Abstract 5541: Daidzein protects against genistein-induced lymph node metastasis, and serve as a radiosensitizer in prostate cancer

Abstract

Abstract We have previously reported that genistein, the major bioactive isoflavone of soybeans, acts as a radiosensitizer for prostate cancer (PCa) both in vitro and in orthotopic mouse models in vivo. However, pure genistein promoted increased spontaneous metastasis to regional lymph nodes, when administered alone in vivo. In contrast to genistein, a natural formulation of soy isoflavones mixture (43% genistein, 21% daidzein and 2% glycitein) did not cause increased metastasis, but like genistein, the soy mixture potentiated the therapeutic effect of radiation. We have now tested whether daidzein, the second main isoflavone of soybeans, could negate genistein-induced lymph node metastasis in PC-3 orthotopic prostate tumors in nude mice. Mice were treated with purified daidzein, or genistein or both combined; and also in conjunction with prostate tumor irradiation. Either daidzein or genistein alone or both combined caused the same extent of prostate tumor growth inhibition than the soy mixture. Treatment with daidzein alone did not increase metastasis to regional lymph nodes but still acted as a potent radiosensitizer for prostate tumors. Treatment with both genistein and daidzein combined did not cause an increase in lymph node metastasis, which is consistent with the findings obtained with the soy mixture. These studies show that pure daidzein could be the component of the soy isoflavones mixture that protects against genistein-induced lymph node metastasis. In order to gain further mechanistic insight on how daidzein negates the adverse effects of genistein, we compared the effects of each isoflavone and the soy mixture in vitro using PC-3 (androgen receptor AR-) and C4-2B (AR+) androgen independent PCa cell lines. We found that daidzein inhibited tumor cell growth and synergized with radiation in clonogenic assays but at doses higher than genistein or the soy mixture. We have previously demonstrated that genistein or the soy mixture cause tumor cell apoptosis and enhance radiation killing by inhibiting cell survival pathways activated by radiation including the repair enzyme/redox activator APE1/Ref-1 and the transcription factors HIF-1α and NF-κB. Compared to the effect of genistein or the soy mixture, daidzein treatment caused milder effects on PARP cleavage, inhibition of expression of APE1/Ref-1 and HIF-1α; and lower inhibition of HIF-1α and NF-κB DNA binding activities. These effects were reproduced in both PC-3 and C4-2B cell lines. Based on these results, we conclude that APE1/Ref-1, NF-κB and HIF-1α molecular pathways were also affected by daidzein, although to a lesser extent than genistein and soy mixture, in both AR+ and AR- PCa cancer cell lines, suggesting that this is an AR-independent mechanism. The protective effect of daidzein against lymph node metastasis induced by genistein appears to be independent of HIF-1α and NF-κB pathways, and remains to be clarified. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5541.