Isoflavone Research Initiative

In contrast to healthy cells, where apoptosis (the programmed cell death) is one of the mechanisms of remaining in control of possibly pathologic conditions, the rate of apoptosis is strongly reduced in cancer cells, rendering cancer cells practically immortal. One of the aims of cancer prevention and treatment is therefore to re-establish a normal rate of apoptosis. Effects of secondary plant metabolites on the rate of apoptosis can be measured in experimental studies. In the case of the isoflavones the relevance of such findings from in vitro-studies has been amply demonstrated in animal experiments. Most importantly, it is consistent with the clinical and epidemiological observations.

Genistein and its synthetic analogues can stop the cell cycle, increase apoptosis in cancer cells, and inhibit angiogenesis (Gamble et al. 2006). Apoptosis seems to be related to ER-β. For instance, the induction of prostate cancer by estrogen correlates with a loss of ER-β. ER-β-agonists such as genistein trigger apoptosis on malign cells, and block angiogenesis (Ho 2004).

Genistein inhibits the growth of human bladder cancer cells in vitro. This effect was attributed to the reduction of the expression of NF-κB and the induction of apoptosis. The application of the glycoside genistin and a soy extract in mice led to the reduction of tumour weight by 56-52 %, an increase of apoptosis and an inhibition of angiogenesis in the tumour. In addition, the soy extract, but not the glycoside genistin inhibited the formation of metastases in the lungs by 95 %, and reduced the expression of NF-κB in tumour tissue (Singh et al. 2006).

Similar effects have been found with liver carcinoma cells in mice: genistein inhibited the growth and the invasive potential of cancer cells in vitro, and increased apoptosis. In vivo, genistein delayed tumour growth and inhibited the invasion of cancer cells into the kidney parenchyma in xenotransplanted animals. Again, genistein was found to inhibit angiogenesis (Gu et al. 2005).

Isoflavones reduce the viability of human PC-3 prostate cancer cells, next to reducing DNA biosynthesis. The effect was due to the aglycones. By gene analysis an inhibition of the expression of the interleukine IL-8 and the matrix metalloprotease MMP-13, and the induction of a protein with inhibiting impact on the cell cycle was found. The most obvious effect was found with genes related to cell division, formation of metastases and angiogenesis (Handayani et al. 2006).

In conclusion, the effects of isoflavones on the rate of apoptosis in tumour cells cannot be separated from the synergistic mechanisms of isoflavones on angiogenesis and other effects contributing to an overall cancer-preventive effect.

References

Gamble, J. R., Xia, P., Hahn, C. N., Drew, J. J., Drogemuller, C. J., Brown, D., and Vadas, M. A. (2006). Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects. Int. J. Cancer 118 (10): 2412-2420.

Gu, Y., Zhu, C. F., Iwamoto, H., and Chen, J. S. (2005). Genistein inhibits invasive potential of human hepatocellular carcinoma by altering cell cycle, apoptosis, and angiogenesis. World J. Gastroenterol. 11 (41): 6512-6517.

Handayani, R., Rice, L., Cui, Y., Medrano, T. A., Samedi, V. G., Baker, H. V., Szabo, N. J., and Shiverick, K. T. (2006). Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J. Nutr. 136 (1): 75-82.

Ho, S. M. (2004). Estrogens and anti-estrogens: key mediators of prostate carcinogenesis and new therapeutic candidates. J. Cell Biochem. 91 (3): 491-503.

Singh, A. V., Franke, A. A., Blackburn, G. L., and Zhou, J. R. (2006). Soy phytochemicals prevent orthotopic growth and metastasis of bladder cancer in mice by alterations of cancer cell proliferation and apoptosis and tumor angiogenesis. Cancer Res. 66 (3): 1851-1858.