The effect of 2-methoxyoestrone-3-O-sulphamate on the growth of breast cancer cells and induced mammary tumours

Abstract

2‐Methoxyoestrogens are emerging as a new class of drug that can inhibit tumour growth and angiogenesis. As sulphamoylation of oestrogens enhances their potency and bioavailability we have synthesized 2‐methoxyoestrone‐3‐O‐sulphamate (2‐MeOEMATE) and compared its ability to inhibit the proliferation of breast cancer cells with that of 2‐methoxyoestrone (2‐MeOE1). 2‐MeOEMATE (1 μM) inhibited the growth of oestrogen receptor positive MCF‐7 breast cancer cells by 52% whereas 2‐MeOE1 had little effect at this concentration. 2‐MeOEMATE also inhibited the growth of oestrogen receptor negative MDA‐MB‐231 breast cancer cells. Exposure of cells to 2‐MeOEMATE caused them to round up and become detached suggesting that this compound may induce cells to undergo apoptosis. Cell cycle analysis revealed that 2‐MeOEMATE caused cells to arrest in the G2/M phase with the increase in G2/M arrested cells being detectable by 12 hr. Exposure of MCF‐7 cells to 2 L‐MeOEMATE for 24 hr followed by culture in drug‐free medium for 24 hr did not reverse the arrest of cells in the G2/M phase. TUNEL analysis confirmed that 2‐MeOEMATE induced apoptosis in a significant proportion of treated MCF‐7 cells. In an in vivo study, employing nitrosomethylurea‐induced mammary tumours in intact rats, 2‐MeOE1 (20mg/kg/d, p.o. for 11 days) had little effect on tumour growth. In contrast, the same dose of 2‐MeOEMATE resulted in the almost complete regression of 2/3 tumours over an 11‐day period. We conclude that 2‐MeOEMATE should have considerable therapeutic potential for the treatment of breast tumours. Int. J. Cancer 85:584–589, 2000. © 2000 Wiley‐Liss, Inc.

Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiolmono- andbis-3-O-sulphamates

“…39 It has previously been reported that a sulphamoylated analogue, 2-MeOEMATE, also induces BCL-2 phosphorylation in MCF-7 cells, leading to the induction of apoptosis. 24,25 In the present study, it was observed that all the sulphamoylated oestrogen derivatives tested have similar effects on the BCL-2 protein. At 1 lM the sulphamoylated analogues induced extensive phosphorylation of the BCL-2 protein, while 2-MeOE2 induced a lesser degree of phosphorylation.…”

“…[24][25][26][27] In MDA-MB-231 cells, while 2-MeOE2 induced a reversible G2-M arrest, the effects induced by sulphamoylated derivatives were irreversible. Similar reversible effects with 2-MeOE2 have also been reported for other cell lines.…”

“…49 Sulphation of 2-MeOE2 to 2-MeOE2-3-sulphate results in abolition of the antiproliferative effects induced by 2-MeOE2, 48 and additional oxidation at C-17 by 17-hydroxysteroid dehydrogenase type 2 generates the less potent oestrone derivative. 24,25,48 It is therefore likely that other nonsulphamoylated compounds are also sulphated and/or oxidised, leading to the formation of inactive derivatives. Subtle changes like these may change the overall conformation of the derivatives, and therefore may interfere with their biologic properties, such as uptake by cells or interaction with specific proteins like tubulin.…”

“…24,25 2-MeOEMATE also inhibited the growth of NMU-induced mammary tumours in rats. 24 Recently it has been shown that sulphamoylated oestradiol derivatives inhibit the cell cycle progression and cell proliferation of an array of normal and drug-resistant breast cancer, prostate, and ovarian cancer cells in vitro. 26,27 In addition, 2-methoxy and 2-ethyl E2-3-O-sulphamates inhibited HUVEC cell proliferation and in vitro angiogenesis.…”

“…23 We have previously demonstrated that oestrone derivatives with short-chain substitution at the C-2 position and sulphamoylation at the C-3 position, such as 2-methoxyoestrone-3-O-sulphamate (2-MeOE-MATE) and 2-ethyloestrone-3-O-sulphamate (2-EtEMATE), induce irreversible G2-M cell cycle arrest and initiate apoptosis. 24,25 2-MeOEMATE also inhibited the growth of NMU-induced mammary tumours in rats. 24 Recently it has been shown that sulphamoylated oestradiol derivatives inhibit the cell cycle progression and cell proliferation of an array of normal and drug-resistant breast cancer, prostate, and ovarian cancer cells in vitro.…”