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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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| Enzymes involved in regulating gene expression by removing acetyl groups from histones, the proteins around which DNA is wrapped. -Many cancers exhibit altered expression levels of HDACs, which can contribute to the dysregulation of genes involved in cell growth, survival, and differentiation. -HDACs can repress the expression of tumor suppressor genes, leading to uncontrolled cell proliferation and survival. This repression can be a key factor in the development and progression of cancer. -HDAC inhibitors (HDACi) have been developed and are being investigated for their ability to reactivate silenced genes, induce cell cycle arrest, and promote apoptosis in cancer cells. -HDAC1, HDAC2): Often overexpressed in various cancers, including breast, prostate, and colorectal cancers. Their overexpression is associated with poor prognosis. -HDAC4, HDAC5): These may have both oncogenic and tumor-suppressive roles depending on the context and cancer type. -While HDACs are not classified as traditional oncogenes, their overexpression and activity can contribute to oncogenic processes. -HDAC inhibitor works by preventing the removal of acetyl groups from histones, thereby modulating gene expression, influencing cell behavior, and potentially reversing aberrant gene silencing seen in various diseases. -HDAC inhibitors can help reactivate these genes, thereby inhibiting growth and inducing apoptosis in cancer cells. |
| 3175- | Ash, | SFN, | Withaferin A and sulforaphane regulate breast cancer cell cycle progression through epigenetic mechanisms |
| - | in-vitro, | BC, | MDA-MB-231 | - | in-vitro, | BC, | MCF-7 |
| 1433- | Ash, | SFN, | A Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells |
| - | in-vitro, | BC, | MCF-7 | - | in-vitro, | BC, | MDA-MB-231 |
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