Isoflavone Research Initiative

Neoangiogenesis is a decisive step in the development of tumours. The cancer needs a sufficient supply of oxygen and nutrients for proper growth. This supply is ensured by a dense system of newly formed microcapillaries. A recent strategy in cancer treatment is the inhibition of neoangiogenesis, the new formation of such microvessels.

The mechanisms of angiogenesis are well-known. Each step in the chain of events leading to angiogenesis is a potential therapeutic target against tumour growth. The signalling cascade is complex and involves a multitude of factors which by themselves will activate enzymes or genes, lead to the formation of certain receptors, or facilitate the migration of cells (outwards for cancer metastases, inwards for endothelial cells needed for microvessel formation).
 
Natural isoflavones and synthetic derivatives have effects on various levels of the signalling cascade of neoangiogenesis, as demonstrated in vitro and in animal experiments (Gamble et al. 2006). Currently, tyrosine kinase inhibitors are tested as potential antiangiogenetic drugs in cancer research. Like genistein they reduce the density of microcapillaries and inhibit the formation of the vascular endothelial growth factor VEGF (Oh et al. 2005). Genistein is also known to inhibit tyrosine kinase – the inhibition of this enzyme by genistein might contribute to the antiangiogenetic effect of the isoflavones.

A synthetic analogue of genistein and daidzein, the isoflavone phenoxodiol (Constantinou and Husband 2002) is currently developed for the application in combination with cytostatics. The aim is the improvement of the efficacy and tolerability of cytostatics such as cisplatin (Alvero et al. 2007; Choueiri et al. 2006a; Choueiri et al. 2006b; de Souza et al. 2006; Klein et al. 2007; Kluger et al. 2007; Mor et al. 2006; Morre et al. 2007). First clinical studies with positive outcome have been published (Choueiri et al. 2006a; Choueiri et al. 2006b; de Souza et al. 2006).
 
The development of substances with marginally changed structure when compared with genistein or daidzein was probably motivated by the possibility of patenting, but is still based on the known characteristics of natural isoflavones. The same effects as demonstrated for phenoxodiol in experimental studies have also been observed with genistein. Moreover, even the clinical findings with phenoxodiol are mirrored in the clinical observations with natural isoflavones.

The principle of tumour treatment by anti-angiogenesis has already been introduced in therapy, e.g., with squalamin (Kiriakidis et al. 2005). The effect can be increased with genistein: In preclinical experiments the combination of a chemical inhibitor of neoangiogenesis and of genistein was found superior over the single drug substance (Pietras and Weinberg 2005).
 
Synergistic effects of genistein with drugs such as tamoxifen, cisplatin, BCNU, dexamethasone, daunorubicin and tiazofurin have been described. Genistein improves the efficiency of radiation therapy in breast and prostate cancer (Ravindranath et al. 2004). In mice genistein also improved the anti-angiogenetic effects of cisplatin, fluorouracil and radiation therapy. Under addition of genistein the density of microcapillaries, the formation of VEGF and the tumour volume was found reduced (McDonnell et al. 2004).

In concentrations which are not cytotoxic (0.1-50 µM) genistein inhibits the formation of the spindle apparatus and the mobility of melanoma and breast cancer cells of the mouse in vitro. At doses of 10 mg/kg per day (intraperitoneally) this effect of genistein translates into a reduced formation of microcapillaries. Similar effects have also been reached with a soy-based nutrition (Farina et al. 2006).

References

Alvero, A. B., Brown, D., Montagna, M., Matthews, M., and Mor, G. (2007). Phenoxodiol-Topotecan co-administration exhibit significant anti-tumor activity without major adverse side effects. Cancer Biol. Ther. 6 (4): 612-617.

Choueiri, T. K., Mekhail, T., Hutson, T. E., Ganapathi, R., Kelly, G. E., and Bukowski, R. M. (2006a). Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer. Ann. Oncol. 17 (5): 860-865.

Choueiri, T. K., Wesolowski, R., and Mekhail, T. M. (2006b). Phenoxodiol: isoflavone analog with antineoplastic activity. Curr. Oncol. Rep. 8 (2): 104-107.

Constantinou, A. I. and Husband, A. (2002). Phenoxodiol (2H-1-benzopyran-7-0,1,3-(4-hydroxyphenyl)), a novel isoflavone derivative, inhibits DNA topoisomerase II by stabilizing the cleavable complex. Anticancer Res. 22 (5): 2581-2585.

de Souza, P. L., Liauw, W., Links, M., Pirabhahar, S., Kelly, G., and Howes, L. G. (2006). Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol), a novel isoflav-3-ene, in patients with advanced cancer. Cancer Chemother. Pharmacol. 58 (4): 427-433.

Farina, H. G., Pomies, M., Alonso, D. F., and Gomez, D. E. (2006). Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer. Oncol. Rep. 16 (4): 885-891.

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.

Kiriakidis, S., Hogemeier, O., Starcke, S., Dombrowski, F., Hahne, J. C., Pepper, M., Jha, H. C., and Wernert, N. (2005). Novel tempeh (fermented soyabean) isoflavones inhibit in vivo angiogenesis in the chicken chorioallantoic membrane assay. Br. J. Nutr. 93 (3): 317-323.

Klein, R., Brown, D., and Turnley, A. M. (2007). Phenoxodiol protects against Cisplatin induced neurite toxicity in a PC-12 cell model. BMC Neurosci. 8: 61

Kluger, H. M., McCarthy, M. M., Alvero, A. B., Sznol, M., Ariyan, S., Camp, R. L., Rimm, D. L., and Mor, G. (2007). The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by Phenoxodiol is associated with Carboplatin sensitization. J. Transl. Med 5: 6-21.

McDonnell, C. O., Holden, G., Sheridan, M. E., Foley, D., Moriarty, M., Walsh, T. N., and Bouchier-Hayes, D. J. (2004). Improvement in efficacy of chemoradiotherapy by addition of an antiangiogenic agent in a murine tumor model. J. Surg. Res. 116 (1): 19-23.

Mor, G., Fu, H. H., and Alvero, A. B. (2006). Phenoxodiol, a novel approach for the treatment of ovarian cancer. Curr. Opin. Investig. Drugs 7 (6): 542-548.

Morre, D. J., Chueh, P. J., Yagiz, K., Balicki, A., Kim, C., and Morre, D. M. (2007). ECTO-NOX target for the anticancer isoflavene phenoxodiol. Oncol. Res. 16 (7): 299-312.

Oh, H. Y., Kwon, S. M., Kim, S. I., Jae, Y. W., and Hong, S. J. (2005). Antiangiogenic effect of ZD1839 against murine renal cell carcinoma (RENCA) in an orthotopic mouse model. Urol. Int. 75 (2): 159-166.

Pietras, R. J. and Weinberg, O. K. (2005). Antiangiogenic Steroids in Human Cancer Therapy. Evid. Based Complement Alternat. Med 2 (1): 49-57.

Ravindranath, M. H., Muthugounder, S., Presser, N., and Viswanathan, S. (2004). Anticancer therapeutic potential of soy isoflavone, genistein. Adv. Exp. Med Biol. 546: 121-165.