Description: <b>2-Deoxyglucose (2-DG)</b> is a glucose analog that enters cells via GLUT transporters and is phosphorylated by hexokinase to 2-DG-6-phosphate, but cannot proceed through glycolysis. This leads to glycolytic blockade, ATP depletion, ER stress, and metabolic stress signaling.<br>
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It has been studied as:
-A glycolysis inhibitor (Warburg-targeting strategy)
-A radiosensitizer
-A metabolic stress amplifier
-An adjunct to pro-oxidant therapies
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-2-DG primarily inhibits hexokinase<br>
-2-DG-6-phosphate accumulates and inhibits hexokinase and glycolytic flux.<br>
-an inhibitor of the glycolysis enzyme hexokinase<br>
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<b>Key Pathways:</b>
1.Glycolysis Inhibition (blocking the glycolytic pathway.)<br>
• blockade leads to energy deprivation—a mechanism of interest particularly in cancer cells that often depend on high glycolytic rates (the “Warburg effect”).<br>
• 2DG is structurally similar to glucose and is taken up into cells via glucose transporters (GLUTs).<br>
• “glycolytic blockade.” deprives the cell of ATP and glycolytic intermediates, crucial for biosynthetic functions in rapidly dividing cancer cells.<br>
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2.Impact on the Pentose Phosphate Pathway (PPP)<br>
• 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.<br>
• Decreased flux through the PPP may reduce production of NADPH.(indirect)<br>
– NADPH is essential for countering oxidative stress by regenerating reduced glutathione (GSH).<br>
• Reduced NADPH levels can compromise the cell’s ability to neutralize ROS, contributing to oxidative damage.<br>
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3.Interference with N-linked Glycosylation<br>
• 2DG can disrupt N-linked glycosylation by competing with mannose in glycoprotein synthesis.<br>
• 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.<br>
• The process of ER stress itself is associated with increased ROS generation as cellular homeostatic mechanisms are overwhelmed.<br>
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4. Mitochondrial Dysfunction and ROS Generation<br>
• While the primary action of 2DG is cytosolic (glycolysis), metabolic stress caused by energy deprivation indirectly affects mitochondrial function.<br>
• Mitochondria may increase ROS production when the electron transport chain is perturbed due to altered cellular energy demands.<br>
– Elevated ROS levels can damage mitochondrial DNA, proteins, and lipids.<br>
• The resulting oxidative damage further impairs mitochondrial efficiency and may trigger intrinsic apoptotic pathways.<br>
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5. Cellular Redox Imbalance<br>
• Inhibition of glycolysis and the subsequent reduction in PPP activity limit NADPH production, a key reducing agent.<br>
• With decreased NADPH, the regeneration of antioxidants such as glutathione and thioredoxin is impaired.<br>
– Accumulation of ROS leads to oxidative stress, damaging cellular components including lipids, proteins, and nucleic acids.<br>
• Oxidative stress may sensitize cancer cells to further apoptotic signaling cascades.<br>
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6. Activation of Stress and Apoptotic Signaling Pathways<br>
• 2DG-mediated metabolic stress and ROS accumulation can activate several stress-related kinases and transcription factors, including:<br>
– AMP-activated protein kinase (AMPK): Activated by energy deprivation, AMPK may shift cellular metabolism and promote cell cycle arrest.<br>
– c-Jun N-terminal kinase (JNK): Often activated by oxidative and ER stress, JNK can promote apoptotic signaling.<br>
– p38 MAPK: Also is responsive to stress stimuli and can drive apoptosis or cell cycle changes.<br>
• These stress responses can initiate apoptosis in cancer cells, particularly if homeostatic mechanisms for dealing with ROS are overwhelmed.<br>
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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.<br>
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Phase I trials have explored ~45–63 mg/kg/day oral dosing, but tolerability varies and metabolic effects are dose-dependent.<br>
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possible hypothetical concern of combination with Caffeic acid phenethyl ester (CAPE) is one of the main active ingredients of
<a href="https://pubmed.ncbi.nlm.nih.gov/37864895/">propolis</a>
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<!-- 2-Deoxyglucose (2-DG) — Cancer-Oriented Time-Scale Flagged Pathway Table -->
<!-- 2-Deoxyglucose (2DG) — Refined Cancer-Oriented Time-Scale Flagged Pathway Table -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer / Tumor Context</th>
<th>Normal Tissue Context</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Hexokinase inhibition / glycolysis blockade</td>
<td>Glycolysis ↓; lactate ↓; ATP ↓ (reported)</td>
<td>High-glucose–dependent tissues vulnerable at higher doses</td>
<td>P, R</td>
<td>Core metabolic choke-point</td>
<td>2-DG enters via GLUTs and is phosphorylated to 2-DG-6-P, which accumulates and inhibits glycolytic flux.</td>
</tr>
<tr>
<td>2</td>
<td>ATP depletion / energy crisis</td>
<td>AMP/ATP ratio ↑; metabolic stress ↑</td>
<td>Systemic fatigue / hypoglycemia-like effects possible</td>
<td>R</td>
<td>Energetic collapse</td>
<td>Highly glycolytic tumors may be particularly sensitive to ATP depletion.</td>
</tr>
<tr>
<td>3</td>
<td>AMPK activation → mTOR suppression</td>
<td>AMPK ↑; mTOR ↓; proliferation ↓</td>
<td>Metabolic adaptation ↑</td>
<td>R, G</td>
<td>Anti-growth signaling</td>
<td>Energy stress activates AMPK, reducing anabolic signaling and biosynthesis.</td>
</tr>
<tr>
<td>4</td>
<td>Interference with N-linked glycosylation</td>
<td>ER stress ↑; UPR ↑; CHOP ↑ (reported)</td>
<td>Protein-folding stress possible</td>
<td>R, G</td>
<td>Proteotoxic stress</td>
<td>2-DG competes with mannose in glycoprotein synthesis, disrupting ER homeostasis.</td>
</tr>
<tr>
<td>5</td>
<td>Pentose Phosphate Pathway (indirect modulation)</td>
<td>NADPH production ↓ (context-dependent)</td>
<td>Redox buffering ↓ at higher stress levels</td>
<td>R</td>
<td>Redox vulnerability</td>
<td>Reduced glycolytic flux may lower PPP-derived NADPH, impairing glutathione regeneration.</td>
</tr>
<tr>
<td>6</td>
<td>Mitochondrial ROS increase (secondary)</td>
<td>ROS ↑ (reported); mitochondrial stress ↑</td>
<td>Oxidative stress ↑ at higher doses</td>
<td>R</td>
<td>Redox destabilization</td>
<td>ROS increase is secondary to metabolic compensation and redox imbalance.</td>
</tr>
<tr>
<td>7</td>
<td>Stress kinase activation (JNK / p38)</td>
<td>Stress MAPKs ↑; apoptosis signaling ↑</td>
<td>↔</td>
<td>R, G</td>
<td>Apoptotic signaling</td>
<td>Energy and ER stress can activate stress-responsive kinases.</td>
</tr>
<tr>
<td>8</td>
<td>Autophagy activation</td>
<td>Autophagy ↑ (adaptive or pro-death)</td>
<td>↔</td>
<td>G</td>
<td>Stress adaptation</td>
<td>Often initially protective under metabolic restriction.</td>
</tr>
<tr>
<td>9</td>
<td>Radiosensitization</td>
<td>Radiation sensitivity ↑ (reported)</td>
<td>—</td>
<td>G</td>
<td>Combination leverage</td>
<td>Energy stress may impair DNA repair capacity.</td>
</tr>
<tr>
<td>10</td>
<td>Safety / tolerability constraint</td>
<td>—</td>
<td>Fatigue, nausea, hypoglycemia-like symptoms</td>
<td>—</td>
<td>Translation constraint</td>
<td>Clinical dosing limited by systemic metabolic effects.</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (glycolytic blockade begins)</li>
<li><b>R</b>: 30 min–3 hr (AMPK activation; ER stress; ROS rise)</li>
<li><b>G</b>: >3 hr (autophagy, apoptosis, radiosensitization outcomes)</li>
</ul>