The effects of 2-methoxy oestrogens and their sulphamoylated derivatives in conjunction with TNF-α on endothelial and fibroblast cell growth, morphology and apoptosis

Y. T. Ho, S. P. Newman, A. Purohit, M. P. Leese, B. V. L. Potter, M. J. Reed

Research output: Contribution to journalArticle

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Abstract

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.
Original languageEnglish
Pages (from-to)189-196
JournalSteroid Biochemistry & Molecular Biology
Volume86
Issue number2
DOIs
Publication statusPublished - 2003

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Endothelial cells
Cell growth
Fibroblasts
Estrogens
Endothelial Cells
Tumor Necrosis Factor-alpha
Apoptosis
Derivatives
Human Umbilical Vein Endothelial Cells
Growth
Cells
Therapeutics
Cytotoxicity
Rats
Tumors
Assays
Cell Cycle Checkpoints
Neoplasms
Enzyme-Linked Immunosorbent Assay
Breast Neoplasms

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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.; Reed, M. J.

In: Steroid Biochemistry & Molecular Biology, Vol. 86, No. 2, 2003, p. 189-196.

Research output: Contribution to journalArticle

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AB - 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.

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