Dietary Genistein Inhibits Metastasis of Human Prostate Cancer in Mice

Abstract

Dietary genistein has been linked to lower prostate cancer (PCa) mortality. Metastasis is the ultimate cause of death from PCa. Cell detachment and invasion represent early steps in the metastatic cascade. We had shown that genistein inhibits PCa cell detachment and cell invasion in vitro. Genistein-mediated inhibition of activation of focal adhesion kinase (FAK) and of the p38 mitogen-activated protein kinase (MAPK)-heat shock protein 27 (HSP27) pathway has been shown by us to regulate PCa cell detachment and invasion effects, respectively. To evaluate the antimetastatic potential of genistein, we developed an animal model suited to evaluating antimetastatic drug efficacy. Orthotopically implanted human PC3-M PCa cells formed lung micrometastasis by 4 weeks in >80% of inbred athymic mice. Feeding mice dietary genistein before implantation led to blood concentrations similar to those measured in genistein-consuming men. Genistein decreased metastases by 96%, induced nuclear morphometric changes in PC3-M cells indicative of increased adhesion (i.e., decreased detachment) but did not alter tumor growth. Genistein increased tumor levels of FAK, p38 MAPK, and HSP27 ''promotility'' proteins. However, the ratio of phosphorylated to total protein trended downward, indicating a failure to increase relative amounts of activated protein. This study describes a murine model of human PCa metastasis well suited for testing antimetastatic drugs. It shows for the first time that dietary concentrations of genistein can inhibit PCa cell metastasis. Increases in promotility proteins support the notion of cellular compensatory responses to antimotility effects induced by therapy. Studies of antimetastatic efficacy in man are warranted and are under way.

Effects of genistein following fractionated lung irradiation in mice

“…In fact there was a trend towards tumor sensitization by the reduction in clonogenic cells recovered from unirradiated and irradiated mice with prolonged treatment with genistein. This is consistent with other reports that genistein has shown potential as an anti-cancer agent in several different cancer cell types such as glioma [181], prostate cancer [150], lung cancer [182], cervical cancer [183] and breast cancer [149]. Our results contribute to evidence that even as an anti-oxidant genistein may be used safely as a protective agent for normal tissue in combination with radiation therapy.…”

“…Diets high in soy isoflavones have been noted for their role in reducing the incidence of breast and prostate cancers [147,148]. Genistein inhibits carcinogenesis in many tumour models through the modulation of genes for cell cycle, survival and apoptosis [139,146] and has been reported to reduce development of metastasis in breast cancer and prostate models [149][150][151].…”

Endocrine disruptors and prostate cancer risk

“…In the human population, direct connections between endocrine disruptors (EDs) and prostate cancer risk have not been established. Nonetheless, due to the hormonal basis of this disease and the evidence that dietary compounds high in isoflavones (e.g., red clover, genistein) can control prostate cancer growth in humans (Jarred et al 2002, Lakshman et al 2008) and animal models (McCormick et al 2007), there is reasonable cause to evaluate and understand any potential relationship between environmental EDs and prostate cancer risk. In addition to epidemiologic studies, there are in vitro studies with human prostate cells and in vivo studies in animal models that indicate associations between EDs and prostate cancer, carcinogenesis, and/or susceptibility.…”

Genistein inhibits growth of human uveal melanoma cells and affects microRNA-27a and target gene expression

“…For example, Shao et al revealed that genistein exerted multiple suppressive effects on human breast carcinoma cells (21). Lakshman et al indicated that dietary genistein could inhibit metastasis of human prostate cancer (22). It has received wide attention by its potential healthbeneficial effects in the last few years (23).…”