshop Proceedings

We hypothesized that the phytosterols beta-sitosterol (BSS), beta-sitosterol glucoside (BSSG), and Moducare (MC; BSS:BSSG = 99:1) could modulate the growth of estrogen-dependent human breast cancer cells in vitro and in vivo. The present study evaluated the estrogenic and antiestrogenic effects of BSS, BSSG, and MC (0.001 to 150 micromol/L) on the proliferation of Michigan Cancer Foundation 7 (MCF-7) cells in vitro. Both BSS (>1 micromol/L) and MC (>50 micromol/L) increased MCF-7 cell proliferation. Treatment with 150 micro mol/L of BSS and MC increased cell growth by 2.4 and 1.5 times, respectively, compared to the negative control (NC) group. However, BSSG had no effect at the concentrations tested. The effects of dietary BSS, BSSG, and MC on the growth of MCF-7 cells implanted in ovariectomized athymic mice were also evaluated. Estrogenic effects of the phytosterols were evaluated in the NC, BSS, BSSG, and MC treatment groups, and antiestrogenic effects were evaluated in the 17 beta-estradiol (E(2)), E(2) + BSS, E(2) + BSSG, and E(2) + MC treatment groups. Mice were treated with dietary BSS (9.8 g/kg AIN93G diet), BSSG (0.2 g/kg diet), or MC (10.0 g/kg diet) for 11 wk. Dietary BSS, BSSG, and MC did not stimulate MCF-7 tumor growth. However, dietary BSS, BSSG, and MC reduced E(2)-induced MCF-7 tumor growth by 38.9% (P < 0.05), 31.6% (P = 0.08), and 42.13% (P < 0.05), respectively. The dietary phytosterols lowered serum E(2) levels by 35.1, 30.2, and 36.5% in the E(2) + BSS, E(2) + BSSG, and E(2) + MC groups, respectively (P < 0.05), compared to that of the E(2) treatment group. Estrogen-responsive pS2 mRNA expression in tumors did not differ among groups, but expression of the antiapoptotic marker B-cell lymphoma/leukemia-2 (bcl-2) in tumors from the E(2) + MC group was downregulated, compared to that of the E(2) treatment group. In summary, BSS and MC stimulated MCF-7 cell growth in vitro. Although BSSG comprises only 1% of MC, BSSG made MC less estrogenic than BSS alone in vitro. However, dietary BSS and MC protected against E(2)-stimulated MCF-7 tumor growth and lowered circulating E(2) levels.

β-Sitosterol, β-Sitosterol Glucoside, and a Mixture of β-Sitosterol and β-Sitosterol Glucoside Modulate the Growth of Estrogen-Responsive Breast Cancer Cells In Vitro and in Ovariectomized Athymic Mice

Due to the estrogenic properties of soy-derived isoflavones, many postmenopausal women are using these compounds as a natural alternative to hormone replacement therapy (HRT). How isoflavones impact breast cancer in postmenopausal women is important, because a majority of breast cancer cases occur in this age group. Chemical induction of mammary tumors in female rats has been used to determine that exposure of the mammary gland to soy isoflavones prior to tumor induction is protective against tumor formation. Here we investigate the effect of dietary genistein on mammary tumors that have already formed. The study was designed to determine the action of dietary genistein in a low endogenous estrogen environment as is observed in postmenopausal women. Animals were ovariectomized (OVX) after mammary tumor development and were then placed into one of three treatment groups: positive-control (OVX+ estradiol implant), genistein (OVX+ 750 p.p.m. genistein) and negative-control (OVX alone). Tumors were distinguished as malignant or benign by histopathological examination and were further characterized as either estrogen-dependent or estrogen-independent using immunohistochemistry to identify the presence of both estrogen receptor (ER) alpha and the progesterone receptor (PR). Genistein at 750 p.p.m. increased the weight of estrogen-dependent adenocarcinomas in ovariectomized rats compared with the negative-control animals. Genistein treatment also resulted in a higher percentage of proliferative cells in tumors and increased uterine weights when compared with negative-control animals. Collectively, these effects are probably due to the estrogenic activity of genistein. Plasma genistein concentrations in animals fed the isoflavone-containing diet were at physiological levels relevant to human exposure. Estradiol concentrations in ovariectomized animals not receiving an estradiol supplement were similar to those observed in postmenopausal women. The data suggest that in an endogenous estrogen environment similar to that of a postmenopausal woman, dietary genistein can stimulate the growth of a mammary carcinogen MNU-induced estrogen-dependent mammary tumors.

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Laura M. Clausen

Papers

β-Sitosterol, β-Sitosterol Glucoside, and a Mixture of β-Sitosterol and β-Sitosterol Glucoside Modulate the Growth of Estrogen-Responsive Breast Cancer Cells In Vitro and in Ovariectomized Athymic Mice

Dietary genistein results in larger MNU-induced, estrogen-dependent mammary tumors following ovariectomy of Sprague–Dawley rats