The Role of 17β-Hydroxysteroid Dehydrogenases in Modulating the Activity of 2-Methoxyestradiol in Breast Cancer Cells

Abstract

The bis -sulfamoylated derivative of 2-methoxyestradiol (2-MeOE2), 2-methoxyestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE), has shown potent antiproliferative and antiangiogenic activity in vitro and inhibits tumor growth in vivo. 2-MeOE2bisMATE is bioavailable, in contrast to 2-MeOE2 that has poor bioavailability. In this study, we have examined the role of 17B-hydroxysteroid dehydrogenase (17B-HSD) type 2 in the metabolism of 2-MeOE2. In MDA-MB-231 cells, which express high levels of 17B-HSD type 2, and in MCF-7 cells transfected with 17B-HSD type 2, highperformance liquid chromatography analysis showed that a significant proportion of 2-MeOE2 was metabolized to inactive 2-methoxyestrone. Furthermore, MCF-7 cells transfected with 17B-HSD type 2 were protected from the cytotoxic effects of 2-MeOE2. In contrast, no significant metabolism of 2-MeOE2bisMATE was detected in transfected cells and 17B-HSD type 2 transfection did not offer protection against 2-MeOE2bisMATE cytotoxicity. This study may go some way to explaining the poor bioavailability of 2-MeOE2, as the gastrointestinal mucosa expresses high levels of 17B-HSD type 2. In addition, this study shows the value of synthesizing sulfamoylated derivatives of 2-MeOE2 with C17-position modifications as these compounds have improved bioavailability and potency both in vitro and in vivo. (Cancer Res 2006; 66(1): 324-30)

Novel in silico-designed estradiol analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations

“…The anti-proliferative effect of 2ME has been shown to stem, at least partially, from its ability to inhibit tubulin assembly through its interaction with the protein at the colchicine site [9,10,23]. The inhibition of pure tubulin polymerization in the in vitro assay indicates that the sulphamoylated compounds are also able to impact tubule formation.…”

“…Advantages of 2ME over classic microtubule poisons include a better tolerated side effect profile, preferential sparing of non-malignant cells, and its inability to function as a substrate of the P-glycoprotein efflux pumps [7,8]. A shortcoming of the compound is its rapid 17 β-hydroxysteroid dehydrogenase mediated metabolism resulting in a poor pharmacokinetic profile [9].…”

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

“…administration of 2-MeOE2bisMATE (Ireson et al, 2004). It is now known that sulphamoylated derivatives of oestrogens have a superior pharmacokinetic profile and are more resistant to metabolism than their non-sulphamoylated counterparts (Newman et al, 2006). Oestrogen sulphamates, such as oestrone-3-Osulphamate (EMATE) were originally identified as potent STS inhibitors, a property shared with 2-MeOE2bisMATE (Raobaikady et al, 2005).…”

“…2-MeOE2 is currently in phase I/II trials for the treatment of breast and prostate cancer but relatively high doses (up to 6 g day À1 ) are used (Dahut et al, 2006). The reason for this is that 2-MeOE2 has a very low bioavailability and is rapidly inactivated by conjugation and oxidation of the hydroxyl groups at the C3/C17 positions of the oestrane nucleus (Liu et al, 2005;Newman et al, 2006). Furthermore, 2MeOE2 has been shown to exhibit mitogenic effects in ER-positive cells that were mediated through the oestrogen receptor (Liu and Zhu, 2004).…”

BCRP expression does not result in resistance to STX140 in vivo, despite the increased expression of BCRP in A2780 cells in vitro after long-term STX140 exposure

“…One of the most efficacious of these compounds is 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140). It is highly anti-proliferative and anti-angiogenic in vitro (Raobaikady et al, 2003;Newman et al, 2004), and is orally bioavailable (Ireson et al, 2004;Newman et al, 2006), potently inhibiting tumour growth (Utsumi et al, 2005;Foster et al, 2008) and angiogenesis (Chander et al, 2007) in vivo. STX140 is currently in pre-clinical development as a novel anticancer therapy .…”