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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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(A) Effect of 2DG on the proliferation of LNCaP and MCF-7 cells. Cells were cultured in 96-well plates and treated with 2DG (0.005–50 mM) for 96 h when their effects on proliferation were measured using a microtitre plate assay. Effect of 2DG and hypoxia on ATP levels in MCF-7 (B) and LNCaP cells (C). Cells were cultured in 96-well plates under normoxia and treated with 2DG (3 mM) for 72 h when their effects on ATP were measured using the microtitre, ATPlite plate assay. Results are expressed as percent of untreated. At this dose of 2DG, no significant inhibition of cell proliferation occurred (data not shown).
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fig2: (A) Effect of 2DG on the proliferation of LNCaP and MCF-7 cells. Cells were cultured in 96-well plates and treated with 2DG (0.005–50 mM) for 96 h when their effects on proliferation were measured using a microtitre plate assay. Effect of 2DG and hypoxia on ATP levels in MCF-7 (B) and LNCaP cells (C). Cells were cultured in 96-well plates under normoxia and treated with 2DG (3 mM) for 72 h when their effects on ATP were measured using the microtitre, ATPlite plate assay. Results are expressed as percent of untreated. At this dose of 2DG, no significant inhibition of cell proliferation occurred (data not shown).

Mentions: The ability of 2DG to inhibit the proliferation of MCF-7 and LNCaP cell lines was examined over a 96-h period under normoxic conditions (Figure 2A). The results show a reduction in MCF-7 and LNCaP cell proliferation with increasing 2DG concentration. The potency of 2DG was similar in both cell lines (MCF-7, IC50: 8.1 mM and LNCaP, IC50: 6.7 mM). The difference in IC50 values between MCF-7 and LNCaP cells was not significant. Based on these findings, 8 mM 2DG was used for all further proliferation studies, as this is the approximate IC50 value for both cell lines.


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)

(A) Effect of 2DG on the proliferation of LNCaP and MCF-7 cells. Cells were cultured in 96-well plates and treated with 2DG (0.005–50 mM) for 96 h when their effects on proliferation were measured using a microtitre plate assay. Effect of 2DG and hypoxia on ATP levels in MCF-7 (B) and LNCaP cells (C). Cells were cultured in 96-well plates under normoxia and treated with 2DG (3 mM) for 72 h when their effects on ATP were measured using the microtitre, ATPlite plate assay. Results are expressed as percent of untreated. At this dose of 2DG, no significant inhibition of cell proliferation occurred (data not shown).
© Copyright Policy
Related In: Results  -  Collection

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

fig2: (A) Effect of 2DG on the proliferation of LNCaP and MCF-7 cells. Cells were cultured in 96-well plates and treated with 2DG (0.005–50 mM) for 96 h when their effects on proliferation were measured using a microtitre plate assay. Effect of 2DG and hypoxia on ATP levels in MCF-7 (B) and LNCaP cells (C). Cells were cultured in 96-well plates under normoxia and treated with 2DG (3 mM) for 72 h when their effects on ATP were measured using the microtitre, ATPlite plate assay. Results are expressed as percent of untreated. At this dose of 2DG, no significant inhibition of cell proliferation occurred (data not shown).
Mentions: The ability of 2DG to inhibit the proliferation of MCF-7 and LNCaP cell lines was examined over a 96-h period under normoxic conditions (Figure 2A). The results show a reduction in MCF-7 and LNCaP cell proliferation with increasing 2DG concentration. The potency of 2DG was similar in both cell lines (MCF-7, IC50: 8.1 mM and LNCaP, IC50: 6.7 mM). The difference in IC50 values between MCF-7 and LNCaP cells was not significant. Based on these findings, 8 mM 2DG was used for all further proliferation studies, as this is the approximate IC50 value for both cell lines.

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