Soy isoflavones in prostate cancer prevention.

O Kucuk MD^a, F Sarkar PhD^a, F Saatcioglu PhD^b, RE Parchment PhD^a, M Cher MD^a, G Hillman PhD^a, W Sakr MD^a, A Majumdar PhD^a, J Kassab^a, Y Li PhD^a, KL Ellis^a, M Che MD^a, B Lazarevic MD^b, S Karlsen PhD^b, D Wood MD^c, D Doerge PhD^d, A Prasad MD PhD^a, M Pollak MD^e, M Hussain MD^c, U Vaishampayan MD^a, J Forman MD^a, M Banerjee PhD^a, MD Powell^a, C Dhabuwala MD^a, J Triest MD^a, E Pontes MD^a, D Grignon MD^a

^aKarmanos Cancer Institute, Wayne State University, Detroit, MI, United States, ^bUniversity of Oslo, Oslo, Norway, ^cUniversity of Michigan Comprehensive Cancer Center, Ann Arbor, MI, United States, ^dNational Toxicological Research Center, FDA, AR, Jefferson, ^eMcGill University, Montreal, Quebec, Canada

AIM: Our studies aim to determine the potential benefit of soy isoflavones in the prevention of prostate cancer development and progression by investigating the in vitro and in vivo effects of genistein and soy isoflavone mixtures and exploring the mechanisms of their actions. METHODS: We have conducted in vitro, animal model and clinical studies and investigated the modulation of molecular pathways of prostate carcinogenesis by soy isoflavones. RESULTS: We have observed that patients with advanced prostate cancer have disease stabilization when given soy isoflavone supplements. Therefore soy isoflavones may have a role in the prevention of progression of prostate cancer. Our studies in animal models have shown that prostate cancer bone metastasis can be inhibited by soy isoflavones. By using cDNA microarray and real-time PCR 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. MMP-9 expression was inhibited in PC-3 cells in vitro and PC-3 bone tumors in vivo after genistein treatment. Previous studies on the effects of genistein on prostate cancer cells have shown that it inhibits the secreted and intracellular levels of the androgen-regulated protein prostate-specific antigen (PSA). Here, we have assessed whether genistein has similar effects on other prostate enriched and/or androgen regulated genes. Similar to findings with PSA, genistein decreased the levels of kallikrein 4 (KLK4) and NKX3.1 proteins, both of which are androgen regulated genes highly enriched to prostate for expression, in LNCaP prostate cancer cells. In contrast, the expression of the six transmembrane protein of prostate 1 (STAMP1), a highly prostate enriched protein likely to be involved in endocytic and exocytic pathways, was upregulated in a dose-dependent manner by genistein in LNCaP cells. We have also observed potentiation of the chemotherapeutic agents and radiation therapy in vitro and in vivo by genistein. We found that genistein abrogated the activation of NF-kB pathway induced by chemotherapy and radiation, thereby making the cancer cells more vulnerable to the effects of chemotherapy and radiation. Neither pretreatment nor simultaneous exposure to genistein sensitized human CFU-gm to the in vitro toxicity of chemotherapeutic agent XK469. These findings confirm the hypothesis that genistein chemosensitization occurs differentially in malignant cells because they lack compensatory mechanisms for loss of NF-kB function. CONCLUSIONS: Genistein inhibits prostate cancer cell growth and induces apoptosis in prostate cancer cells and prevents metastasis in animal models. Furthermore, genistein potentiates the effects of chemotherapy and radiation in cell culture and animal model experiments. Finally, soy isoflavones slow the progression of disease in humans with advanced prostate cance

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 793 (Dietary influences).