Database Query Results : Ashwagandha(Withaferin A), , Hif1a

Ash, Ashwagandha(Withaferin A): Click to Expand ⟱

Features:

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):

Hsp90-axis disruption (incl. client protein destabilization) leading to proteostasis stress and multi-client oncoprotein depletion
Covalent targeting of intermediate filaments (notably vimentin) with downstream effects on adhesion/migration, EMT programs, and angiogenic endothelium
Pro-oxidative stress signaling in cancer cells with mitochondrial dysfunction, ER stress/UPR engagement, and apoptosis execution
Inflammation and survival signaling suppression (notably NF-κB-centric programs; context-dependent immune modulation)
Contextual transcriptional/epigenetic modulation (e.g., HDAC/DNMT-related signals) contributing to anti-proliferative phenotypes
Metabolic stress signaling (glycolysis/HIF-1α/ATP depletion) as a secondary vulnerability in susceptible models

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↓ 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

Mechanistic pathway map for Ashwagandha (Withaferin A) in cancer biology

Rank	Pathway / Axis	Cancer Cells	Normal Cells	TSF	Primary Effect	Notes / Interpretation
1	Hsp90 proteostasis axis	Hsp90 functional inhibition → client proteins ↓ (Akt/EGFR/HER2/Raf/Cdk etc.) → growth/survival signaling ↓	Stress-response engagement possible; tolerability is dose/formulation dependent	R	Multi-node oncogenic network destabilization	Often presented as ATP-independent Hsp90 inhibition with downstream proteasomal degradation of clients; mechanistically central because it collapses multiple driver pathways at once.
2	Vimentin and intermediate filament remodeling	Vimentin function/organization ↓ → migration/invasion ↓, EMT programs ↓ (context-dependent)	Endothelial and stromal cytoskeleton can be affected; may underlie anti-angiogenic activity	P	Anti-motility / anti-metastatic leverage	WA behaves as a reactive small molecule with reported covalent interaction with vimentin; cytoskeletal perturbation can be rapid and not strictly transcription-driven.
3	Mitochondrial ROS increase	ROS ↑ → ΔΨm ↓, cyt-c ↑, caspase cascade ↑ → apoptosis ↑	Often ROS ↔ or ↓ with antioxidant response ↑ (model-dependent)	P/R	Selective redox toxicity in susceptible tumors	Frequently paired with ER stress/UPR activation; selectivity is commonly framed as “push cancer over its redox limit,” but this is highly dose- and context-dependent.
4	ER stress and UPR axis	ER stress ↑, UPR ↑ → proteotoxic stress → apoptosis/autophagy shifts (model-dependent)	Adaptive UPR may occur; excessive dosing can stress normal tissues	R	Proteotoxic stress amplification	Mechanistically synergistic with Hsp90 disruption and ROS signaling; can manifest as GRP78/BiP and related markers ↑ in some systems.
5	NF-κB inflammatory survival signaling	NF-κB ↓ → cytokine/pro-survival programs ↓, invasion-associated signaling ↓	Anti-inflammatory signaling ↓ may be beneficial in some contexts; immune effects can be mixed	G	Survival/inflammation program suppression	Often aligned with COX-2 and inflammasome-related readouts in inflammatory models; oncology relevance is strongest where NF-κB is a core survival node.
6	EMT and metastasis signaling	EMT ↓, MMPs ↓, uPA ↓, CXCR4/SDF1 axis ↓ (model-dependent)	Wound-healing programs can be affected (context-dependent)	G	Anti-invasive phenotype	Partly downstream of cytoskeletal (vimentin) effects and NF-κB/TGF-β-linked programs; directionality can vary by tumor lineage and assay.
7	Glycolysis and HIF-1α	HIF-1α ↓, glycolysis flux ↓, ATP ↓ (susceptible models)	Usually ↔ at low exposure; metabolic stress possible at higher exposure	G	Metabolic vulnerability unmasking	Often secondary to upstream stress (ROS/proteostasis) rather than a primary enzymatic inhibitor; interpret as (context-dependent).
8	Cell cycle checkpoint control	Cell-cycle arrest ↑ (often G2/M reported), CDK/cyclin signaling ↓	Proliferating normal cells may also be sensitive at higher exposure	G	Anti-proliferative enforcement	Common phenotype readout across WA studies; mechanistic “why” may differ by model (proteostasis vs ROS vs mitotic machinery/cytoskeleton).
9	NRF2 and antioxidant defense	NRF2 ↓ and antioxidant enzymes ↓ reported in some cancer models; sometimes mixed ↔	NRF2 ↑ and antioxidant enzymes ↑ reported in some normal-tissue protection contexts	G	Redox buffering divergence	Highly model-dependent; WA can behave as a stressor that either suppresses or activates NRF2-linked programs depending on timing, dose, and baseline redox state.
10	Clinical Translation Constraint	Micromolar in-vitro dosing common; human oncology exposure/target engagement remains sparsely defined	Supplement heterogeneity (WA content), drug-interaction risk, and organ-specific toxicity signals (notably liver; thyroid) constrain use	—	Formulation + PK + safety gating	Human data exist (phase I osteosarcoma; ongoing ovarian combo), but WA is not an approved anticancer drug and standardized products/target engagement biomarkers are not yet mature.

TSF legend: P: 0–30 min R: 30 min–3 hr G: >3 hr

Hif1a, HIF1α/HIF1a: Click to Expand ⟱

Source:

Type:

Hypoxia-Inducible-Factor 1A (HIF1A gene, HIF1α, HIF-1α protein product)
-Dominantly expressed under hypoxia(low oxygen levels) in solid tumor cells
-HIF1A induces the expression of vascular endothelial growth factor (VEGF)
-High HIF-1α expression is associated with Poor prognosis
-Low HIF-1α expression is associated with Better prognosis

-Functionally, HIF-1α is reported to regulate glycolysis, whilst HIF-2α regulates genes associated with lipoprotein metabolism.
-Cancer cells produce HIF in response to hypoxia in order to generate more VEGF that promote angiogenesis

Key mediators of aerobic glycolysis regulated by HIF-1α.
-GLUT-1 → regulation of the flux of glucose into cells.
-HK2 → catalysis of the first step of glucose metabolism.
-PKM2 → regulation of rate-limiting step of glycolysis.
-Phosphorylation of PDH complex by PDK → blockage of OXPHOS and promotion of aerobic glycolysis.
-LDH (LDHA): Rapid ATP production, conversion of pyruvate to lactate;

HIF-1α Inhibitors:
-Curcumin: disruption of signaling pathways that stabilize HIF-1α (ie downregulate).
-Resveratrol: downregulate HIF-1α protein accumulation under hypoxic conditions.
-EGCG: modulation of upstream signaling pathways, leading to decreased HIF-1α activity.
-Emodin: reduce HIF-1α expression. (under hypoxia).
-Apigenin: inhibit HIF-1α accumulation.

Scientific Papers found: Click to Expand⟱

3177-

Ash,

Emerging Role of Hypoxia-Inducible Factors (HIFs) in Modulating Autophagy: Perspectives on Cancer Therapy

Review,

Var,

Hif1a↓, Withaferin A, a steroidal lactone derived from Withania somnifera (ashwagandha), has demonstrated the ability to decrease HIF-1α production in breast cancer cells (MDA-MB-231)
ROS↑, It also stimulates autophagy by stimulating ROS generation and endoplasmic reticulum (ER) stress pathways
ER Stress↑,

5398-

Ash,

Withaferin-A inhibits colorectal cancer growth and metastasis by targeting the HSP90/HIF-1α/EMT axis

in-vitro,

CRC,

HCT116

in-vitro,

CRC,

SW48

TumCG↓, WA inhibits CRC’s growth, migration, and invasion by inhibiting the HSP90/HIF-1α/EMT axis.
TumCMig↓,
TumCI↓,
HSP90↓,
Hif1a↓,
EMT↓,

1358-

Ash,

Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms

Review,

Var,

TumCCA↑,
Apoptosis↑,
TumAuto↑,
Ferroptosis↑,
TumCP↓,
CSCs↓,
TumMeta↓,
EMT↓,
angioG↓,
Vim↓,
HSP90↓,
annexin II↓, annexin II proteins directly bind to WA
m-FAM72A↓,
BCR-ABL↓,
Mortalin↓,
NRF2↓,
cMYB↓,
ROS↑, WA inhibits proliferation through ROS-mediated intrinsic apoptosis
ChemoSen↑, WA and cisplatin, WA produced ROS, while cisplatin caused DNA damage, suggesting that lower doses of cisplatin combined with suboptimal doses of WA could achieve the same effect
eff↑, sulforaphane and WA showed synergistic effects on epigenetic modifiers and cell proliferation in breast cancer cells
ChemoSen↑, WA and sorafenib caused G2/M arrest in anaplastic and papillary thyroid cancer cells
ChemoSen↑, combination of WA and 5-FU executed PERK axis-mediated endoplasmic reticulum (ER) stress-induced autophagy and apoptosis
eff↑, WA and carnosol also exhibit a synergistic effect on pancreatic cancer
*BioAv↓, Saurabh by Saurabh et al and Tianming et al reported oral bioavailability values 1.8% and 32.4 ± 4.8%, respectively, in male rats.
ROCK1↓, In another study, WA reduces macrophage infiltration and inhibits the expression of protein tyrosine kinase-2 (Pyk2), rho-associated kinase 1 (ROCK1), and VEGF in a hepatocellular carcinoma xenograft model, thereby suppressing tumor invasion and angi
TumCI↓,
Sp1/3/4↓, Furthermore, WA exerts potent anti-angiogenic activity in vivo.174 In the Ehrlich ascites tumor model, WA exerts its anti-angiogenic activity by reducing the binding of the transcription factor specificity protein 1 (Sp1) to VEGF
VEGF↓, n another study, WA reduces macrophage infiltration and inhibits the expression of protein tyrosine kinase-2 (Pyk2), rho-associated kinase 1 (ROCK1), and VEGF in a hepatocellular carcinoma xenograft model, thereby suppressing tumor invasion and angio
Hif1a↓, Furthermore, WA suppresses the AK4-HIF-1α signaling axis and acts as a potent antimetastatic agent in lung cancer.Citation79
EGFR↓, WA synergistically inhibited wild-type epidermal growth factor receptor (EGFR) lung cancer cell viability

1180-

Ash,

Withaferin A Inhibits Liver Cancer Tumorigenesis by Suppressing Aerobic Glycolysis through the p53/IDH1/HIF-1α Signaling Axis

in-vitro,

Liver,

HepG2

IDH1↑, IDH1 expression was downregulated in human liver cancer cells compared to normal liver cells
Glycolysis↓, decreased levels of several glycolytic enzymes
P53↑,
Hif1a↓,

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 4

Pathway results for Effect on Cancer / Diseased Cells:

Clinical Biomarkers ⓘ

EGFR↓, 1,
Total Targets: 34

Pathway results for Effect on Normal Cells:

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,
Total Targets: 1

Scientific Paper Hit Count for: Hif1a, HIF1α/HIF1a

4 Ashwagandha(Withaferin A)

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

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:36  Target#:143  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

Database Query Results : Ashwagandha(Withaferin A), , Hif1a

Mechanistic pathway map for Ashwagandha (Withaferin A) in cancer biology

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Protein Folding & ER Stress ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Pathway results for Effect on Normal Cells:

Drug Metabolism & Resistance ⓘ

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