The biochemistry and medical significance of the flavonoids.

Flavonoids: antioxidants or signalling molecules?

Natural antioxidants from residual sources.

Plants consumed by humans contain thousands of phenolic compounds. The effects of dietary polyphenols are of great current interest due to their antioxidative and possible anticarcinogenic activities. A popular belief is that dietary polyphenols are anticarcinogens because they are antioxidants, but direct evidence for this supposition is lacking. This chapter reviews the inhibition of tumorigenesis by phenolic acids and derivatives, tea and catechins, isoflavones and soy preparations, quercetin and other flavonoids, resveratrol, and lignans as well as the mechanisms involved based on studies in vivo and in vitro. Polyphenols may inhibit carcinogenesis by affecting the molecular events in the initiation, promotion, and progression stages. Isoflavones and lignans may influence tumor formation by affecting estrogen-related activities. The bioavailability of the dietary polyphenols is discussed extensively, because the tissue levels of the effective compounds determine the biological activity. Understanding the bioavailability and blood and tissue levels of polyphenols is also important in extrapolating results from studies in cell lines to animal models and humans. Epidemiological studies concerning polyphenol consumption and human cancer risk suggest the protective effects of certain food items and polyphenols, but more studies are needed for clear-cut conclusions. Perspectives on the application of dietary polyphenols for the prevention of human cancer and possible concerns on the consumption of excessive amounts of polyphenols are discussed.

Inhibition of carcinogenesis by dietary polyphenolic compounds

Advances in copper complexes as anticancer agents.

Two citrus flavonoids, hesperetin and naringenin, found in oranges and grapefruit, respectively, and four noncitrus flavonoids, baicalein, galangin, genistein, and quercetin, were tested singly and in one‐to‐one combinations for their effects on proliferation and growth of a human breast carcinoma cell line, MDA‐MB‐435. The concentration at which cell proliferation was inhibited by 50% (IC50), based on incorporation of [3H]thymidine, varied from 5.9 to 140 μg/ml for the single flavonoids, with the most potent being baicalein. IC50 values for the one‐to‐one combinations ranged from 4.7 μg/ml (quercetin + hesperetin, quercetin + naringenin) to 22.5 μxglml (naringenin + hesperetin). All the flavonoids showed low cytotoxicity (>500 μg/ml for 50% cell death). Naringenin is present in grapefruit mainly as its glycosylated form, naringin. These compounds, as well as grapefruit and orange juice concentrates, were tested for their ability to inhibit development of mammary tumors induced by 7,12‐dimethylbe...

Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices

Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen

Tocotrienols are a form of vitamin E, having an unsaturated isoprenoid side-chain rather than the saturated side-chain of tocopherols. The tocotrienol-rich fraction (TRF) from palm oil contains alpha-tocopherol and a mixture of alpha-, gamma- and delta-tocotrienols. Earlier studies have shown that tocotrienols display anticancer activity. We previously reported that TRF, alpha-, gamma- and delta-tocotrienols inhibited proliferation of estrogen receptor-negative MDA-MB-435 human breast cancer cells with 50% inhibitory concentrations (IC50) of 180, 90, 30 and 90 microg/mL, respectively, whereas alpha-tocopherol had no effect at concentrations up to 500 microg/mL. Further experiments with estrogen receptor-positive MCF-7 cells showed that tocotrienols also inhibited their proliferation, as measured by [3H] thymidine incorporation. The IC50s for TRF, alpha-tocopherol, alpha-, gamma- and delta-tocotrienols were 4, 125, 6, 2 and 2 microg/mL, respectively. Tamoxifen, a widely used synthetic antiestrogen inhibits the growth of MCF-7 cells with an IC50 of 0.04 microg/mL. We tested 1:1 combinations of TRF, alpha-tocopherol and the individual tocotrienols with tamoxifen in both cell lines. In the MDA-MB-435 cells, all of the combinations were found to be synergistic. In the MCF-7 cells, only 1:1 combinations of gamma- or delta-tocotrienol with tamoxifen showed a synergistic inhibitory effect on the proliferative rate and growth of the cells. The inhibition by tocotrienols was not overcome by addition of excess estradiol to the medium. These results suggest that tocotrienols are effective inhibitors of both estrogen receptor-negative and -positive cells and that combinations with tamoxifen should be considered as a possible improvement in breast cancer therapy.

Inhibition of Proliferation of Estrogen Receptor–Negative MDA-MB-435 and –Positive MCF-7 Human Breast Cancer Cells by Palm Oil Tocotrienols and Tamoxifen, Alone and in Combination

The tocotrienol-rich fraction (TRF) of palm oil consists of tocotrienols and some alpha-tocopherol (alpha-T). Tocotrienols are a form of vitamin E having an unsaturated side-chain, rather than the saturated side-chain of the more common tocopherols. Because palm oil has been shown not to promote chemically-induced mammary carcinogenesis, we tested effects of TRF and alpha-T on the proliferation, growth, and plating efficiency (PE) of the MDA-MB-435 estrogen-receptor-negative human breast cancer cells. TRF inhibited the proliferation of these cells with a concentration required to inhibit cell proliferation by 50% of 180 microgram/mL whereas alpha-T had no effect at concentrations up to 1000 microgram/mL as measured by incorporation of [3H]thymidine. The effects of TRF and alpha-T also were tested in longer-term growth experiments, using concentrations of 180 and 500 microgram/mL. We found that TRF inhibited the growth of these cells by 50%, whereas alpha-T did not. Their effect on the ability of these cells to form colonies also was studied, and it was found that TRF inhibited PE, whereas alpha T had no effect. These results suggest that the inhibition is due to the presence of tocotrienols in TRF rather than alpha T.

Effect of tocotrienols on the growth of a human breast cancer cell line in culture.

Compositions and methods for the prevention and treatment of neoplastic diseases are described Individuals at a high risk of developing or having neoplasia undergoing conventional therapies may be treated with an effective dose of triterpene derivatives in limonoids, polyphenolic flavonoid compounds, tocotrienols or a combination of these agents

Najla Guthrie

Papers

Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices

Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen

Inhibition of Proliferation of Estrogen Receptor–Negative MDA-MB-435 and –Positive MCF-7 Human Breast Cancer Cells by Palm Oil Tocotrienols and Tamoxifen, Alone and in Combination

Effect of tocotrienols on the growth of a human breast cancer cell line in culture.

Compositions and methods for treatment of neoplastic diseases with combinations of limonoids, flavonoids and tocotrienols