Article

Tagg SL, Foster PA, Leese MP, Potter BVL, Reed MJ, Purohit A, Newman SP2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer. Br J Cancer 99: 1842-1848

Oncology Drug Discovery and Women's Health Group, Faculty of Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, UK.
British Journal of Cancer (Impact Factor: 4.84). 12/2008; 99(11):1842-8. DOI: 10.1038/sj.bjc.6604752
Source: PubMed

ABSTRACT

Drug combination therapy is a key strategy to improve treatment efficacy and survival of cancer patients. In this study the effects of combining 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140), a microtubule disruptor, with 2-deoxy-D-glucose (2DG) were assessed in MCF-7 (breast) and LNCaP (prostate) xenograft models in vivo. In mice bearing MCF-7 xenografts, daily p.o. administration of STX140 (5 mg kg(-1)) resulted in a 46% (P<0.05) reduction of tumour volume. However, the combination of STX140 (5 mg kg(-1) p.o.) and 2DG (2 g kg(-1) i.p.) reduced tumour volume by 76% (P<0.001). 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate also reduced tumour vessel density. 2-Deoxy-D-glucose alone had no significant effect on tumour volume or vessel density. A similar benefit of the combination treatment was observed in the LNCaP prostate xenograft model. In vitro the degree of inhibition of cell proliferation by STX140 was unaffected by oxygen concentrations. In contrast, the inhibition of proliferation by 2DG was enhanced under hypoxia by 20 and 25% in MCF-7 and LNCaP cells, respectively. The combination of STX140 and 2DG in LNCaP cells under normoxia or hypoxia inhibited proliferation to a greater extent than either compound alone. These results suggest that the antiangiogenic and microtubule disruption activities of STX140 may make tumours more susceptible to inhibition of glycolysis by 2DG. This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

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    • "Moreover, they can be delivered orally and are highly effective against many human cancer cell types assessed in vitro and also against human tumour cell lines engrafted into mice (Ireson et al, 2004; Chander et al, 2007). In combination, 2-MEbisMATE (STX140) and 2-deoxyglucose exhibit synergy in reducing tumour volume and STX140 may sensitise tumours to inhibition of glycolysis (Tagg et al, 2008). Another novel 2ME2 variant, STX3451 (2-(3-Bromo-4,5- dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroi- soquinoline; Figure 1A), is a non-steroidal tetrahydroisoquinoline sulphamate derivative that displays high anti-proliferative activity across the NCI 60 cell line panel (average GI 50 50 nM; Dohle et al, 2014). "
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    ABSTRACT: Background: Both the number and size of tumours in NF1 patients increase in response to the rise in steroid hormones seen at puberty and during pregnancy. The size of tumours decreases after delivery, suggesting that hormone-targeting therapy might provide a viable new NF1 treatment approach. Our earlier studies demonstrated that human NF1 tumour cell lines either went through apoptosis or ceased growth in the presence of 2-methoxyoestradiol (2ME2), a naturally occurring anticancer metabolite of 17-β estradiol. Previous reports of treatment with sulfamoylated steroidal and non-steroidal derivatives of 2ME2 showed promising reductions in tumour burden in hormone-responsive cancers other than NF1. Here we present the first studies indicating that 2ME2 derivatives could also provide an avenue for treating NF1, for which few treatment options are available. Methods: STX3451, (2-(3-Bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), a non-steroidal sulphamate analogue of 2ME2, was tested in dose-dependent studies of malignant and benign NF1 human tumour cell lines and cell lines with variable controlled neurofibromin expression. The mechanisms of action of STX3451 were also analysed. Results: We found that STX3451-induced apoptosis in human malignant peripheral nerve sheath tumour (MPNST) cell lines, even in the presence of elevated oestrogen and progesterone. It inhibits both PI3 kinase and mTOR signalling pathways. It disrupts actin- and microtubule-based cytoskeletal structures in cell lines derived from human MPNSTs and in cells derived from benign plexiform neurofibromas. STX3451 selectively kills MPNST-derived cells, but also halts growth of other tumour-derived NF1 cell lines. Conclusion: STX3451 provides a new approach for inducing cell death and lowering tumour burden in NF1 and other hormone-responsive cancers with limited treatment options.
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    • "One such compound is STX140 (2-methoxyestradiol-bis-sulfamate; Figure 1) which shows oral efficacy against a range of in vitro cancer cell lines and in vivo xenograft tumor models [3]–[16]. Our previous work demonstrates that in breast cancer cells STX140, as measured by tubulin binding assays [4] and as observed in MCF-7 cells using immunohistochemistry [17], causes microtubule disruption and therefore tubulin destabilisation. "
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    • "Antiproliferative activity induced by 2-methoxyestradiol-bis-sulphamate was detected in the estrogen receptor positive human breast adenocarcinoma MCF-7 cell line (0.1–1 μM), prostate cancer cell line (LNACaP), tumorigenic estrogen receptor negative breast adenocarcinoma cell line (MDA-MB-231), esophageal carcinoma SNO cells, HeLa and the CAL51 human breast carcinoma cell line [26], [27], [28], [29], [30], [31], [32], [33]. In vivo antiproliferative activity was discovered in xenografts derivative of estrogen receptor positive human breast adenocarcinoma wild type cell line (MCF-7WT), mitoxantrone resistant breast adenocarcinoma cell line (MCF-7 MR), drug resistant human adenocarcinoma cell line (MCF-7 DOX40), prostate cancer cell line (LNACaP), MDA-MB-435 and prostate hormone independent PC-3 xenograft model [31], [34], [35], [36], [37], [38], [39]. "
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    Full-text · Article · Sep 2013 · PLoS ONE
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