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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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| GRP78 (Pgp, BiP or ERp72) is a central regulator of endoplasmic reticulum (ER) function due to its roles in protein folding and assembly, targeting misfolded protein for degradation, ER Ca(2+)-binding and controlling the activation of trans-membrane ER stress sensors. -GRP78 protein, a marker for endoplasmic reticulum stress -GRP78’s role as a master regulator of the unfolded protein response (UPR) and cellular stress responses The association of P-gp and inhibition of cell death in cancerous cells has also been reported in several studies including in hepatocellular, colorectal, prostate cancer, and gastric cancer. Although counterintuitive due to its prominent role in cancer resistance, P-gp has been linked to favorable prognosis. ERp72 can promote cancer cell proliferation, migration, and invasion by regulating various signaling pathways, including the PI3K/AKT and MAPK/ERK pathways. Additionally, ERp72 can also inhibit apoptosis (programmed cell death) in cancer cells, which can contribute to tumor progression. Overexpressed in: Breast, lung colorectal, prostrate, ovarian, pancreatic. -GRP78 is frequently upregulated in a variety of solid tumors and hematological malignancies. -Overexpression of GRP78 in cancer cells is often regarded as a marker of increased ER stress due to the reduced oxygen and nutrient supply typically encountered in the tumor microenvironment. -Elevated GRP78 levels can contribute to tumor cell survival by enhancing the adaptive UPR, allowing cancer cells to cope with therapeutic and metabolic stress. |
| 1373- | Ash, | Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells |
| - | in-vitro, | Kidney, | Caki-1 |
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