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| 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 |
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| Cytochrome c ** The term "release of cytochrome c" ** an increase in level for the cytosol. Small hemeprotein found loosely associated with the inner membrane of the mitochondrion where it plays a critical role in cellular respiration. Cytochrome c is highly water-soluble, unlike other cytochromes. It is capable of undergoing oxidation and reduction as its iron atom converts between the ferrous and ferric forms, but does not bind oxygen. It also plays a major role in cell apoptosis. The term "release of cytochrome c" refers to a critical step in the process of programmed cell death, also known as apoptosis. In its new location—the cytosol—cytochrome c participates in the apoptotic signaling pathway by helping to form the apoptosome, which activates caspases that execute cell death. Cytochrome c is a small protein normally located in the mitochondrial intermembrane space. Its primary role in healthy cells is to participate in the electron transport chain, a process that helps produce energy (ATP) through oxidative phosphorylation. Mitochondrial outer membrane permeability leads to the release of cytochrome c from the mitochondria into the cytosol. The release of cytochrome c is a pivotal event in apoptosis where cytochrome c moves from the mitochondria to the cytosol, initiating a chain reaction that leads to programmed cell death. On the one hand, cytochrome c can promote cancer cell survival and proliferation by regulating the activity of various signaling pathways, such as the PI3K/AKT pathway. This can lead to increased cell growth and resistance to apoptosis, which are hallmarks of cancer. On the other hand, cytochrome c can also induce apoptosis in cancer cells by interacting with other proteins, such as Apaf-1 and caspase-9. This can lead to the activation of the intrinsic apoptotic pathway, which can result in the death of cancer cells. Overexpressed in Breast, Lung, Colon, and Prostrate. Underexpressed in Ovarian, and Pancreatic. |
| 3160- | Ash, | Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal |
| - | Review, | Var, | NA |
| 3176- | Ash, | Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I-DNA complex |
| - | in-vitro, | NA, | NA |
| 1369- | Ash, | Withaferin A inhibits cell proliferation of U266B1 and IM-9 human myeloma cells by inducing intrinsic apoptosis |
| - | in-vitro, | Melanoma, | U266 |
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