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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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Effects of 2DG and STX140 on the proliferation of MCF-7 (A) and LNCaP (B) cells. Cells were cultured in 96-well plates, under normoxia or hypoxia, and treated with 2DG (8 mM) and/or STX140 (0.1–1 μM) for 72 h when their effects on proliferation were measured by using a microtitre plate assay. Results are expressed as percent of proliferation of untreated cells in normoxia. In both cell lines 2DG alone was significantly (P<0.001) more potent in hypoxia vs normoxia. There was no significant benefit of 2DG+STX140 in MCF-7 cells. In LNCaP cells under normoxia, 2DG+0.1 μM STX140 gave significantly greater inhibition than 2DG alone (*P<0.05) and 0.1 μM STX140 alone (P<0.001). Under hypoxia, 2DG+0.5 μM STX140 and 2DG+1.0 μM STX140 gave significantly greater inhibition than 2DG alone (*P<0.05 and **P<0.01) and 0.5 and 1.0 μM STX140 alone (P<0.001) (ns=not significant vs untreated normoxia).
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fig3: Effects of 2DG and STX140 on the proliferation of MCF-7 (A) and LNCaP (B) cells. Cells were cultured in 96-well plates, under normoxia or hypoxia, and treated with 2DG (8 mM) and/or STX140 (0.1–1 μM) for 72 h when their effects on proliferation were measured by using a microtitre plate assay. Results are expressed as percent of proliferation of untreated cells in normoxia. In both cell lines 2DG alone was significantly (P<0.001) more potent in hypoxia vs normoxia. There was no significant benefit of 2DG+STX140 in MCF-7 cells. In LNCaP cells under normoxia, 2DG+0.1 μM STX140 gave significantly greater inhibition than 2DG alone (*P<0.05) and 0.1 μM STX140 alone (P<0.001). Under hypoxia, 2DG+0.5 μM STX140 and 2DG+1.0 μM STX140 gave significantly greater inhibition than 2DG alone (*P<0.05 and **P<0.01) and 0.5 and 1.0 μM STX140 alone (P<0.001) (ns=not significant vs untreated normoxia).

Mentions: The growth-inhibitory effects of 2DG and STX140, used alone and in combination, were compared in MCF-7 and LNCaP cells, under both normoxia and hypoxia in vitro (Figure 3A and B). The growth inhibition was determined after 72 h. Compared with normoxic untreated controls, STX140 (0.5 μM) inhibited cell proliferation by 45 and 48% in MCF-7 cells (P<0.01, Figure 3A) under normoxia and hypoxia, respectively, and by 65% in LNCaP cells (P<0.001, Figure 3B) under both normoxia and hypoxia. Under normoxic conditions, in both cell types, 2DG alone (8 mM) inhibited cell proliferation by 50%. Under hypoxic conditions 2DG inhibited cell proliferation by 70 and 75% in MCF-7 and LNCaP cells, respectively, a significant increase in efficacy relative to normoxic conditions (P<0.01). Compared with STX140 at 0.5 μM, 2DG (8 mM) alone is significantly more effective at inhibiting tumour cell proliferation in both cell types (MCF-7: P<0.01 and LNCaP: P<0.05) under hypoxia, but not under normoxia (Figure 3A and B). The addition of STX140 (0.1–0.5 μM) did not further enhance the inhibition of cell proliferation seen with 8 mM 2DG in MCF-7 cells either in normoxia or in hypoxia (Figure 3A). However, improved efficacy was seen when combining the two agents in vitro in the LNCaP cells. The combination of 0.1 μM STX140 and 8 mM 2DG was more potent (*P<0.05) than either compound alone under normoxia at these concentrations. In contrast, this result was not seen under hypoxic conditions with the same concentrations. However, 8 mM 2DG plus either 0.5 or 1.0 μM STX140 was more potent (*P<0.05 and **P<0.01, respectively) than either compound alone under hypoxia at these concentrations; this result was not seen under normoxia with the same concentrations.


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 and STX140 on the proliferation of MCF-7 (A) and LNCaP (B) cells. Cells were cultured in 96-well plates, under normoxia or hypoxia, and treated with 2DG (8 mM) and/or STX140 (0.1–1 μM) for 72 h when their effects on proliferation were measured by using a microtitre plate assay. Results are expressed as percent of proliferation of untreated cells in normoxia. In both cell lines 2DG alone was significantly (P<0.001) more potent in hypoxia vs normoxia. There was no significant benefit of 2DG+STX140 in MCF-7 cells. In LNCaP cells under normoxia, 2DG+0.1 μM STX140 gave significantly greater inhibition than 2DG alone (*P<0.05) and 0.1 μM STX140 alone (P<0.001). Under hypoxia, 2DG+0.5 μM STX140 and 2DG+1.0 μM STX140 gave significantly greater inhibition than 2DG alone (*P<0.05 and **P<0.01) and 0.5 and 1.0 μM STX140 alone (P<0.001) (ns=not significant vs untreated normoxia).
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fig3: Effects of 2DG and STX140 on the proliferation of MCF-7 (A) and LNCaP (B) cells. Cells were cultured in 96-well plates, under normoxia or hypoxia, and treated with 2DG (8 mM) and/or STX140 (0.1–1 μM) for 72 h when their effects on proliferation were measured by using a microtitre plate assay. Results are expressed as percent of proliferation of untreated cells in normoxia. In both cell lines 2DG alone was significantly (P<0.001) more potent in hypoxia vs normoxia. There was no significant benefit of 2DG+STX140 in MCF-7 cells. In LNCaP cells under normoxia, 2DG+0.1 μM STX140 gave significantly greater inhibition than 2DG alone (*P<0.05) and 0.1 μM STX140 alone (P<0.001). Under hypoxia, 2DG+0.5 μM STX140 and 2DG+1.0 μM STX140 gave significantly greater inhibition than 2DG alone (*P<0.05 and **P<0.01) and 0.5 and 1.0 μM STX140 alone (P<0.001) (ns=not significant vs untreated normoxia).
Mentions: The growth-inhibitory effects of 2DG and STX140, used alone and in combination, were compared in MCF-7 and LNCaP cells, under both normoxia and hypoxia in vitro (Figure 3A and B). The growth inhibition was determined after 72 h. Compared with normoxic untreated controls, STX140 (0.5 μM) inhibited cell proliferation by 45 and 48% in MCF-7 cells (P<0.01, Figure 3A) under normoxia and hypoxia, respectively, and by 65% in LNCaP cells (P<0.001, Figure 3B) under both normoxia and hypoxia. Under normoxic conditions, in both cell types, 2DG alone (8 mM) inhibited cell proliferation by 50%. Under hypoxic conditions 2DG inhibited cell proliferation by 70 and 75% in MCF-7 and LNCaP cells, respectively, a significant increase in efficacy relative to normoxic conditions (P<0.01). Compared with STX140 at 0.5 μM, 2DG (8 mM) alone is significantly more effective at inhibiting tumour cell proliferation in both cell types (MCF-7: P<0.01 and LNCaP: P<0.05) under hypoxia, but not under normoxia (Figure 3A and B). The addition of STX140 (0.1–0.5 μM) did not further enhance the inhibition of cell proliferation seen with 8 mM 2DG in MCF-7 cells either in normoxia or in hypoxia (Figure 3A). However, improved efficacy was seen when combining the two agents in vitro in the LNCaP cells. The combination of 0.1 μM STX140 and 8 mM 2DG was more potent (*P<0.05) than either compound alone under normoxia at these concentrations. In contrast, this result was not seen under hypoxic conditions with the same concentrations. However, 8 mM 2DG plus either 0.5 or 1.0 μM STX140 was more potent (*P<0.05 and **P<0.01, respectively) than either compound alone under hypoxia at these concentrations; this result was not seen under normoxia with the same concentrations.

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