| Features: Diagnostic agent used in PET, can determine glucose metabolism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2-Deoxyglucose (2-DG) 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.It has been studied as: -A glycolysis inhibitor (Warburg-targeting strategy) -A radiosensitizer -A metabolic stress amplifier -An adjunct to pro-oxidant therapies-2-DG primarily inhibits hexokinase -2-DG-6-phosphate accumulates and inhibits hexokinase and glycolytic flux. -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.(indirect) – 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. Phase I trials have explored ~45–63 mg/kg/day oral dosing, but tolerability varies and metabolic effects are dose-dependent. possible hypothetical concern of combination with Caffeic acid phenethyl ester (CAPE) is one of the main active ingredients of propolis
Time-Scale Flag (TSF): P / R / G
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| Source: |
| Type: enzymes |
| Tricarboxylic Acid (TCA) cycle, also known as the Citric Acid cycle or Krebs cycle, is a key metabolic pathway that plays a central role in cellular energy production. The TCA cycle is a series of chemical reactions that occur in the mitochondria and involve the breakdown of acetyl-CoA, a molecule produced from the breakdown of carbohydrates, fats, and proteins. The TCA cycle produces: 1. NADH and FADH2 2. ATP 3. GTP Expression of TCA cycle enzymes is often downregulated in cancer cells. Since cancer cells often exhibit rewired metabolism, including alterations in the use of the TCA cycle, researchers are exploring potential therapeutic interventions that target metabolic enzymes or pathways. TCA cycle is essential for normal cellular metabolism, its role in cancer is multifaceted. Cancer cells often reprogram their metabolism—including the TCA cycle—to support rapid growth, adapt to hypoxia, and manage oxidative stress. Mutations in key TCA cycle enzymes generate oncometabolites that further contribute to cancer progression by disrupting normal cellular regulation. Rather than saying the TCA cycle is globally over- or underexpressed in cancer, it is more accurate to say that cancer cells reprogram the cycle—with selective upregulation of parts important for biosynthesis and survival and mutations or downregulation of other parts—to best support their growth and survival in a challenging microenvironment. Oncometabolites -Some metabolites in the Krebs cycle, when accumulated to abnormal levels due to genetic mutations or enzyme deficiencies, are termed “oncometabolites” because they can promote tumorigenesis. -Mutations in succinate dehydrogenase (SDH) can lead to accumulation of succinate. -Mutations in fumarate hydratase (FH) result in an accumulation of fumarate. -Mutations in isocitrate dehydrogenase (IDH1 and IDH2) result in a neomorphic enzyme activity that converts α-ketoglutarate (α-KG) to 2-hydroxyglutarate: |
| 5173- | Ash, | 2DG, | Withaferin A inhibits lysosomal activity to block autophagic flux and induces apoptosis via energetic impairment in breast cancer cells |
| - | in-vitro, | BC, | MCF-7 | - | in-vitro, | BC, | MDA-MB-231 | - | in-vitro, | BC, | MDA-MB-468 | - | in-vitro, | BC, | T47D |
Query results interpretion may depend on "conditions" listed in the research papers. Such Conditions may include : -low or high Dose -format for product, such as nano of lipid formations -different cell line effects -synergies with other products -if effect was for normal or cancerous cells
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