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| Ashwagandha (Withaferin A) — Withaferin A (WA; WFA) is a bioactive steroidal lactone (a “withanolide”) found in Withania somnifera (ashwagandha/Indian ginseng), with most translational oncology discussion centered on WA as a small-molecule electrophile rather than the whole-herb supplement. It is best classified as a natural-product small molecule (steroidal lactone/withanolide) with pleiotropic proteostasis, cytoskeletal, redox-stress, and inflammatory signaling effects; in supplements, WA exposure depends strongly on extract standardization (root vs leaf, % withanolides) and formulation. Primary mechanisms (ranked):
Bioavailability / PK relevance: WA shows measurable systemic exposure in animals (reported oral bioavailability in rats), but PK is variable across species, doses, and extract matrices; human exposure data exist from a phase I osteosarcoma study and from healthy-volunteer PK work on standardized Withania extracts measuring circulating withanolides (including WA). WA is lipophilic and subject to first-pass metabolism; typical pharmacodynamic in-vitro micromolar concentrations may exceed achievable unbound plasma levels depending on formulation and dosing. In-vitro vs systemic exposure relevance: Many mechanistic cancer studies use ~1–10 µM WA; translation requires caution because free (unbound) systemic concentrations and tumor penetration are not well-constrained in humans, and whole-extract products can have low/variable WA content (model- and formulation-dependent). Clinical evidence status: Limited human oncology evidence: a phase I study in advanced high-grade osteosarcoma reported feasibility/safety and proposed a daily dose level; an active clinical trial evaluates an ashwagandha/withaferin-A strategy with liposomal doxorubicin in recurrent ovarian cancer. Most anticancer support remains preclinical, while non-oncology human data for ashwagandha primarily address stress/sleep and are not evidence of anticancer efficacy. 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↓">GSH↓ Catalase↓ HO1↓ GPx↓ - Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑">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 Mechanistic pathway map for Ashwagandha (Withaferin A) in cancer biology
TSF legend: P: 0–30 min R: 30 min–3 hr G: >3 hr |
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| Glutathione (GSH) is a thiol antioxidant that scavenges reactive oxygen species (ROS), resulting in the formation of oxidized glutathione (GSSG). Decreased amounts of GSH and a decreased GSH/GSSG ratio in tissues are biomarkers of oxidative stress. Glutathione is a powerful antioxidant found in every cell of the body, composed of three amino acids: cysteine, glutamine, and glycine. It plays a crucial role in protecting cells from oxidative stress, detoxifying harmful substances, and supporting the immune system. cancer cells can have elevated levels of glutathione, which may help them survive in the oxidative environment created by the immune response and chemotherapy. This can make cancer cells more resistant to treatment. While glutathione can be obtained from certain foods (like fruits, vegetables, and meats), its absorption from supplements is debated. Some people take N-acetylcysteine (NAC) or other precursors to boost glutathione levels, but the effects on cancer prevention or treatment are still being studied. Depleting glutathione (GSH) to raise reactive oxygen species (ROS) is a strategy that has been explored in cancer research and therapy. Many cancer cells have altered redox states and may rely on GSH to survive. Increasing ROS levels can induce stress in these cells, potentially leading to cell death. Certain drugs and compounds can deplete GSH levels. For example, agents like buthionine sulfoximine (BSO) inhibit the synthesis of GSH, leading to its depletion. Cancer cells tend to exhibit higher levels of intracellular GSH, possibly as an adaptive response to a higher metabolism and thus higher steady-state levels of reactive oxygen species (ROS). "...intracellular glutathione (GSH) exhibits an astounding antioxidant activity in scavenging reactive oxygen species (ROS)..." "Cancer cells have a high level of GSH compared to normal cells." "...cancer cells are affluent with high antioxidant levels, especially with GSH, whose appearance at an elevated concentration of ∼10 mM (10 times less in normal cells) detoxifies the cancer cells." "Therefore, GSH depletion can be assumed to be the key strategy to amplify the oxidative stress in cancer cells, enhancing the destruction of cancer cells by fruitful cancer therapy." The loss of GSH is broadly known to be directly related to the apoptosis progression. |
| 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 |
| 3172- | Ash, | Implications of Withaferin A for the metastatic potential and drug resistance in hepatocellular carcinoma cells via Nrf2-mediated EMT and ferroptosis |
| - | in-vitro, | HCC, | HepG2 | - | in-vitro, | Nor, | HL7702 |
| 3163- | Ash, | Rad, | Withaferin A, a steroidal lactone, selectively protects normal lymphocytes against ionizing radiation induced apoptosis and genotoxicity via activation of ERK/Nrf-2/HO-1 axis |
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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