Soy is a safe and potent radiosensitizer for prostate cancer in vitro and in vivo compared to pure genistein.

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To improve prostate cancer (PCa) radiotherapy, we have previously shown that purified genistein, the major component of soy, was a potent radiosensitizer and potentiated tumor cell killing in vitro and in vivo. Pre-treatment with genistein enhanced radiation-induced cell killing of PC-3 human PCa cells, and genistein administered before and after tumor irradiation enhanced primary tumor growth inhibition and controlled metastasis to lymph nodes using an orthotopic metastatic PCa model of PC-3 cells in nude mice. Paradoxically, in this model, single therapy with purified genistein caused increased spontaneous metastasis to para-aortic regional lymph nodes. To clarify whether a formulation of soy (43% genistein + 21% daidzein + 2% glycitein) representative of the soy pills used to treat patients abrogates increased metastasis observed with pure genistein, we investigated the effect of soy alone and combined with radiation on PCa in vitro and in vivo. We found that the formulation of soy was more potent than pure genistein at inhibition of PC-3 cell colony formation and potentiated radiation-induced cell killing in a clonogenic assay. Furthermore, soy was more potent than pure genistein at decreasing activation of NF-κB, a transcription factor critically involved in cancer cell survival. Like pure genistein, soy also abrogated radiation-induced activation of NF-κB. We also investigated the effect of soy or genistein alone and combined with radiation on the expression of APE1/Ref-1, a DNA repair/redox protein implicated in tumor cell survival and radioresistance. Soy and genistein alone were effective at downregulating APE1/Ref-1 expression, with soy being more potent, while each considerably reduced APE1/Ref-1 upregulation in response to radiation. Based on studies demonstrating a link between APE1/Ref-1 redox activity and NF-κB, we propose a mechanism of increased cell death following treatment with soy isoflavones by decreasing APE1/Ref-1 redox-mediated activation of NF-κB. This hypothesis was confirmed by concomitant changes in cleaved PARP protein, a marker for apoptosis. Moreover, soy treatment alone did not promote increased metastasis to lymph nodes in contrast to purified genistein in our in vivo model. The combination of soy with prostate tumor irradiation led to greater control of primary tumor growth and metastasis than soy or radiation alone, similar to our previous findings with pure genistein. Histologically, tumors treated with soy and radiation confirmed greater tumor destruction with extensive apoptosis, fibrosis and abnormalities in residual tumor cells, e.g., atypical giant cells, than tumors treated with soy or radiation alone. Our studies demonstrate the safety and potential for the use of soy formulation to enhance clinical strategies for prostate cancer radiotherapy and suggest potential targets for novel therapeutic agents.