Abstract
The cytotoxicity of two compounds described as anti-angiogenic, the isoflavone genistein and the oestrogen metabolite 2-methoxyestradiol, has been studied in different human tumour cell lines. Since the degradation of the extracellular matrix is one of the essential steps in angiogenesis, the potential modulatory effects of both compounds on the proteolytic balance in media conditioned by different human tumour cells have been also investigated. The IC50 values for 2-methoxyestradiol were lower than those for genistein on all the cell lines tested. In all the cell lines expressing measurable amounts of active enzymes, genistein induced a shift towards antiproteolysis in both matrix metalloproteinase/tissue inhibitor of metalloproteinase and urokinase/plasminogen activator inhibitor proteolytic balances. On the other hand, 2-methoxyestradiol did not produce any clear net shift of the proteolytic balance, with the significant exception of the matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in WAC-2 cells, a neuroblastoma cell line with enhanced expression of the N-myc oncogene.
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References
Akiyama, T., Ishida, I., Nakagawa, S., Ogawara, H., Watanabe, S., Itoh, N., Shibuya, M. & Fuami, Y. (1987) Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 262: 5592–5595.
Alvarez, O., Carmichael, D. F. & Declerk, Y. A. (1990) Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst 82: 589–595.
Andreasen, P. A., Georg, B., Lund, L. R., Riccio, A. & Stacey, S. N. (1990) Plasminogen activators inhibitors: hormonally regulated serpins. Mol Cell Endocrinol 68: 1–19.
Barnes, S., Peterson, G., Grubbs, C. & Setchell, K. (1994). Potential role of dietary isoflavones in the prevention of cancer. In Diet and Cancer: Markers, Prevention, and Treatment, Jacubs MM (ed) pp. 135–147. Plenum Press: New York
Blasi, F., Riccio, A. & Sebatio, G. (1986). Human plasminogen activators: genes and protein structure. In Human Genes and Diseases, Blasi F (ed), pp. 377–414. Wiley: London
D’Amato, R. J., Lin, C. M., Flynn, E., Folkman, J. & Hamel, E. (1994) 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc Natl Acad Sci USA 91: 3964–3968.
Danø, K., Andreasen, P. A., Grøhndahl-Hansen, J., Kristensen, P., Nielsen, L. S. & Skriver, L. (1985) Plasminogen activators, tissue degradation and cancer. Adv Cancer Res 44: 139–266.
Donaldson, K. L., Goolsby, G., Kiener, P. A. & Wahl, A. F. (1994) Activation of p34dcd2 coincident with taxol-induced apoptosis. Cell Growth Differ 5: 1041–1050.
Dunn, J. E. (1975) Cancer epidemiology in populations of the United States – with emphasis on Hawaii and California – and Japan. Cancer Res 35: 3240–3245.
Edmonard, H. & Grimaud, J. A. (1990) Matrix metalloproteinases. A review. Cell Mol Biol 36: 131–153.
Folkman, J. (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med 1: 27–31.
Folkman, J. & Shing, Y. (1992) Angiogenesis. J Biol Chem 267: 10931–10934.
Fotsis, T., Pepper, M., Adlercreutz, H., Fleischman, G., Hase, T., Montesano, R. & Schweigerer, L. (1993) Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci USA 90: 2690–2694.
Fotsis, T., Zhang, Y., Pepper, M. S., Adlercreutz, H., Montesano, R., Nauroth, P. P. & Schweigerer, L. (1994) The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature 368: 237–239.
García de Veas, R., Schweigerer, L. & Medina, M. A. (1995) Matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression in paediatric tumor cells. Effects of tumor cell proliferation modulators on gelatinolytic activity. J Cancer Res Clin Oncol 121: 275–278.
Gohji, K., Fujimoto, N., Fujii, A., Komiyama, T., Okawa, J. & Nakajima, M. (1996) Prognostic significance of circulating matrix metalloproteinase-2 to tissue inhibitor of metalloproteinases-2 ratio in recurrence of urothelial cancer after complete resection. Cancer Res 56: 3196–3198.
Gorczyca, W., Gong, J., Ardelt, B., Traganos, F. & Darzynkiewicz, Z. (1993) The cell cycle related differences in susceptibility of HL-60 cells to apoptosis induced by various antitumor agents. Cancer Res 53: 3186–3192.
Holmgren, L., O’Reilly, M. S. & Folkman, J. (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med 1: 149–153.
Kohn, E. C. & Liotta, L. A. (1995) Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res 55: 1856–1862.
Lau, H. K. F., Kim, M., Koo, J., Chiu, B. & Murray, D. (1995) Increase of a urokinase receptor-related low-molecular-weight molecule in colorectal adenocarcinomas. Clin Exp Metastasis 13: 492–498.
Liotta, L. A., Tryggvason, K., Garbisa, S., Hart, I. R., Foltz, C. M. & Shaflie, S. (1980) Metastatic potential correlates with enzymatic degradation of basement matrix collagen. Nature 284: 67–69.
Liotta, L., Rao, C. N. & Bardsky, S. H. (1983) Tumor invasion and the extracellular matrix. Lab Invest 49: 639–649.
Liotta, L. A., Steeg, P. S. & Stetler-Stevenson, W. G. (1991) Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336.
Messina, M. J., Persky, V., Setchell, K. D. R. & Barnes, S. (1994) Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr Cancer 21: 113–131.
Montesano, R. (1992) Regulation of angiogenesis in vitro. Eur J Clin Invest 22: 504–515.
Mossmann, T. (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Method 65: 55–63.
Nuovo, G. J., MacConnell, P. B., Simsir, A., Valea, F. & French, D. L. (1995) Correlation of the in situ detection of polymerase chain reaction-amplified metalloproteinase complementary DNAs and their inhibitors with prognosis in cervical carcinoma. Cancer Res 55: 267–275.
Packman, K. S., Demeure, M. D., Doffek, K. M. & Wilson, S. D. (1995) Increased plasminogen activator and type IV collagenase activity in invasive follicular thyroid carcinoma cells. Surgery 118: 1011–1017.
Parker, S. L., Tong, T., Bolden, S. & Wingo, P. A. (1996) Cancer statistics. CA Cancer J Clin 65: 5–27.
Peterson, G. & Barnes, S. (1991) Genistein inhibition of the growth of human breast cancer cells: independence from estrogen receptors and the multi-drug resistance gene. Biochem. Biophys Res Commun 179: 661–667.
Peterson, G. & Barnes, S. (1996) Genistein inhibits both estrogen and growth factor-stimulated proliferation of human breast cancer cells. Cell Growth Differ 7: 1345–1351.
Schweigerer, L., Breit, S., Wenzel, A., Tsunamoto, K., Ludwig, R. & Schwab, M. (1990) Augmented N-MYC expression advances the malignant phenotype of human neuroblastoma cells: evidence for induction of autocrine growth factor activity. Cancer Res 50: 4411–4416.
Schweigerer, L., Christeleit, K., Fleischmann, G., Adlercreutz, H., Wahala, K., Hase, T., Schwab, M., Ludwig, R. & Fotsis, T. (1992) Identification in human urine of a natural growth inhibitor for cells derived from solid paediatric tumors. Eur J Clin Invest 22: 260–264.
Severson, R. K., Nomura, A. M. Y., Grove, J-S & Stemmerman, G. N. (1989) A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res 49: 1857–1860.
Stearns, M. E. & Wang, M. (1993) Type IV collagenase (MWr 72,000) expression in human prostate: benign and malignant tissue. Cancer Res 53: 878–883.
Tsuchiya, Y., Sato, H., Endo, Y., Okada, Y., Mai, M., Takuma, S. & Seiki, M. (1993) Tissue inhibitor of metalloproteinase 1 is a negative regulator of the metastatic ability of a human gastric cancer cell line, kkls, in the chick embryo. Cancer Res 53: 1397–1402.
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Fajardo, I., Quesada, A., Castro, I. et al. A comparative study of the effects of genistein and 2-methoxyestradiol on the proteolytic balance and tumour cell proliferation. Br J Cancer 80, 17–24 (1999). https://doi.org/10.1038/sj.bjc.6690315
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DOI: https://doi.org/10.1038/sj.bjc.6690315
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