The effects of 2-methoxy oestrogens and their sulphamoylated derivatives in conjunction with TNF-α on endothelial and fibroblast cell growth, morphology and apoptosis
Ho, Y. T., Newman, S. P., Purohit, A., Leese, M. P., Potter, B. V. L. and Reed, M. J., 2003. The effects of 2-methoxy oestrogens and their sulphamoylated derivatives in conjunction with TNF-α on endothelial and fibroblast cell growth, morphology and apoptosis. Steroid Biochemistry & Molecular Biology, 86 (2), pp. 189-196.
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2-Methoxyoestradiol (2-MeOE2) is a potent anti-angiogenic agent. Its 3- and 17-sulphamoylated derivatives have been demonstrated to induce G(2)-M Cell cycle arrest and apoptosis in breast cancer cells in vitro as well as tumour regression in rats in vivo with greater potency than the parent oestrogen. To determine whether the anti-cancer properties of these derivatives can be synergistically enhanced with low-dose TNF-alpha co-treatment, we investigated the effects of these treatments in adult human fibroblasts and human umbilical vein endothelial cells (HUVECs). Treatment of fibroblasts with 0.1 muM 2-methoxyoestradiol-3,17-bis sulphamate (2-MeOE2bisMATE) but not 2-MeOE2 caused a reversible morphology change and induced G(2)-M arrest (from 12 to 33%) but not subsequent apoptosis. In contrast, treatment of HUVECs did not induce morphology change or G(2)-M arrest. Using a nucleosomal ELISA assay, we showed that TNF-alpha (20 ng/ml) combination treatment synergistically increases 0.1 muM 2-MeOE2bisMATE-induced but not 0.1 muM 2-MeOE2-induced apoptosis in HUVECs. These results suggest that TNF-alpha co-treatment may be a beneficial method of increasing the potency of 2-substituted oestrogens as anti-angiogenic agents through synergistic induction of apoptosis in endothelial cells while maintaining low cytotoxicity to fibroblasts. (C) 2003 Elsevier Ltd. All rights reserved.
|Creators||Ho, Y. T., Newman, S. P., Purohit, A., Leese, M. P., Potter, B. V. L. and Reed, M. J.|
|Departments||Faculty of Science > Pharmacy & Pharmacology|
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