| Features: |
| Withaferin A is a steroidal lactone derived from the medicinal plant Withania somnifera (commonly known as Ashwagandha). The main active constituents of Ashwagandha leaves are alkaloids and steroidal lactones (commonly known as Withanolides). -The main constituents of ashwagandha are withanolides such as withaferin A, alkaloids, steroidal lactones, tropine, and cuscohygrine. Ashwagandha is an herb that may reduce stress, anxiety, and insomnia. *-Ashwagandha is often characterized as an antioxidant. -Some studies suggest that while ashwagandha may protect normal cells from oxidative damage, it can simultaneously stress cancer cells by tipping their redox balance toward cytotoxicity. Pathways: -Induction of Apoptosis and ROS Generation -Hsp90 Inhibition and Proteasomal Degradation Cell culture studies vary widely, typically ranging from low micromolar (e.g., 1–10 µM). In animal models (commonly mice), Withaferin A has been administered in doses ranging from approximately 2 to 10 mg/kg body weight. - General wellness, Ashwagandha supplements are sometimes taken in doses ranging from 300 mg to 600 mg of an extract (often standardized to contain a certain percentage of withanolides) once or twice daily. - 400mg of WS extract was given 3X/day to schizophrenia patients. report#2001. - Ashwagandha Pure 400mg/capsule is available from mcsformulas.com. -Note half-life 4-6 hrs?. BioAv Pathways: - well-recognized for promoting ROS in cancer cells, while no effect(or reduction) on normal cells. - ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓, Prx, - Confusing results about Lowering AntiOxidant defense in Cancer Cells: NRF2↓, TrxR↓**, SOD↓, GSH↓ Catalase↓ HO1↓ GPx↓ - Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑, - lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓ - inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, TIMP2, uPA↓, VEGF↓, ROCK1↓, NF-κB↓, CXCR4↓, SDF1↓, TGF-β↓, α-SMA↓, ERK↓ - reactivate genes thereby inhibiting cancer cell growth : HDAC↓(combined with sulfor), DNMT1↓, DNMT3A↓, P53↑, HSP↓, Sp proteins↓, TET↑ - cause Cell cycle arrest : TumCCA↑, cyclin E↓, CDK2↓, CDK4↓, - inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, ERK↓, EMT↓, TOP1↓, - inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, OXPHOS↓, GRP78↑, GlucoseCon↓ - inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, PDGF↓, EGFR↓, Integrins↓, - inhibits Cancer Stem Cells : CSC↓, β-catenin↓, sox2↓, - Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK, α↓, ERK↓, JNK, - Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective, - Selectivity: Cancer Cells vs Normal Cells |
| Source: |
| Type: effect |
| The Warburg effect is a metabolic phenomenon in which cancer cells preferentially use glycolysis for energy production, even in the presence of oxygen. Targeting the pathways involved in the Warburg effect is a promising strategy for cancer treatment. The Warburg effect is always accompanied by a hypoxic condition, and activation of HIF-1a contributes to the Warburg effect through coordinated upregulation of glycolysis and downregulation of oxidative phosphorylation. Warburg effect (GLUT1, LDHA, HK2, and PKM2). Here are some of the key pathways and potential targets: Note: use database Filter to find inhibitors: Ex pick target HIF1α, and effect direction ↓ 1.Glycolysis Inhibitors:(2-DG, 3-BP) -HK2 Inhibitors: such as 2-deoxyglucose, can reduce glycolysis -PFK1 Inhibitors: such as PFK-158, can reduce glycolysis -PFKFB Inhibitors: -PKM2 Inhibitors: (Shikonin) -Can reduce glycolysis -LDH Inhibitors: (Gossypol, FX11) -Reducing the conversion of pyruvate to lactate. -Inhibiting the production of ATP and NADH. -GLUT1 Inhibitors: (phloretin, WZB117) -A key transporter involved in glucose uptake. -GLUT3 Inhibitors: -PDK1 Inhibitors: (dichloroacetate) - A key enzyme involved in the regulation of glycolysis. 2.Gluconeogenesis pathway: -FBP1 Activators: can increase gluconeogenesis -PEPCK1 Inhibitors: can reduce gluconeogenesis 3.Pentose phosphate pathway: -G6PD Inhibitors: can reduce the pentose phosphate pathway 4.Mitochondrial metabolism: -MPC1 Inhibitors: can reduce mitochondrial metabolism and inhibit cancer -SDH Inhibitors: can reduce mitochondrial metabolism and inhibit cancer cell growth. 5.Hypoxia-inducible factor 1 alpha (HIF1α) pathway: -HIF1α inhibitors: (PX-478,Shikonin) -Reduce expression of glycolytic genes and inhibit cancer cell growth. 6.AMP-activated protein kinase (AMPK) pathway: -AMPK activators: (metformin,AICAR,berberine) -Can increase AMPK activity and inhibit cancer cell growth. 7.mTOR pathway: -mTOR inhibitors:(rapamycin,everolimus) -Can reduce mTOR activity and inhibit cancer cell growth. |
| 2388- | Ash, | Withaferin A decreases glycolytic reprogramming in breast cancer |
| - | in-vitro, | BC, | MDA-MB-231 | - | in-vitro, | BC, | MDA-MB-468 | - | in-vitro, | BC, | MCF-7 | - | in-vitro, | BC, | MDA-MB-453 |
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