Limits...
Chronic Dietary Administration of the Glycolytic Inhibitor 2-Deoxy-D-Glucose (2-DG) Inhibits the Growth of Implanted Ehrlich's Ascites Tumor in Mice.

Singh S, Pandey S, Bhatt AN, Chaudhary R, Bhuria V, Kalra N, Soni R, Roy BG, Saluja D, Dwarakanath BS - PLoS ONE (2015)

Bottom Line: Non-adoption of restricted diet for an extended period has limited its practical implementation in humans with a compelling need to develop agents that mimic effects similar to DER, without reduction in actual dietary intake.Dietary 2-DG significantly reduced the tumor incidence, delayed the onset, and compromised the tumor growth along with enhanced survival.We observed reduced blood glucose and serum insulin levels along with decreased proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine positive (BrdU+) tumor cells in 2-DG fed mice.

View Article: PubMed Central - PubMed

Affiliation: Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. SK Mazumdar Road, Delhi, India; Medical Biotechnology Laboratory, Dr B.R Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.

ABSTRACT

Background: Dietary energy restriction (DER) has been well established as a potent anticancer strategy. Non-adoption of restricted diet for an extended period has limited its practical implementation in humans with a compelling need to develop agents that mimic effects similar to DER, without reduction in actual dietary intake. Glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), has recently been shown to possess potential as an energy restriction mimetic agent (ERMA). In the present study we evaluated the effect of dietary 2-DG administration on a mouse tumor model, with a focus on several potential mechanisms that may account for the inhibition of tumorigenesis.

Methodology/principal findings: Swiss albino strain 'A' mice were administered with 0.2% and 0.4% w/v 2-DG in drinking water for 3 months prior to tumor implantation (Ehrlich's ascites carcinoma; EAC) and continued till the termination of the study with no adverse effects on general physiology and animal growth. Dietary 2-DG significantly reduced the tumor incidence, delayed the onset, and compromised the tumor growth along with enhanced survival. We observed reduced blood glucose and serum insulin levels along with decreased proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine positive (BrdU+) tumor cells in 2-DG fed mice. Also, reduced levels of certain key players of metabolic pathways such as phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt and hypoxia inducible factor-1 alpha (HIF-1α) were also noted in tumors of 2-DG fed mice. Further, decrease in CD4+/CD8+ ratio and T-regulatory cells observed in 2-DG fed mice suggested enhanced antitumor immunity and T cell effector function.

Conclusion/significance: These results strongly suggest that dietary 2-DG administration in mice, at doses easily achievable in humans, suitably modulates several pleotrophic factors mimicking DER and inhibits tumorigenesis, emphasizing the use of ERMAs as a promising cancer preventive strategy.

No MeSH data available.


Related in: MedlinePlus

Dietary 2-DG significantly inhibited the process of tumorigenesis in transplanted Erhlich ascites carcinoma (EAC) tumor model.(A) Tumor latency (palpable) and incidence, (B) Tumor volume, (C) Tumor weight (day 28), (D) Representative photographs of animals showing differences in the tumor size (upper panel) and in-vivo optical images (lower panel). Intensity of the signals showing the NIR-dye tumor specific uptake in mice from each treatment group demonstrating tumor burden (day 28), (E) Representative photomicrographs of histological analysis (H & E staining) showing intra-tumoral morphology of EAC tumors from (i) Control, (ii) 0.2% 2-DG and (iii) 0.4% 2-DG mice. *, p < 0.05; **, p < 0.01; ***, p < 0.001
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4489743&req=5

pone.0132089.g004: Dietary 2-DG significantly inhibited the process of tumorigenesis in transplanted Erhlich ascites carcinoma (EAC) tumor model.(A) Tumor latency (palpable) and incidence, (B) Tumor volume, (C) Tumor weight (day 28), (D) Representative photographs of animals showing differences in the tumor size (upper panel) and in-vivo optical images (lower panel). Intensity of the signals showing the NIR-dye tumor specific uptake in mice from each treatment group demonstrating tumor burden (day 28), (E) Representative photomicrographs of histological analysis (H & E staining) showing intra-tumoral morphology of EAC tumors from (i) Control, (ii) 0.2% 2-DG and (iii) 0.4% 2-DG mice. *, p < 0.05; **, p < 0.01; ***, p < 0.001

Mentions: The tumor implantation was carried out to investigate the effects of 2-DG on the process of tumorigenesis. Dietary 2-DG lowered the overall incidence of EAC tumors by nearly 40% and 25% at doses 0.2% and 0.4% respectively (Fig 4A). In addition, 2-DG significantly delayed the onset (median days) of palpable tumors by 9 days (9 vs 18 days) and 5 days (9 vs 14 days) in 0.2% and 0.4% groups respectively (Fig 4A; Log-rank test: p < 0.05). Tumor development was assessed at 2 post-implantation time points (Fig 4B); one at 28th day post implant (inset), where a reduction in the average tumor volume of 26% (p > 0.05; non-significant) in 0.2% 2-DG group and 60% (p < 0.001) in 0.4% 2-DG group was observed. The wet weight of tumors in 2-DG fed mice was also significantly lower at both doses, with the mean tumor weight of 0.52 ± 0.19 g (p < 0.05) and 0.54 ± 0.12 g (p < 0.05) in 0.2% and 0.4% 2-DG respectively versus 1.14 ± 0.16 g in control (day 28, Fig 4C). In the second one at 60 days post-implant, there was a 24.2% (P < 0.01) and 47.8% (P < 0.001) reduction in the tumor volume in 0.2% and 0.4% 2-DG groups respectively. Representative photographs depicting the gross tumor size differences observable between the 2-DG fed and the control mice are shown in Fig 4D (upper panel). Also, the tumors from 2-DG fed mice exhibited lower tumor neovascularisation (vascular density) than the tumors of the control mice (S1 Fig).


Chronic Dietary Administration of the Glycolytic Inhibitor 2-Deoxy-D-Glucose (2-DG) Inhibits the Growth of Implanted Ehrlich's Ascites Tumor in Mice.

Singh S, Pandey S, Bhatt AN, Chaudhary R, Bhuria V, Kalra N, Soni R, Roy BG, Saluja D, Dwarakanath BS - PLoS ONE (2015)

Dietary 2-DG significantly inhibited the process of tumorigenesis in transplanted Erhlich ascites carcinoma (EAC) tumor model.(A) Tumor latency (palpable) and incidence, (B) Tumor volume, (C) Tumor weight (day 28), (D) Representative photographs of animals showing differences in the tumor size (upper panel) and in-vivo optical images (lower panel). Intensity of the signals showing the NIR-dye tumor specific uptake in mice from each treatment group demonstrating tumor burden (day 28), (E) Representative photomicrographs of histological analysis (H & E staining) showing intra-tumoral morphology of EAC tumors from (i) Control, (ii) 0.2% 2-DG and (iii) 0.4% 2-DG mice. *, p < 0.05; **, p < 0.01; ***, p < 0.001
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4489743&req=5

pone.0132089.g004: Dietary 2-DG significantly inhibited the process of tumorigenesis in transplanted Erhlich ascites carcinoma (EAC) tumor model.(A) Tumor latency (palpable) and incidence, (B) Tumor volume, (C) Tumor weight (day 28), (D) Representative photographs of animals showing differences in the tumor size (upper panel) and in-vivo optical images (lower panel). Intensity of the signals showing the NIR-dye tumor specific uptake in mice from each treatment group demonstrating tumor burden (day 28), (E) Representative photomicrographs of histological analysis (H & E staining) showing intra-tumoral morphology of EAC tumors from (i) Control, (ii) 0.2% 2-DG and (iii) 0.4% 2-DG mice. *, p < 0.05; **, p < 0.01; ***, p < 0.001
Mentions: The tumor implantation was carried out to investigate the effects of 2-DG on the process of tumorigenesis. Dietary 2-DG lowered the overall incidence of EAC tumors by nearly 40% and 25% at doses 0.2% and 0.4% respectively (Fig 4A). In addition, 2-DG significantly delayed the onset (median days) of palpable tumors by 9 days (9 vs 18 days) and 5 days (9 vs 14 days) in 0.2% and 0.4% groups respectively (Fig 4A; Log-rank test: p < 0.05). Tumor development was assessed at 2 post-implantation time points (Fig 4B); one at 28th day post implant (inset), where a reduction in the average tumor volume of 26% (p > 0.05; non-significant) in 0.2% 2-DG group and 60% (p < 0.001) in 0.4% 2-DG group was observed. The wet weight of tumors in 2-DG fed mice was also significantly lower at both doses, with the mean tumor weight of 0.52 ± 0.19 g (p < 0.05) and 0.54 ± 0.12 g (p < 0.05) in 0.2% and 0.4% 2-DG respectively versus 1.14 ± 0.16 g in control (day 28, Fig 4C). In the second one at 60 days post-implant, there was a 24.2% (P < 0.01) and 47.8% (P < 0.001) reduction in the tumor volume in 0.2% and 0.4% 2-DG groups respectively. Representative photographs depicting the gross tumor size differences observable between the 2-DG fed and the control mice are shown in Fig 4D (upper panel). Also, the tumors from 2-DG fed mice exhibited lower tumor neovascularisation (vascular density) than the tumors of the control mice (S1 Fig).

Bottom Line: Non-adoption of restricted diet for an extended period has limited its practical implementation in humans with a compelling need to develop agents that mimic effects similar to DER, without reduction in actual dietary intake.Dietary 2-DG significantly reduced the tumor incidence, delayed the onset, and compromised the tumor growth along with enhanced survival.We observed reduced blood glucose and serum insulin levels along with decreased proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine positive (BrdU+) tumor cells in 2-DG fed mice.

View Article: PubMed Central - PubMed

Affiliation: Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. SK Mazumdar Road, Delhi, India; Medical Biotechnology Laboratory, Dr B.R Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.

ABSTRACT

Background: Dietary energy restriction (DER) has been well established as a potent anticancer strategy. Non-adoption of restricted diet for an extended period has limited its practical implementation in humans with a compelling need to develop agents that mimic effects similar to DER, without reduction in actual dietary intake. Glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), has recently been shown to possess potential as an energy restriction mimetic agent (ERMA). In the present study we evaluated the effect of dietary 2-DG administration on a mouse tumor model, with a focus on several potential mechanisms that may account for the inhibition of tumorigenesis.

Methodology/principal findings: Swiss albino strain 'A' mice were administered with 0.2% and 0.4% w/v 2-DG in drinking water for 3 months prior to tumor implantation (Ehrlich's ascites carcinoma; EAC) and continued till the termination of the study with no adverse effects on general physiology and animal growth. Dietary 2-DG significantly reduced the tumor incidence, delayed the onset, and compromised the tumor growth along with enhanced survival. We observed reduced blood glucose and serum insulin levels along with decreased proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine positive (BrdU+) tumor cells in 2-DG fed mice. Also, reduced levels of certain key players of metabolic pathways such as phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt and hypoxia inducible factor-1 alpha (HIF-1α) were also noted in tumors of 2-DG fed mice. Further, decrease in CD4+/CD8+ ratio and T-regulatory cells observed in 2-DG fed mice suggested enhanced antitumor immunity and T cell effector function.

Conclusion/significance: These results strongly suggest that dietary 2-DG administration in mice, at doses easily achievable in humans, suitably modulates several pleotrophic factors mimicking DER and inhibits tumorigenesis, emphasizing the use of ERMAs as a promising cancer preventive strategy.

No MeSH data available.


Related in: MedlinePlus