Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model

Abstract

We previously reported that genistein, the bioactive isoflavone of soybeans, acts as a radiosensitizer for prostate cancer. Pretreatment of tumor cells with genistein potentiated radiation-induced killing in vitro and in orthotopic models in vivo. However, pure genistein promoted increased lymph node metastasis, when administered alone in vivo. We investigated in vitro and in vivo the effects of soy isoflavones (genistein, daidzein and glycitein) as soy pills of similar composition are used in human interventions but not pure genistein. Soy isoflavones inhibited cell survival and potentiated radiation cell killing in PC-3 tumor cells, in vitro. Increased cell killing correlated with inhibition of antiapoptotic molecules Bcl-xL and survivin, upregulation of proapoptotic Bax molecule and PARP cleavage, suggesting activation of apoptotic pathways. In vivo, using the PC-3 orthotopic metastatic mouse model, soy isoflavones and prostate tumor irradiation led to enhanced control of primary tumor growth and metastasis, as observed with pure genistein and radiation. Interestingly, treatment with soy isoflavones did not increase metastasis to para-aortic lymph nodes in contrast to the consistent increase caused by pure genistein. Histologically prostate tumors, treated with soy isoflavones and radiation, showed tumor destruction and in situ tissue alterations, comparable with genistein and radiation effects. However, genistein, but not soy isoflavones, caused induction of HIF1-a in prostate tumors, suggesting that induction of hypoxia by pure genistein could contribute to increased metastasis. Our studies demonstrate the safety and potential role of soy isoflavones for enhancing the therapeutic effect of radiotherapy in prostate cancer. ' 2007 Wiley-Liss, Inc.Key words: prostate cancer; soy isoflavones; genistein; radiation In the United States, prostate cancer (PCa) is the most commonly diagnosed cancer in men as well as the second leading cause of male cancer deaths. 1,2 Localized PCa is sensitive to conventional radiotherapy using megavoltage photons (X-rays), yet residual disease causes clinical relapse. 2 Thus, for improving the local control of PCa, the combination of radiation with additional antitumor agents is warranted. Epidemiological studies indicate that there is an inverse association between prostate cancer risk and consumption of phytoestrogens including isoflavones. [3][4][5] The isoflavones in soybeans mainly include genistein, daidzein and glycitein. 5 Genistein, the most bioactive isoflavone, has demonstrated inhibition of tumor cell growth in human tumor cell lines. 5 In particular, genistein inhibited the growth of human PCa cells in vitro by affecting the cell cycle and inducing apoptosis. 5 To improve the therapeutic efficacy of radiotherapy for prostate cancer, we have previously investigated the potential of genistein to act as a radiosensitizer. 6-9 Genistein significantly increased tumor cell death when given prior to radiation in several human cancer cell lines in vitro, including the PC-3 PCa...

Down-regulation of Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 Expression by Soy Isoflavones Enhances Prostate Cancer Radiotherapy In vitro and In vivo

“…Serum levels of about 3 Amol/L genistein and 0.5 Amol/L daidzein were measured in mice treated with genistein, whereas equal levels of genistein (1.7 Amol/L) and daidzein (1.6 Amol/L) were measured in mice treated with soy isoflavones compared with baseline levels in control mice (0.3 Amol/L; ref. 18). The effect of genistein alone was not significant; however, genistein + radiation significantly inhibited tumor growth by 85% compared with each modality alone (P < 0.05; Fig.…”

“…We recently found that a mixture of soy isoflavones, consisting of genistein, daidzein, and glycitein, was safer than genistein in the in vivo model because it did not cause increased spontaneous lymph node metastasis. In addition, soy isoflavones were effective at potentiation of tumor growth inhibition induced by radiation, resulting in the arrest of prostate tumor growth and spontaneous metastasis to lymph nodes (18). Such a mixture of soy isoflavones is more representative of the soy supplements used for human interventions, whereas pure genistein is not used as a supplement.…”

Perspectives on the Role of Isoflavones in Prostate Cancer

“…Confirming the paradox even in this model, genistein alone induced metastasis to lymph nodes but afforded significant protection when combined with radiation therapy. It was later suggested that induction of metastasis in the lymph nodes by genistein alone involves induction of HIF-1α (66). Also, a mixture of soy isoflavones (genistein + daidzein + glycitein, Fig 1) potentiated radiotherapy almost similar to genistein alone but did not induce metastasis by itself in the absence of radiation therapy.…”

Dietary Manipulation for Therapeutic Effect in Prostate Cancer

“…Synergy or enhanced activity has been reported in prostate cancer cell lines using isoflavones in combination with paclitaxel (Ping et al, 2010), radiation (Raffoul et al, 2007), and docetaxel (Burich et al, 2008). Phenoxodiol, a novel isoflavone, in combination with cisplatin has been shown to be synergistic against DU145 cells and probably additive in PC3 cells (McPherson et al, 2009).…”

“…Phenoxodiol, a novel isoflavone, in combination with cisplatin has been shown to be synergistic against DU145 cells and probably additive in PC3 cells (McPherson et al, 2009). In vivo combination therapy of soy isoflavones and radiation for prostate cancer has also been investigated, with favorable effects on the control of the disease (Raffoul et al, 2007;Wang et al, 2006). Docetaxel effect in castration-resistant prostate cancer patients was improved by lycopene via insulin-like growth factor 1 receptor perturbation (Tang et al, 2011).…”