Flavonoid Effects Relevant to Cancer

Abstract

Flavonoids, such as daidzein and genistein, present in dietary plants like soybean, have unique chemical properties with biological activity relevant to cancer. Many flavonoids and polyphenols, including resveratrol in red wine and epigallocatechin gallate in green tea, are known antioxidants. Some of these compounds have estrogenic (and antiestrogenic) activity and are commonly referred to as phytoestrogens. A yeast-based estrogen receptor (ER) reporter assay has been used to measure the ability of flavonoids to bind to ER and activate estrogen responsive genes. Recently, estrogenic compounds were also shown to trigger rapid, nongenomic effects. The molecular mechanisms, however, have not been completely detailed and little information exists regarding their relevance to cancer progression. As a preliminary step toward elucidating rapid phytoestrogen action on breast cancer cells, we investigated the effect of 17-beta estradiol (E2), genistein, daidzein and resveratrol on the activation status of signaling proteins that regulate cell survival and invasion, the cell properties underlying breast cancer progression. The effect of these estrogenic compounds on the activation, via phosphorylation, of Akt/protein kinase B (Akt) and focal adhesion kinase (FAK) were analyzed in ER-positive and -negative human breast cancer cell lines. E2, genistein and daidzein increased whereas resveratrol decreased both Akt and FAK phosphorylation in nonmetastatic ER-positive T47D cells. In metastatic ER-negative MDA-MB-231 cells, all estrogenic compounds tested increased Akt and FAK phosphorylation. The inhibitory action of resveratrol on cell survival and proliferation is ER dependent. Therefore, all estrogenic compounds tested, including resveratrol, may exert supplementary ER-independent nongenomic effects on cell survival and migration in breast cancer cells.

Inhibitory effects of genistein on metastasis of human hepatocellular carcinoma

“…Genistein has a wide range of biological actions that suggest it may be of use in cancer treatment. Its molecular actions include: an inhibitory effect on protein tyrosine kinases, DNA topoisomerase Ⅰ and Ⅱ, and ribosomal S6 kinase; antiestrogenicity; antioxidant activity; anti-angiogenesis activity; suppression of cell proliferation; induction of differentiation and modulation of apoptosis [13][14][15] . However, few data are available on the effects of genistein on metastasis of HCC.…”

Nutritional flavonoids impact on nuclear and extranuclear estrogen receptor activities

“…At concentrations more physiologically achievable in the plasma (from 0.1 µM to 10 µM) after the consumption of meals rich in flavonoids (Manach et al, 2004), these compounds are thought to protect against degenerative diseases (i.e., E2-related cancers) by regulating ER activity (Birt et al, 2001;Brownson et al, 2002;Totta et al, 2004). This has allowed us to enter a new era of understanding the mechanisms by which flavonoids exert their effects on human health.…”

“…On the contrary, Asian women (large isoflanoids consumers) and vegetarians have a lower than average breast cancer risk (Limer and Speirs, 2004). In addition, flavonoids have been shown to induce responses consistent with the protective effects of fruit and vegetable rich diets against cancer in both in vitro test systems and small animal models (Hollman et al, 1996;Gamet-Payrastre et al, 1999;Birt et al, 2001;Brownson et al, 2002;KeinanBoker et al, 2004). The anticancer effect of nutritional flavonoids could represent other anti-estrogenic effects ascribed to these compounds.…”

An Analogue of Resveratrol HS-1793 Exhibits Anticancer Activity Against MCF-7 Cells Via Inhibition of Mitochondrial Biogenesis Gene Expression

“…For instance, resveratrol-induced apoptosis has repeatedly been reported to be accompanied by increased caspase activity (Ferry et al, 2002;Kim et al, 2004;Wolter et al, 2001). In addition, resveratrol-induced apoptosis was shown to be associated with Bax mitochondrial translocation (Mahyar-Roemer et al, 2002), inhibition of AKT activity (Brownson et al, 2002), up-regulation of the oncogene suppressor p53 (Narayanan et al, 2003), and down-regulation of cyclin D1 (Joe et al, 2002). In other studies, resveratrol has been shown to act via c-Jun NH 2 -terminal kinase (JNK), as resveratrol-induced p53-dependent transcriptional activity and apoptosis were blocked upon expression of a dominant-negative mutant of JNK or upon disruption of JNK1 or JNK2.…”