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

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 actua...

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Veröffentlicht in:PloS one 2015-07, Vol.10 (7), p.e0132089-e0132089
Hauptverfasser: Singh, Saurabh, Pandey, Sanjay, Bhatt, Anant Narayan, Chaudhary, Richa, Bhuria, Vikas, Kalra, Namita, Soni, Ravi, Roy, Bal Gangadhar, Saluja, Daman, Dwarakanath, Bilikere S
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container_issue 7
container_start_page e0132089
container_title PloS one
container_volume 10
creator Singh, Saurabh
Pandey, Sanjay
Bhatt, Anant Narayan
Chaudhary, Richa
Bhuria, Vikas
Kalra, Namita
Soni, Ravi
Roy, Bal Gangadhar
Saluja, Daman
Dwarakanath, Bilikere S
description 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. 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. 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.
doi_str_mv 10.1371/journal.pone.0132089
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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. 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. 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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. 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. 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.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Aging</subject><subject>AKT protein</subject><subject>Analysis</subject><subject>Angiogenesis</subject><subject>Animal growth</subject><subject>Animals</subject><subject>Antimetabolites, Antineoplastic - administration &amp; dosage</subject><subject>Antimetabolites, Antineoplastic - blood</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Antimetabolites, Antineoplastic - therapeutic use</subject><subject>Antineoplastic agents</subject><subject>Ascites</subject><subject>Biomedical research</subject><subject>Biotechnology</subject><subject>Blood glucose</subject><subject>Blood Glucose - analysis</subject><subject>Brain cancer</subject><subject>Bromodeoxyuridine</subject><subject>Caloric Restriction</subject><subject>Cancer therapies</subject><subject>Carcinoma, Ehrlich Tumor - 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administration &amp; dosage</topic><topic>Antimetabolites, Antineoplastic - blood</topic><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Antimetabolites, Antineoplastic - therapeutic use</topic><topic>Antineoplastic agents</topic><topic>Ascites</topic><topic>Biomedical research</topic><topic>Biotechnology</topic><topic>Blood glucose</topic><topic>Blood Glucose - analysis</topic><topic>Brain cancer</topic><topic>Bromodeoxyuridine</topic><topic>Caloric Restriction</topic><topic>Cancer therapies</topic><topic>Carcinoma, Ehrlich Tumor - blood supply</topic><topic>Carcinoma, Ehrlich Tumor - drug therapy</topic><topic>Carcinoma, Ehrlich Tumor - immunology</topic><topic>CD4 antigen</topic><topic>CD4-CD8 Ratio</topic><topic>CD8 antigen</topic><topic>Cell cycle</topic><topic>Cell Division - drug effects</topic><topic>Cytotoxicity</topic><topic>Deoxyglucose - administration &amp; dosage</topic><topic>Deoxyglucose - blood</topic><topic>Deoxyglucose - pharmacology</topic><topic>Deoxyglucose - therapeutic use</topic><topic>Diet</topic><topic>Dietary intake</topic><topic>Dietary restrictions</topic><topic>Drinking water</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Energy</topic><topic>Female</topic><topic>Glucose</topic><topic>Glycolysis</topic><topic>Glycolysis - drug effects</topic><topic>Growth</topic><topic>Hypoxia</topic><topic>Immunity</topic><topic>Immunoregulation</topic><topic>Implantation</topic><topic>Inhibitors</topic><topic>Insulin</topic><topic>Insulin - blood</topic><topic>Insulin-like growth factors</topic><topic>Ionizing radiation</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Matrix Metalloproteinase 9 - analysis</topic><topic>Metabolic pathways</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mimicry</topic><topic>Neoplasm Proteins - physiology</topic><topic>Neovascularization, Pathologic - drug therapy</topic><topic>Nuclear medicine</topic><topic>Physiological aspects</topic><topic>Premedication</topic><topic>Proliferating cell nuclear antigen</topic><topic>Prostate</topic><topic>Random Allocation</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>T cells</topic><topic>T-Lymphocytes, Regulatory - drug effects</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Tumor Burden - drug effects</topic><topic>Tumor cells</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Saurabh</creatorcontrib><creatorcontrib>Pandey, Sanjay</creatorcontrib><creatorcontrib>Bhatt, Anant Narayan</creatorcontrib><creatorcontrib>Chaudhary, Richa</creatorcontrib><creatorcontrib>Bhuria, Vikas</creatorcontrib><creatorcontrib>Kalra, Namita</creatorcontrib><creatorcontrib>Soni, Ravi</creatorcontrib><creatorcontrib>Roy, Bal Gangadhar</creatorcontrib><creatorcontrib>Saluja, Daman</creatorcontrib><creatorcontrib>Dwarakanath, Bilikere S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing &amp; Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological &amp; Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>ProQuest_Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science &amp; Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central</collection><collection>Advanced Technologies &amp; Aerospace Collection</collection><collection>Agricultural &amp; Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>https://resources.nclive.org/materials</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Singh, Saurabh</au><au>Pandey, Sanjay</au><au>Bhatt, Anant Narayan</au><au>Chaudhary, Richa</au><au>Bhuria, Vikas</au><au>Kalra, Namita</au><au>Soni, Ravi</au><au>Roy, Bal Gangadhar</au><au>Saluja, Daman</au><au>Dwarakanath, Bilikere S</au><au>Huang, Cheng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chronic Dietary Administration of the Glycolytic Inhibitor 2-Deoxy-D-Glucose (2-DG) Inhibits the Growth of Implanted Ehrlich's Ascites Tumor in Mice</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-07-02</date><risdate>2015</risdate><volume>10</volume><issue>7</issue><spage>e0132089</spage><epage>e0132089</epage><pages>e0132089-e0132089</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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. 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. 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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26135741</pmid><doi>10.1371/journal.pone.0132089</doi><oa>free_for_read</oa></addata></record>
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subjects 1-Phosphatidylinositol 3-kinase
Aging
AKT protein
Analysis
Angiogenesis
Animal growth
Animals
Antimetabolites, Antineoplastic - administration & dosage
Antimetabolites, Antineoplastic - blood
Antimetabolites, Antineoplastic - pharmacology
Antimetabolites, Antineoplastic - therapeutic use
Antineoplastic agents
Ascites
Biomedical research
Biotechnology
Blood glucose
Blood Glucose - analysis
Brain cancer
Bromodeoxyuridine
Caloric Restriction
Cancer therapies
Carcinoma, Ehrlich Tumor - blood supply
Carcinoma, Ehrlich Tumor - drug therapy
Carcinoma, Ehrlich Tumor - immunology
CD4 antigen
CD4-CD8 Ratio
CD8 antigen
Cell cycle
Cell Division - drug effects
Cytotoxicity
Deoxyglucose - administration & dosage
Deoxyglucose - blood
Deoxyglucose - pharmacology
Deoxyglucose - therapeutic use
Diet
Dietary intake
Dietary restrictions
Drinking water
Drug Screening Assays, Antitumor
Energy
Female
Glucose
Glycolysis
Glycolysis - drug effects
Growth
Hypoxia
Immunity
Immunoregulation
Implantation
Inhibitors
Insulin
Insulin - blood
Insulin-like growth factors
Ionizing radiation
Kinases
Laboratories
Lymphocytes
Lymphocytes T
Matrix Metalloproteinase 9 - analysis
Metabolic pathways
Metabolism
Mice
Mimicry
Neoplasm Proteins - physiology
Neovascularization, Pathologic - drug therapy
Nuclear medicine
Physiological aspects
Premedication
Proliferating cell nuclear antigen
Prostate
Random Allocation
Rodents
Signal transduction
Signal Transduction - drug effects
T cells
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - immunology
Tumor Burden - drug effects
Tumor cells
Tumorigenesis
Tumors
title Chronic Dietary Administration of the Glycolytic Inhibitor 2-Deoxy-D-Glucose (2-DG) Inhibits the Growth of Implanted Ehrlich's Ascites Tumor in Mice
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