Soy Isoflavones in the Treatment of Prostate Cancer

Epidemiological studies suggest an inverse association between soy intake and prostate cancer (Pca) risk. We have previously observed that soy isoflavone genistein induces apoptosis and inhibits growth of both androgen-sensitive and androgen-independent Pca cells in vitro. To determine the clinical effects of soy isoflavones on Pca we conducted a pilot study in patients with Pca who had rising serum prostate-specific antigen (PSA) levels. Patients with Pca were enrolled in the study if they had either newly diagnosed and untreated disease under watchful waiting with rising PSA (group I) or had increasing serum PSA following local therapy (group II) or while receiving hormone therapy (group III). The study intervention consisted of 100 mg of soy isoflavone (Novasoy) taken by mouth twice daily for a minimum of 3 or maximum of 6 mo. Forty-one patients were enrolled (4 in group I, 18 in group II, and 19 in group III) and had a median PSA level of 13.3 ng/ml. Thirty-nine patients could be assessed for response. Soy isoflavone supplementation was given for a median of 5.5 (range 0.8–6) mo per patient. Although there were no sustained decreases in PSA qualifying for a complete or partial response, stabilization of the PSA occurred in 83% of patients in hormone-sensitive (group II) and 35% of hormone-refractory (group III) patients. There was a decrease in the rate of the rise of serum PSA in the whole group (P = 0.01) with rates of rise decreasing from 14 to 6% in group II (P = 0.21) and from 31 to 9% in group III (P = 0.05) following the soy isoflavone intervention. Serum genistein and daidzein levels increased during supplementation from 0.11 to 0.65 μM (P = 0.00002) and from 0.11 to 0.51 μM (P = 0.00001), respectively. No significant changes were observed in serum levels of testosterone, IGF-1, IGFBP-3, or 5-OHmdU. These data suggest that soy isoflavones may benefit some patients with Pca. Introduction Epidemiologic studies have shown an inverse association between soy consumption and prostate cancer (Pca) risk (1–4). Isoflavones have been suggested as the principal chemical constituents responsible for the potential preventive effect of soy against Pca (5). In some Asian countries with high soy consumption, the incidence of latent and small prostate carcinomas is the same as in Western countries, whereas the mortality from clinically diagnosed Pca is lower (6), suggesting that soy isoflavones may also inhibit the progression of Pca. A variety of possible mechanisms have been proposed for the activity of soy isoflavones in Pca, which include estrogen-like effects (7), prevention of oxidative DNA damage (8,9), reduction in cancer cell proliferation (10), inhibition of angiogenesis (11), modulation of steroid-metabolizing enzymes (12), tyrosine kinase (13) and topoisomerase II (14), and effects on signal transduction molecules (15). We have previously observed that soy isoflavone genistein inhibits Pca cell growth in culture in a dose-dependent manner accompanied by a G2/M cell cycle arrest (15). Genistein-induced inhibition of cell growth was associated with down-regulation of cyclin B, up-regulation of the p21WAF1, and induction of apoptosis. We have also observed that oxidative stress (TNF-α or H2O2) –induced activation of transcription factor NF-κB can be abrogated by genistein in Pca cell lines (16) and by soy isoflavone supplementation in normal human volunteers (17). These data provided the rationale for investigating the invivoeffectsofgenistein inpatientswithPca.Becauseserum prostate-specific antigen (PSA) is a well-established marker that correlates with Pca progression, we conducted a pilot study to investigate the effect of soy isoflavone supplementation in patients with rising serum PSA levels. NUTRITION AND CANCER, 47(2), 111–117 Copyright © 2003, Lawrence Erlbaum Associates, Inc. M. Hussain, Z. Djuric, J. Fontana, and O. Kucuk are affiliated with the Division of Hematology and Oncology, Wayne State University and the Barbara Karmanos Cancer Institute, Detroit, MI 48201. J. Fontana is also affiliated with the VA Medical Center, Wayne State University and the Barbara Karmanos Cancer Institute, Detroit, MI 48201. M. Banerjee is affiliated with the Center for Healthcare Effectiveness Research, Detroit, MI, 48201. F. H. Sarkar, S. Chinni, and J. Davis are affiliated with the Department of Pathology, Wayne State University Wayne State University and the Barbara Karmanos Cancer Institute, Detroit, MI 48201. M. N. Pollak is affiliated with the Department of Medicine, McGill University and Jewish General Hospital, Montreal, Quebec, Canada. D. Doerge is affiliated with the Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079. J. Forman is affiliated with the Department of Radiation Oncology, Wayne State University and the Barbara Karmanos Cancer Institute, Detroit, MI 48201. D. P. Wood is affiliated with the Department of Urology, Wayne State University and the Barbara Karmanos Cancer Institute, Detroit, MI 48201. D ow nl oa de d by [ M cG ill U ni ve rs ity L ib ra ry ] at 0 8: 36 1 3 D ec em be r 20 11