| 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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| Also called CCND1 Gatekeeper of Cell-Cycle Commitment The main function of cyclin D1 is to maintain cell cycle and to promote cell proliferation. Cyclin D1 is a key regulatory protein involved in the cell cycle, particularly in the transition from the G1 phase to the S phase. It is part of the cyclin-dependent kinase (CDK) complex, where it binds to CDK4 or CDK6 to promote cell cycle progression. Cyclin D1 is crucial for the regulation of the cell cycle. Overexpression or dysregulation of cyclin D1 can lead to uncontrolled cell proliferation, a hallmark of cancer. Cyclin D1 is often found to be overexpressed in various cancers. Cyclin D1 can interact with tumor suppressor proteins, such as retinoblastoma (Rb). When cyclin D1 is overexpressed, it can lead to the phosphorylation and inactivation of Rb, releasing E2F transcription factors that promote the expression of genes required for DNA synthesis and cell cycle progression. Cyclin D1 is influenced by various signaling pathways, including the PI3K/Akt and MAPK pathways, which are often activated in cancer. In some cancers, high levels of cyclin D1 expression have been associated with poor prognosis, making it a potential biomarker for cancer progression and treatment response. |
| 2423- | 2DG, | SRF, | 2-Deoxyglucose and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells |
| - | in-vitro, | HCC, | NA |
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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