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


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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    • "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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    PLoS ONE 09/2013; 8(9):e71935. DOI:10.1371/journal.pone.0071935 · 3.23 Impact Factor
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    • "However, it is becoming extensively clear that many oncogene-activated signalling pathways converge towards an adaptation of tumor cell metabolism to provide energy and essential biomolecules required for the rapid cell division [4] [5] [6]. Within the last years, a large variety of different solid tumors have been associated with increased metabolism (i.e., prostate cancer [7], breast cancer [8], glioblastoma [9], ovarian carcinoma [10], pancreatic cancer [11], and many others). It is now accepted that the metabolism of cancer cells has extremely unique characteristics compared to the one of healthy nonproliferating cells [4]. "
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    ABSTRACT: During the last decade, the development of anticancer therapies has focused on targeting neoplastic-related metabolism. Cancer cells display a variety of changes in their metabolism, which enable them to satisfy the high bioenergetic and biosynthetic demands for rapid cell division. One of the crucial alterations is referred to as the "Warburg effect", which involves a metabolic shift from oxidative phosphorylation towards the less efficient glycolysis, independent of the presence of oxygen. Although there are many examples of solid tumors having altered metabolism with high rates of glucose uptake and glycolysis, it was only recently reported that this phenomenon occurs in hematological malignancies. This review presents evidence that targeting the glycolytic pathway at different levels in hematological malignancies can inhibit cancer cell proliferation by restoring normal metabolic conditions. However, to achieve cancer regression, high concentrations of glycolytic inhibitors are used due to limited solubility and biodistribution, which may result in toxicity. Besides using these inhibitors as monotherapies, combinatorial approaches using standard chemotherapeutic agents could display enhanced efficacy at eradicating malignant cells. The identification of the metabolic enzymes critical for hematological cancer cell proliferation and survival appears to be an interesting new approach for the targeted therapy of hematological malignancies.
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