| 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
|
| Source: |
| Type: |
| Destruction of mitochondrial transmembrane potential, which is widely regarded as one of the earliest events in the process of cell apoptosis. Mitochondria are organelles within eukaryotic cells that produce adenosine triphosphate (ATP), the main energy molecule used by the cell. For this reason, the mitochondrion is sometimes referred to as “the powerhouse of the cell”. Mitochondria produce ATP through process of cellular respiration—specifically, aerobic respiration, which requires oxygen. The citric acid cycle, or Krebs cycle, takes place in the mitochondria. The mitochondrial membrane potential is widely used in assessing mitochondrial function as it relates to the mitochondrial capacity of ATP generation by oxidative phosphorylation. The mitochondrial membrane potential is a reliable indicator of mitochondrial health. In cancer cells, ΔΨm is often decreased, which can lead to changes in cellular metabolism, increased glycolysis, increased reactive oxygen species (ROS) production, and altered cell death pathways. The membrane of malignant mitochondria is hyperpolarized (−220 mV) in comparison to their healthy counterparts (−160 mV), which facilitates the penetration of positively charged molecules to the cancer cells mitochondria. The MMP is a critical indicator of mitochondrial function, directly reflecting the organelle's capacity to generate ATP through oxidative phosphorylation. |
| 2435- | 2DG, | Targeting hexokinase 2 for oral cancer therapy: structure-based design and validation of lead compounds |
| - | in-vitro, | SCC, | CAL27 |
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
Filter Conditions: Pro/AntiFlg:% IllCat:% CanType:% Cells:% prod#:19 Target#:197 State#:% Dir#:1
wNotes=0 sortOrder:rid,rpid