The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth

Abstract

The formation of new blood vessels (angiogenesis) is critical for the growth of tumours and is a dominant feature in various angiogenic diseases such as diabetic retinopathy, arthritis, haemangiomas and psoriasis. Recognition of the potential therapeutic benefits of controlling pathological angiogenesis has led to a search for angiogenesis inhibitors. Here we report that 2-methoxyoestradiol, an endogenous oestrogen metabolite of previously unknown function, is a potent inhibitor of endothelial cell proliferation and migration as well as angiogenesis in vitro. Moreover, when administered orally in mice, it strongly inhibits the neovascularization of solid tumors and suppresses their growth. Unlike the angiostatic steroids of corticoid structure, it does not require the co-administration of heparin or sulphated cyclodextrins for activity. Thus, 2-methoxyoestradiol is the first steroid to have high antiangiogenic activity by itself. Our results suggest that this compound may have therapeutic potential in cancer and other angiogenic diseases.

Thiram inhibits angiogenesis and slows the development of experimental tumours in mice

“…Inhibition of SOD-1 by TR could decrease the capacity of endothelial cells to scavenge the increased level of superoxides, resulting in growth arrest, apoptosis, and inhibition of angiogenesis. These data are in good agreement with recent findings demonstrating that another SOD-1 inhibitor (Huang et al, 2000) -2-methoxyoestradiol is also anti-angiogenic (Fotsis et al, 1994). No damage was observed in already established (non-proliferating) blood vessels in the treated animals.…”

“…Since angiogenesis is characterised by proliferating endothelial cells and reoxygenation, we speculated that inhibition of SOD-1 will diminish the ability of endothelial cells to confront the increased level of ROS during angiogenesis, thus, resulting in inhibition of angiogenesis, of tumour development and metastasis. This assumption is consistent with recent findings demonstrating that the anti-angiogenic compound 2-methoxyoestradiol (Fotsis et al, 1994) is a SOD-1 inhibitor (Huang et al, 2000).…”

Superinduction of wild-type p53 protein after 2-methoxyestradiol treatment of Ad5p53-transduced cells induces tumor cell apoptosis

“…Indeed, 2-MeOE 2 has been shown to reduce the tumor vascularization critical for tumor growth in vivo and to be noncytotoxic to normal human skin ®broblasts even at a concentration of 100 mM (Fotis et al, 1994). However, the mechanism whereby 2-MeOE 2 can increase wt p53 levels is not clear.…”

In vitro and in vivo antitumor effect of 2‐methoxyestradiol on human melanoma

“…Potential mechanisms of its in vivo action included decreasing the proliferation rate or apoptosis induction of tumor cells, or the inhibition of vascularization. 14,15,25,36,37 There are few data available on the effects of 2ME 2 on human melanoma cells. In a recent report, apoptosis induction in 1 melanoma cell line was documented.…”

“…10,11,14 -16 2ME 2 has been demonstrated to induce G 2 /M cell cycle arrest and apoptosis in a variety of tumor cell lines in vitro, 10,[17][18][19][20] and to inhibit the growth and vascularization of primary tumors, or lung colony formation in mice injected with murine or human tumor cells. 10,11,14,15,17,18,20,21 Several mechanisms of action have been suggested for the effects of 2ME 2 . Its antiproliferative activity has been attributed to the disruption of microtubule function through its effects on tubulin polymerization or depolymerization, or altering microtubule stability.…”