Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein.

Prostate cancer frequently metastasizes to the bone, and the treatment outcome for metastatic prostate cancer has been disappointing so far. Dietary genistein, derived primarily from soy product, has been proposed to be partly responsible for the low rate of prostate cancer in Asians. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells, but there are no studies documenting comprehensive gene expression profiles and antitumor effects of dietary genistein on human prostate cancer grown in human bone environment. In this study, we investigated the effects of genistein on PC3 prostate cancer cells and experimental PC3 bone tumors created by injecting PC3 cells into human bone fragments previously implanted in severe combined immunodeficient (SCID) mice (SCID human model). We found that genistein significantly inhibited PC3 bone tumor growth using both prevention and intervention strategies. By using microarray and real-time polymerase chain reaction technology, we found that genistein regulated the expression of multiple genes involved in the control of cell growth, apoptosis, and metastasis both in vitro and in vivo. For example, the expression of various metalloproteinases (MMPs) in PC3 bone tumors was inhibited by genistein treatment, whereas osteoprotegerin was upregulated. MMP immunostaining and transfection experiments also demonstrated that MMP-9 expression was inhibited in PC3 cells in vitro and PC3 bone tumors in vivo after genistein treatment. These results, particularly the in vivo results, demonstrate that dietary genistein may inhibit prostate cancer bone metastasis by regulating metastasis-related genes. Genistein may thus be a promising agent for the prevention and/or treatment of prostate cancer.

Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappaB in BxPC-3 pancreatic cancer cell line.

Cancer chemotherapeutic strategies should be devised to provide higher tumor response and lower toxicity for combination chemotherapy. Genistein has been shown to inhibit the growth of various cancer cells in vitro and in vivo without toxicity to normal cells. The antitumor effects of genistein could be in part due to inactivation of NF-kappaB activity. In contrast, chemotherapeutic agents inadvertently induce NF-kappaB activity, which may lead to chemoresistance. In this study, we investigated whether the inactivation of NF-kappaB by genistein would enhance the efficacy of chemotherapeutic agents. BxPC-3 pancreatic cancer cells were pretreated with 30 micromol/L genistein for 24 hours and then exposed to lower concentrations of chemotherapeutic agents for an additional 24 hours. Cell growth inhibition assay, apoptosis assay, and NF-kappaB EMSA were performed. The combination of 30 micromol/L genistein with 1 nmol/L docetaxel or 100 nmol/L cisplatin elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced more apoptosis in BxPC-3 cells compared with single agents. Moreover, the NF-kappaB activity was significantly increased within 2 hours of docetaxel or cisplatin treatment, and the NF-kappaB-inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results clearly suggest that genistein pretreatment, which inactivates NF-kappaB activity, together with other cellular effects of genistein, may contribute to increased cell growth inhibition and apoptosis inducing effects of nontoxic doses of docetaxel and cisplatin, which could be a novel strategy for the treatment of pancreatic cancer.