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2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer.

Tagg SL, Foster PA, Leese MP, Potter BV, Reed MJ, Purohit A, Newman SP - Br. J. Cancer (2008)

Bottom Line: 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.This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

View Article: PubMed Central - PubMed

Affiliation: Oncology Drug Discovery and Women's Health Group, Faculty of Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, UK.

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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Structures of glucose (A) and 2DG (B). Glucose and 2DG differ at the second carbon. Chemical structure of STX140 (C).
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fig1: Structures of glucose (A) and 2DG (B). Glucose and 2DG differ at the second carbon. Chemical structure of STX140 (C).

Mentions: Normal healthy cells undergo aerobic respiration to produce ATP; however, Warburg showed that, even in the presence of oxygen, cancer cells create ATP anaerobically, relying on glycolysis, the Warburg effect (Warburg and Dickens, 1930). Hence, inhibiting glycolysis could specifically target cancer cells without having deleterious effects on normal cells. Glycolysis is inhibited by using the glucose analogue, 2-deoxy-D-glucose (2DG), where the C-2 hydroxy group of glucose is replaced by a hydrogen (Figure 1, A and B). Both glucose and 2DG are phosphorylated by hexokinase; however, in contrast to glucose 6-phosphate, 2DG 6-phosphate cannot be further metabolised to fructose-6-phosphate by phosphoglucose isomerase (Nirenberg and Hogg, 1958). In addition to blocking the glycolytic pathway, 2DG competes with glucose for uptake by the hexose (GLUT) transporters (Wachsberger et al, 2002), thus limiting the uptake of glucose by the cell.


2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer.

Tagg SL, Foster PA, Leese MP, Potter BV, Reed MJ, Purohit A, Newman SP - Br. J. Cancer (2008)

Structures of glucose (A) and 2DG (B). Glucose and 2DG differ at the second carbon. Chemical structure of STX140 (C).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2600694&req=5

fig1: Structures of glucose (A) and 2DG (B). Glucose and 2DG differ at the second carbon. Chemical structure of STX140 (C).
Mentions: Normal healthy cells undergo aerobic respiration to produce ATP; however, Warburg showed that, even in the presence of oxygen, cancer cells create ATP anaerobically, relying on glycolysis, the Warburg effect (Warburg and Dickens, 1930). Hence, inhibiting glycolysis could specifically target cancer cells without having deleterious effects on normal cells. Glycolysis is inhibited by using the glucose analogue, 2-deoxy-D-glucose (2DG), where the C-2 hydroxy group of glucose is replaced by a hydrogen (Figure 1, A and B). Both glucose and 2DG are phosphorylated by hexokinase; however, in contrast to glucose 6-phosphate, 2DG 6-phosphate cannot be further metabolised to fructose-6-phosphate by phosphoglucose isomerase (Nirenberg and Hogg, 1958). In addition to blocking the glycolytic pathway, 2DG competes with glucose for uptake by the hexose (GLUT) transporters (Wachsberger et al, 2002), thus limiting the uptake of glucose by the cell.

Bottom Line: 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.This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

View Article: PubMed Central - PubMed

Affiliation: Oncology Drug Discovery and Women's Health Group, Faculty of Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, UK.

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.

Show MeSH
Related in: MedlinePlus