Limits...
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.

Show MeSH

Related in: MedlinePlus

Effects of 2DG, STX140 and hypoxia on cell cycle and apoptosis in MCF-7 (A) and LNCaP (B) cells. For cell cycle analysis the cells were fixed, treated with RNase, stained with propidium iodide and analysed using a flow cytometer (FACScan, Becton Dickinson, Cowley, UK). For quantification of apoptosis the cells were re-suspended in binding buffer and then stained with fluorescein-conjugated Annexin V antibody and propidium iodide before flow cytometric analysis. Apoptotic cells are defined as cells positive for Annexin V and negative for propidium iodide. All treatments lasted for 48 h (ΔΔΔP<0.001 vs normoxia control; □P<0.05 vs normoxia control, hypoxia control and 2DG alone in normoxia; ▪▪P<0.01 vs normoxia control; +++P<0.001 vs normoxia STX140; **P<0.01 vs normoxia and hypoxia control; ••P<0.01 vs STX140 in hypoxia 2DG combined with STX140 under normoxia; ♦♦♦P<0.001 vs normoxia control; and ns=not significant).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2600694&req=5

fig4: Effects of 2DG, STX140 and hypoxia on cell cycle and apoptosis in MCF-7 (A) and LNCaP (B) cells. For cell cycle analysis the cells were fixed, treated with RNase, stained with propidium iodide and analysed using a flow cytometer (FACScan, Becton Dickinson, Cowley, UK). For quantification of apoptosis the cells were re-suspended in binding buffer and then stained with fluorescein-conjugated Annexin V antibody and propidium iodide before flow cytometric analysis. Apoptotic cells are defined as cells positive for Annexin V and negative for propidium iodide. All treatments lasted for 48 h (ΔΔΔP<0.001 vs normoxia control; □P<0.05 vs normoxia control, hypoxia control and 2DG alone in normoxia; ▪▪P<0.01 vs normoxia control; +++P<0.001 vs normoxia STX140; **P<0.01 vs normoxia and hypoxia control; ••P<0.01 vs STX140 in hypoxia 2DG combined with STX140 under normoxia; ♦♦♦P<0.001 vs normoxia control; and ns=not significant).

Mentions: To understand the possible mechanisms for STX140/2DG-mediated cell death, both the cell cycle state and mechanism of cell death were assessed by FACS analysis (Figure 4A and B). Earlier studies showed that STX140 induced cell cycle arrest and apoptosis in a range of tumour cell lines (Day et al, 2003; Raobaikady et al, 2005; Newman et al, 2007). In both cell types 2DG alone in normoxia had little effect compared with untreated controls, although a reduction in the S-phase population was seen in LNCaP cells (ΔΔΔP<0.001). In LNCaP cells under hypoxia, 2DG alone significantly (□P<0.05) reduced the number of cells in G1 and G2/M compared with normoxic and hypoxic controls and with 2DG alone in normoxia. Despite this, no significant increase in cells undergoing apoptosis was detected. In MCF-7 cells under hypoxia a small increase was seen in the G2/M and apoptotic cell population compared with normoxia alone (▪▪P<0.01). Similar data were seen for STX140 in hypoxia compared with STX140 in normoxia in MCF-7 cells (+++P<0.001). However, 2DG had little effect in MCF-7 cells under hypoxia and the extent of apoptosis measured was the same as seen for hypoxia alone.


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)

Effects of 2DG, STX140 and hypoxia on cell cycle and apoptosis in MCF-7 (A) and LNCaP (B) cells. For cell cycle analysis the cells were fixed, treated with RNase, stained with propidium iodide and analysed using a flow cytometer (FACScan, Becton Dickinson, Cowley, UK). For quantification of apoptosis the cells were re-suspended in binding buffer and then stained with fluorescein-conjugated Annexin V antibody and propidium iodide before flow cytometric analysis. Apoptotic cells are defined as cells positive for Annexin V and negative for propidium iodide. All treatments lasted for 48 h (ΔΔΔP<0.001 vs normoxia control; □P<0.05 vs normoxia control, hypoxia control and 2DG alone in normoxia; ▪▪P<0.01 vs normoxia control; +++P<0.001 vs normoxia STX140; **P<0.01 vs normoxia and hypoxia control; ••P<0.01 vs STX140 in hypoxia 2DG combined with STX140 under normoxia; ♦♦♦P<0.001 vs normoxia control; and ns=not significant).
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Effects of 2DG, STX140 and hypoxia on cell cycle and apoptosis in MCF-7 (A) and LNCaP (B) cells. For cell cycle analysis the cells were fixed, treated with RNase, stained with propidium iodide and analysed using a flow cytometer (FACScan, Becton Dickinson, Cowley, UK). For quantification of apoptosis the cells were re-suspended in binding buffer and then stained with fluorescein-conjugated Annexin V antibody and propidium iodide before flow cytometric analysis. Apoptotic cells are defined as cells positive for Annexin V and negative for propidium iodide. All treatments lasted for 48 h (ΔΔΔP<0.001 vs normoxia control; □P<0.05 vs normoxia control, hypoxia control and 2DG alone in normoxia; ▪▪P<0.01 vs normoxia control; +++P<0.001 vs normoxia STX140; **P<0.01 vs normoxia and hypoxia control; ••P<0.01 vs STX140 in hypoxia 2DG combined with STX140 under normoxia; ♦♦♦P<0.001 vs normoxia control; and ns=not significant).
Mentions: To understand the possible mechanisms for STX140/2DG-mediated cell death, both the cell cycle state and mechanism of cell death were assessed by FACS analysis (Figure 4A and B). Earlier studies showed that STX140 induced cell cycle arrest and apoptosis in a range of tumour cell lines (Day et al, 2003; Raobaikady et al, 2005; Newman et al, 2007). In both cell types 2DG alone in normoxia had little effect compared with untreated controls, although a reduction in the S-phase population was seen in LNCaP cells (ΔΔΔP<0.001). In LNCaP cells under hypoxia, 2DG alone significantly (□P<0.05) reduced the number of cells in G1 and G2/M compared with normoxic and hypoxic controls and with 2DG alone in normoxia. Despite this, no significant increase in cells undergoing apoptosis was detected. In MCF-7 cells under hypoxia a small increase was seen in the G2/M and apoptotic cell population compared with normoxia alone (▪▪P<0.01). Similar data were seen for STX140 in hypoxia compared with STX140 in normoxia in MCF-7 cells (+++P<0.001). However, 2DG had little effect in MCF-7 cells under hypoxia and the extent of apoptosis measured was the same as seen for hypoxia alone.

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