2DG, 2-DeoxyGlucose: Click to Expand ⟱
Features: Diagnostic agent used in PET, can determine glucose metabolism
2-DeoxyGlucose inhibits the production of glucose-6-phosphate from glucose at the phosphoglucoisomerase level. -an inhibitor of the glycolysis enzyme hexokinase

Key Pathways: 1.Glycolysis Inhibition (blocking the glycolytic pathway.)
• blockade leads to energy deprivation—a mechanism of interest particularly in cancer cells that often depend on high glycolytic rates (the “Warburg effect”).
• 2DG is structurally similar to glucose and is taken up into cells via glucose transporters (GLUTs).
• “glycolytic blockade.” deprives the cell of ATP and glycolytic intermediates, crucial for biosynthetic functions in rapidly dividing cancer cells.

2.Impact on the Pentose Phosphate Pathway (PPP)
• The inhibition of glycolysis may indirectly affect the PPP and PPP is essential for reducing equivalents (NADPH), which are needed for cell survival and proliferation.
• Decreased flux through the PPP may reduce production of NADPH.
– NADPH is essential for countering oxidative stress by regenerating reduced glutathione (GSH).
• Reduced NADPH levels can compromise the cell’s ability to neutralize ROS, contributing to oxidative damage.

3.Interference with N-linked Glycosylation
• 2DG can disrupt N-linked glycosylation by competing with mannose in glycoprotein synthesis.
• This disruption can lead to endoplasmic reticulum (ER) stress and may trigger the unfolded protein response (UPR), contributing to cancer cell apoptosis or impaired growth.
• The process of ER stress itself is associated with increased ROS generation as cellular homeostatic mechanisms are overwhelmed.

4. Mitochondrial Dysfunction and ROS Generation
• While the primary action of 2DG is cytosolic (glycolysis), metabolic stress caused by energy deprivation indirectly affects mitochondrial function.
• Mitochondria may increase ROS production when the electron transport chain is perturbed due to altered cellular energy demands.
– Elevated ROS levels can damage mitochondrial DNA, proteins, and lipids.
• The resulting oxidative damage further impairs mitochondrial efficiency and may trigger intrinsic apoptotic pathways.

5. Cellular Redox Imbalance
• Inhibition of glycolysis and the subsequent reduction in PPP activity limit NADPH production, a key reducing agent.
• With decreased NADPH, the regeneration of antioxidants such as glutathione and thioredoxin is impaired.
– Accumulation of ROS leads to oxidative stress, damaging cellular components including lipids, proteins, and nucleic acids.
• Oxidative stress may sensitize cancer cells to further apoptotic signaling cascades.

6. Activation of Stress and Apoptotic Signaling Pathways
• 2DG-mediated metabolic stress and ROS accumulation can activate several stress-related kinases and transcription factors, including:
– AMP-activated protein kinase (AMPK): Activated by energy deprivation, AMPK may shift cellular metabolism and promote cell cycle arrest.
– c-Jun N-terminal kinase (JNK): Often activated by oxidative and ER stress, JNK can promote apoptotic signaling.
– p38 MAPK: Also is responsive to stress stimuli and can drive apoptosis or cell cycle changes.
• These stress responses can initiate apoptosis in cancer cells, particularly if homeostatic mechanisms for dealing with ROS are overwhelmed.

Understanding these detailed pathways helps explain why 2DG can preferentially affect cancer cells that rely heavily on glycolysis (the Warburg effect) while also illuminating how ROS and oxidative damage contribute to its overall antitumor efficacy.

some Phase I trials, doses in the range of 45–63 mg/kg/day (administered orally)

do not combine with Caffeic acid phenethyl ester (CAPE) is one of the main active ingredients of propolis
Scientific Papers found: Click to Expand⟱
1336- 2DG,    2-deoxy-D-glucose induces oxidative stress and cell killing in human neuroblastoma cells
- in-vitro, GBM, SK-N-SH
ROS↑, selectively enhancing metabolic oxidative stress.
GlucoseCon↓, mimic in vitro glucose deprivation that selectively kills cancer cells by oxidative stress.
other↓, Treatment with antioxidants protects neuroblastoma cells from 2DG-induced cell killing

1337- 2DG,  Rad,    2-deoxy-D-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer
- in-vivo, NA, NA
ChemoSen↑, combination of 2DG and ionizing radiation resulted in greater inhibition of tumor growth and increased survival, relative to either agent alone
GlucoseCon↓,
ROS↑,

1339- 2DG,  Cisplatin,    2-Deoxy-d-Glucose Combined with Cisplatin Enhances Cytotoxicity via Metabolic Oxidative Stress in Human Head and Neck Cancer Cells
- in-vitro, HNSCC, FaDu
ChemoSen↑, combination of 2DG and cisplatin resulted in a significant decrease in cell survival when compared with 2DG or cisplatin alone
ROS↑,
GSH↓,
other↓, Simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC) inhibited parameters indicative of oxidative stress, as well as protected FaDu cells from the cytotoxic effects of cisplatin alone and the combination of 2DG and cisplatin.

2325- 2DG,    Research Progress of Warburg Effect in Hepatocellular Carcinoma
- Review, Var, NA
HK2↓, 2-Deoxyglucose (2-DG) is a widely studied HK2 inhibitor that has been reported to inhibit glycolysis by inhibiting hexokinase
Glycolysis↓,
PKM2↓, In rat HCC models, 2-DG was shown to reduce PKM2 and LDHA expression, leading to decreased aerobic glycolysis and tumor cell death
LDHA↓,
TumCD↑,
ChemoSen↑, Combining 2-DG with sorafenib demonstrated superior antitumor effects compared to sorafenib alone, suggesting its potential for synergistic action with other anticancer drugs
eff↑, Moreover, DHA combined with 2-DG can reportedly induce apoptosis in A549 and PC-9 cells

2326- 2DG,    Caloric Restriction Mimetic 2-Deoxyglucose Alleviated Inflammatory Lung Injury via Suppressing Nuclear Pyruvate Kinase M2–Signal Transducer and Activator of Transcription 3 Pathway
- in-vivo, Nor, NA
PKM2↓, Treatment with 2-DG had no obvious effects on the total level of pyruvate kinase M2 (PKM2), but it significantly suppressed LPS-induced elevation of PKM2 in the nuclei.
Inflam↓, provided anti-inflammatory benefits in lethal inflammation.
TNF-α↓, LPS-induced elevation of pulmonary TNF-α (Figure 2C) and IL-6 (Figure 2D) were also suppressed by 2-DG.
IL6↓,
OS↑, Posttreatment with 2-DG Improved the Survival of LPS-Insulted Mice

2327- 2DG,    2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents
- Review, Var, NA
Glycolysis↓, 2-DG inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate isomerase, and inducing cell death
HK2↓,
mt-ROS↑, 2-DG-mediated glucose deprivation stimulates reactive oxygen species (ROS) production in mitochondria, also leading to AMPK activation and autophagy stimulation.
AMPK↑,
PPP↓, 2-DG has been shown to block the pentose phosphate shunt
NADPH↓, Decreased levels of NADPH correlate with reduced glutathione levels, one of the major cellular antioxidants.
GSH↓,
Bax:Bcl2↑, Valera et al. also observed that in bladder cancer cells, 2-DG treatment modulates the Bcl-2/Bax protein ratio, driving apoptosis induction
Apoptosis↑,
RadioS↑, 2-DG radiosensitization results from its effect on thiol metabolism
eff↓, (NAC) treatment, downregulated glutamate cysteine ligase activity, or overexpression of ROS scavenging enzymes
Half-Life↓, its plasma half-life was only 48 min [117]) make 2-DG a rather poor drug candidate
other↝, Adverse effects of 2-DG administration in humans include fatigue, sweating, dizziness, and nausea, mimicking the symptoms of hypoglycemia
eff↓, Moreover, 2-DG has to be used at relatively high concentrations (≥5 mmol/L) in order to compete with blood glucose

2423- 2DG,  SRF,    2-Deoxyglucose and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells
- in-vitro, HCC, NA
ChemoSen↑, 2DG and sorafenib in combination suppressed the proliferation and motility of HCC cells more effectively than 2DG or sorafenib alone,
TumCP↓, In the present study, 3 µM 2DG and 30 µM sorafenib significantly suppressed the proliferation of HLF and HCC PLC/PRF/5 cells.
cycD1↓, Sorafenib and 2DG independently decrease cyclin D1 expression
MMP9↓, expression of MMP9 significantly decreased when cells were treated with a combination of 2DG and sorafenib compared with 2DG or sorafenib alone

2424- 2DG,  SRF,    The combination of the glycolysis inhibitor 2-DG and sorafenib can be effective against sorafenib-tolerant persister cancer cells
- in-vitro, HCC, Hep3B - in-vitro, HCC, HUH7
ChemoSen↓, combination of 2-DG and sorafenib reduced persister tumor growth in mice
Glycolysis↓, The glycolysis inhibitor 2-Deoxy-D-glucose (2-DG), an inhibitor of all forms of HK
HK1↓,
HK2↓,
ATP↓, reducing ATP production

2432- 2DG,    Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth
- in-vitro, Lung, H23 - in-vitro, Lung, KP2 - in-vivo, NA, NA
HK2↓, 2-DG, an inhibitor of HK2, inhibited human and mouse lung cancer cell growth through inducing cell apoptosis and autophagy.
Apoptosis↑,
TumAuto↑,
TumCG↓, these studies showed that the 2-DG, HK2 inhibitor, suppresses lung cancer cell growth in vivo.

2433- 2DG,    Hexokinase inhibitor 2-deoxyglucose coordinates citrullination of vimentin and apoptosis of fibroblast-like synoviocytes by inhibiting HK2 /mTORC1-induced autophagy
- in-vitro, Arthritis, NA - in-vivo, NA, NA
Vim↓, 2-DG reduced cVIM and increased apoptosis by inhibiting autophagy of fibroblast-like synoviocytes.
HK2↓, 2-DG decreased HK2

2434- 2DG,    Inhibition of Key Glycolytic Enzyme Hexokinase 2 Ameliorates Psoriasiform Inflammation in vitro and in vivo
- in-vitro, PSA, NA - in-vivo, PSA, NA
HK2↓, Two commonly used inhibitors, 2-Deoxy-D-glucose (2-DG) and 3-BrPA, have also been discovered
NF-kB↓,
NLRP3↓, Knockdown of HK in previous study inhibits activation of NLRP3 by extracellular ATP

2435- 2DG,    Targeting hexokinase 2 for oral cancer therapy: structure-based design and validation of lead compounds
- in-vitro, SCC, CAL27
MMP↓, inhibition of HK2 led to the loss of mitochondrial membrane potential and increased mitophagy as a potential mechanism of anticancer action.
HK2↓, standard HK2 inhibitor 2-deoxyglucose (2-DG

566- ART/DHA,  2DG,    Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells
- in-vitro, Lung, A549 - in-vitro, Lung, PC9
GlucoseCon↓,
ATP↓,
lactateProd↓,
p‑S6↓,
mTOR↓,
GLUT1↓,
Casp9↑,
Casp8↑,
Casp3↑,
Cyt‑c↑,
AIF↑,
ROS↑, generation of ROS is critical for the toxic effects of DHA

912- QC,  2DG,    Selected polyphenols potentiate the apoptotic efficacy of glycolytic inhibitors in human acute myeloid leukemia cell lines. Regulation by protein kinase activities
Apoptosis↑,
ROS↓, 2-DG (5 mM) and Quer (10–40 μM) reduced the basal intracellular ROS content in HL60 cells
GSH∅, GSH levels were not significantly affected by treatment for 3 h
other↑, activated apoptosis throughout the mitochondrial (“intrinsic”) executioner pathway


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 14

Results for Effect on Cancer/Diseased Cells:
AIF↑,1,   AMPK↑,1,   Apoptosis↑,3,   ATP↓,2,   Bax:Bcl2↑,1,   Casp3↑,1,   Casp8↑,1,   Casp9↑,1,   ChemoSen↓,1,   ChemoSen↑,4,   cycD1↓,1,   Cyt‑c↑,1,   eff↓,2,   eff↑,1,   GlucoseCon↓,3,   GLUT1↓,1,   Glycolysis↓,3,   GSH↓,2,   GSH∅,1,   Half-Life↓,1,   HK1↓,1,   HK2↓,7,   IL6↓,1,   Inflam↓,1,   lactateProd↓,1,   LDHA↓,1,   MMP↓,1,   MMP9↓,1,   mTOR↓,1,   NADPH↓,1,   NF-kB↓,1,   NLRP3↓,1,   OS↑,1,   other↓,2,   other↑,1,   other↝,1,   PKM2↓,2,   PPP↓,1,   RadioS↑,1,   ROS↓,1,   ROS↑,4,   mt-ROS↑,1,   p‑S6↓,1,   TNF-α↓,1,   TumAuto↑,1,   TumCD↑,1,   TumCG↓,1,   TumCP↓,1,   Vim↓,1,  
Total Targets: 49

Results for Effect on Normal Cells:

Total Targets: 0

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:19  Target#:%  State#:%  Dir#:%
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