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

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):

  1. Hsp90-axis disruption (incl. client protein destabilization) leading to proteostasis stress and multi-client oncoprotein depletion
  2. Covalent targeting of intermediate filaments (notably vimentin) with downstream effects on adhesion/migration, EMT programs, and angiogenic endothelium
  3. Pro-oxidative stress signaling in cancer cells with mitochondrial dysfunction, ER stress/UPR engagement, and apoptosis execution
  4. Inflammation and survival signaling suppression (notably NF-κB-centric programs; context-dependent immune modulation)
  5. Contextual transcriptional/epigenetic modulation (e.g., HDAC/DNMT-related signals) contributing to anti-proliferative phenotypes
  6. 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
Akt, PKB-Protein kinase B: Click to Expand ⟱
Source: HalifaxProj(inhibit)
Type:
Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes; Akt2 is an important signaling molecule in the insulin signaling pathway. It is required to induce glucose transport.

Inhibitors:
-Curcumin: downregulate AKT phosphorylation and signaling.
-Resveratrol
-Quercetin: inhibit the PI3K/AKT pathway.
-Epigallocatechin Gallate (EGCG)
-Luteolin and Apigenin: inhibit AKT phosphorylation


Scientific Papers found: Click to Expand⟱
5396- Ash,    Withania Somnifera (Ashwagandha) and Withaferin A: Potential in Integrative Oncology
- Review, Var, NA
selectivity↑, WS was shown to impede the growth of new cancer cells, but not normal cells,
ROS↑, help induce programmed death of cells by generating reactive oxygen species (ROS), and sensistize cancer cells to apoptosis
Apoptosis↑,
ChemoSen↑, Pre-clinical studies in several cancer types have shown up to 80% inhibition using combination chemotherapy [19].
RadioS↑, It was not until 1996, that WFA’s radiosensitizer activity was reported that caused V79 cell survival reduction where 1-h pre-treatment at 2.1 µM dose before radiation significantly killed cells
NF-kB↓, inhibiting NF-κB activation
ER-α36↓, WFA, it was found the phytochemical downregulated the estrogen receptor-α (ER-α) protein in MCF-7 cells.
P53↑, WFA selectively activated p53 in tumor cells treated with the leaf extract of Ashwagandha [71] leading to growth arrest and apoptosis.
*ROS∅, opposed to the normal human mammary epithelial cells (HMEC) [72] which did not increase ROS production.
γH2AX↑, The group found an increase in γ-H2AX and number of cells expressing the phosphorylated form which is a marker for DNA damage in WFA treated MCF-7 cells.
DNAdam↑,
MMP↓, As ROS is well known to affect mithochondrial membrane potential, they found a change in mitochondrial membrane potential and altered mitochondrial morphology in WFA treated cells.
XIAP↓, XIAP (X-linked inhibitor of apoptosis protein), cIAP-2 (cellular inhibitor of apoptosis protein-2) and Survivin proteins were found to be reduced in MDA-MB-231 and MCF-7 cells when treated with WFA
IAP1↓,
survivin↓,
SOD↓, figure 2
Dose↝, doses of 3 and 4 mg/kg and the authors found 59% reduction of tumor and polyp initiation and progression in the WFA treated mice compared to the controls [80].
IL6↓, WFA downregulated expression of inflammatory markers in these tumors such as IL-6, TNF-α, COX-2 along with pro-survival markers such as pAkt, Notch1 and NF-κβ [80].
TNF-α↓,
COX2↓,
p‑Akt↓,
NOTCH1↓,
FOXO↑, figure 3 prostrate cancer
Casp↑,
MMP2↓,
CSCs↓, WFA treatment significantly reduced ALDH+ CSC population, whereas Cisplatin treatment increased CSC population.
*ROS↓, WFA was found to increase cellular survival in simulated injury and in H2O2-induced cell apoptosis along with inhibition of oxidative stress.
*SOD2↑, Thus, via upregulation of SOD2, SOD3, Prdx-1 by H2O2, WFA treatment leads to inhibition of the antioxidants and Akt-dependent improvement of cardiomyocyte caspase-3 [103].
chemoP↑, First, given the safety record of WS, it can be used as an adjunct therapy that can aid in reducing the adverse effects associated with radio and chemotherapy due to its anti-inflammatory properties.
ChemoSen↑, Second, WS can also be combined with other conventional therapies such as chemotherapies to synergize and potentiate the effects due to radiotherapy and chemotherapy due to its ability to aid in radio- and chemosensitization, respectively.
RadioS↑,

5395- Ash,    Withaferin A Targets Heat Shock Protein 90 in Pancreatic Cancer Cells
- vitro+vivo, PC, PANC1 - in-vitro, PC, MIA PaCa-2
TumCP↓, Withaferin A exhibited potent antiproliferative activity against pancreatic cancer cells in vitro
HSP90↓, WA inhibited Hsp90 chaperone activity to induce degradation of Hsp90 client proteins (Akt, Cdk4 and glucocorticoid receptor)
Akt↓,
CDK4↓,
TumCG↓, WA (3, 6 mg/kg) inhibited tumor growth in pancreatic Panc-1 xenografts by 30% and 58%, respectively.
Apoptosis↑, Withaferin A induces apoptosis in pancreatic cancer cells
AntiCan↑, Withaferin A exhibits anticancer activity in pancreatic cancer xenografts

5175- Ash,    Withaferin A Induces Proteasome Inhibition, Endoplasmic Reticulum Stress, the Heat Shock Response and Acquisition of Thermotolerance
- in-vitro, Cerv, CCL-102
Inflam↓, In the present study, withaferin A (WA), a steroidal lactone with anti-inflammatory and anti-tumor properties, inhibited proteasome activity
AntiTum↑,
Proteasome↓,
ER Stress↑, and induced endoplasmic reticulum (ER) and cytoplasmic HSP accumulation in Xenopus laevis A6 kidney epithelial cells.
HSPs↑,
GRP94↑, WA induced the accumulation of HSPs including ER chaperones, BiP and GRP94, as well as cytoplasmic/nuclear HSPs, HSP70 and HSP30.
Akt↑, WA-induced an increase in the relative levels of the protein kinase, Akt,
eff↑, WA acted synergistically with mild heat shock to enhance HSP70 and HSP30 accumulation to a greater extent than the sum of both stressors individually
HSP70/HSPA5↑, WA Induced Accumulation of BiP, GRP94, HSP70 and HSP30

5172- Ash,    Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells
Akt↓, WA, a natural compound, resulted in significant inhibition of AKT activity and led to the inhibition of cell proliferation, migration and invasion
TumCP↓,
TumCMig↓,
TumCI↓,
EMT↓, by downregulating the epithelial to mesenchymal transition (EMT) markers in CRC cells overexpressing AKT
Snail↓, Further, significant inhibition of some important EMT markers, i.e., Snail, Slug, β-catenin and vimentin, was observed in WA-treated human CRC cells overexpressing AKT
Slug↓,
β-catenin/ZEB1↓,
Vim↓,
angioG↓, Significant inhibition of micro-vessel formation and the length of vessels were evident in WA-treated tumors, which correlated with a low expression of the angiogenic marker RETIC

3166- Ash,    Exploring the Multifaceted Therapeutic Potential of Withaferin A and Its Derivatives
- Review, Var, NA
*p‑PPARγ↓, preventing the phosphorylation of peroxisome proliferator-activated receptors (PPARγ)
*cardioP↑, cardioprotective activity by AMP-activated protein kinase (AMPK) activation and suppressing mitochondrial apoptosis.
*AMPK↑,
*BioAv↝, The oral bioavailability was found to be 32.4 ± 4.8% after 5 mg/kg intravenous and 10 mg/kg oral WA administration.
*Half-Life↝, The stability studies of WA in gastric fluid, liver microsomes, and intestinal microflora solution showed similar results in male rats and humans with a half-life of 5.6 min.
*Half-Life↝, WA reduced quickly, and 27.1% left within 1 h
*Dose↑, WA showed that formulation at dose 4800 mg having equivalent to 216 mg of WA, was tolerated well without showing any dose-limiting toxicity.
*chemoPv↑, Here, we discuss the chemo-preventive effects of WA on multiple organs.
IL6↓, attenuates IL-6 in inducible (MCF-7 and MDA-MB-231)
STAT3↓, WA displayed downregulation of STAT3 transcriptional activity
ROS↓, associated with reactive oxygen species (ROS) generation, resulted in apoptosis of cells. The WA treatment decreases the oxidative phosphorylation
OXPHOS↓,
PCNA↓, uppresses human breast cells’ proliferation by decreasing the proliferating cell nuclear antigen (PCNA) expression
LDH↓, WA treatment decreases the lactate dehydrogenase (LDH) expression, increases AMP protein kinase activation, and reduces adenosine triphosphate
AMPK↑,
TumCCA↑, (SKOV3 andCaOV3), WA arrest the G2/M phase cell cycle
NOTCH3↓, It downregulated the Notch-3/Akt/Bcl-2 signaling mediated cell survival, thereby causing caspase-3 stimulation, which induces apoptosis.
Akt↓,
Bcl-2↓,
Casp3↑,
Apoptosis↑,
eff↑, Withaferin-A, combined with doxorubicin, and cisplatin at suboptimal dose generates ROS and causes cell death
NF-kB↓, reduces the cytosolic and nuclear levels of NF-κB-related phospho-p65 cytokines in xenografted tumors
CSCs↓, WA can be used as a pharmaceutical agent that effectively kills cancer stem cells (CSCs).
HSP90↓, WA inhibit Hsp90 chaperone activity, disrupting Hsp90 client proteins, thus showing antiproliferative effects
PI3K↓, WA inhibited PI3K/AKT pathway.
FOXO3↑, Par-4 and FOXO3A proapoptotic proteins were increased in Pten-KO mice supplemented with WA.
β-catenin/ZEB1↓, decreased pAKT expression and the β-catenin and N-cadherin epithelial-to-mesenchymal transition markers in WA-treated tumors control
N-cadherin↓,
EMT↓,
FASN↓, WA intraperitoneal administration (0.1 mg) resulted in significant suppression of circulatory free fatty acid and fatty acid synthase expression, ATP citrate lyase,
ACLY↓,
ROS↑, WA generates ROS followed by the activation of Nrf2, HO-1, NQO1 pathways, and upregulating the expression of the c-Jun-N-terminal kinase (JNK)
NRF2↑,
HO-1↑,
NQO1↑,
JNK↑,
mTOR↓, suppressing the mTOR/STAT3 pathway
neuroP↑, neuroprotective ability of WA (50 mg/kg b.w)
*TNF-α↓, WA attenuate the levels of neuroinflammatory mediators (TNF-α, IL-1β, and IL-6)
*IL1β↓,
*IL6↓,
*IL8↓, WA decreases the pro-inflammatory cytokines (IL-6, TNFα, IL-8, IL-18)
*IL18↓,
RadioS↑, radiosensitizing combination effect of WA and hyperthermia (HT) or radiotherapy (RT)
eff↑, WA and cisplatin at suboptimal dose generates ROS and causes cell death [41]. The actions of this combination is attributed by eradicating cells, revealing markers of cancer stem cells like CD34, CD44, Oct4, CD24, and CD117

1357- Ash,    Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways
- in-vitro, GBM, U87MG - in-vitro, GBM, U251 - in-vitro, GBM, GL26
TumCP↓,
TumCCA↑, G2/M cell cycle
Akt↓,
mTOR↓,
p70S6↓,
p85S6K↓,
AMPKα↑,
TSC2↑,
HSP70/HSPA5↑,
HO-1↑,
HSF1↓,
Apoptosis↑,
ROS↑, Withaferin A elevates pro-oxidant potential in GBM cells and induces a cellular oxidative stress response
eff↓, Pre-treatment with a thiol-antioxidant protects GBM cells from the anti-proliferative and cytotoxic effects of withaferin A NAC pretreatment was able to completely prevent cell cycle shift to G2/M arrest following 1µM WA treatment at 24h

3162- Ash,    Molecular insights into cancer therapeutic effects of the dietary medicinal phytochemical withaferin A
- Review, Var, NA
lipid-P↓, Oral cancer 20 mg/Kg ↓Lipid peroxidation : ↑SOD, glutathione peroxidase, p53, Bcl-2
SOD↑,
GPx↑,
P53↑,
Bcl-2↑,
E6↓, Cervival cancer 8mg/Kg ↓E6, E7: ↑p53, pRb, Cyclin B1, P34 Cdc2, p21, PCNA
E7↓,
pRB↑,
CycB/CCNB1↑,
CDC2↑,
P21↑,
PCNA↓,
ALDH1A1↓, Mammary cancer 0-1 mg/mouse (5-10) ↓Mammosphere number, ALDH1 activity. Vimentin, glycolysis
Vim↓,
Glycolysis↓,
cMyc↓, Mesotheliome cancer 5 mg/Kg ↓Proteasomal chymotrypsin, C-Myc : ↑ Bax, CARP-1
BAX↑,
NF-kB↓,
Casp3↑, caspase-3 activation
CHOP↑, WA is found to increase activation of Elk1 and CHOP (CCAAT-enhancer-binding protein homologous protein) by RSK, as well as up-regulation of DR5 by selectively suppressing pathway ERK
DR5↑,
ERK↓,
Wnt↓, WA inhibits Wnt/β-catenin pathway via suppression of AKT signalling, which inhibits cancer cell motility and sensitises for cell death
β-catenin/ZEB1↓,
Akt↓,
HSP90↓, WA-dependent inhibition of heat shock protein (HSP) chaperone functions. WA inhibits the activity of HSP90-mediated function

3160- Ash,    Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal
- Review, Var, NA
TumCCA↑, withaferin A suppressed cell proliferation in prostate, ovarian, breast, gastric, leukemic, and melanoma cancer cells and osteosarcomas by stimulating the inhibition of the cell cycle at several stages, including G0/G1 [86], G2, and M phase
H3↑, via the upregulation of phosphorylated Aurora B, H3, p21, and Wee-1, and the downregulation of A2, B1, and E2 cyclins, Cdc2 (Tyr15), phosphorylated Chk1, and Chk2 in DU-145 and PC-3 prostate cancer cells.
P21↑,
cycA1/CCNA1↓,
CycB/CCNB1↓,
cycE/CCNE↓,
CDC2↓,
CHK1↓,
Chk2↓,
p38↑, nitiated cell death in the leukemia cells by increasing the expression of p38 mitogen-activated protein kinases (MAPK)
MAPK↑,
E6↓, educed the expression of human papillomavirus E6/E7 oncogenes in cervical cancer cells
E7↓,
P53↑, restored the p53 pathway causing the apoptosis of cervical cancer cells.
Akt↓, oral dose of 3–5 mg/kg withaferin A attenuated the activation of Akt and stimulated Forkhead Box-O3a (FOXO3a)-mediated prostate apoptotic response-4 (Par-4) activation,
FOXO3↑,
ROS↑, the generation of reactive oxygen species, histone H2AX phosphorylation, and mitochondrial membrane depolarization, indicating that withaferin A can cause the oxidative stress-mediated killing of oral cancer cells [
γH2AX↑,
MMP↓,
mitResp↓, withaferin A inhibited the expansion of MCF-7 and MDA-MB-231 human breast cancer cells by ROS production, owing to mitochondrial respiration inhibition
eff↑, combination treatment of withaferin A and hyperthermia induced the death of HeLa cells via a decrease in the mitochondrial transmembrane potential and the downregulation of the antiapoptotic protein myeloid-cell leukemia 1 (MCL-1)
TumCD↑,
Mcl-1↓,
ER Stress↑, . Withaferin A also attenuated the development of glioblastoma multiforme (GBM), both in vitro and in vivo, by inducing endoplasmic reticulum stress via activating the transcription factor 4-ATF3-C/EBP homologous protein (ATF4-ATF3-CHOP)
ATF4↑,
ATF3↑,
CHOP↑,
NOTCH↓, modulating the Notch-1 signaling pathway and the downregulation of Akt/NF-κB/Bcl-2 . withaferin A inhibited the Notch signaling pathway
NF-kB↓,
Bcl-2↓,
STAT3↓, Withaferin A also constitutively inhibited interleukin-6-induced phosphorylation of STAT3,
CDK1↓, lowering the levels of cyclin-dependent Cdk1, Cdc25C, and Cdc25B proteins,
β-catenin/ZEB1↓, downregulation of p-Akt expression, β-catenin, N-cadherin and epithelial to the mesenchymal transition (EMT) markers
N-cadherin↓,
EMT↓,
Cyt‑c↑, depolarization and production of ROS, which led to the release of cytochrome c into the cytosol,
eff↑, combinatorial effect of withaferin A and sulforaphane was also observed in MDA-MB-231 and MCF-7 breast cancer cells, with a dramatic reduction of the expression of the antiapoptotic protein Bcl-2 and an increase in the pro-apoptotic Bax level, thus p
CDK4↓, downregulates the levels of cyclin D1, CDK4, and pRB, and upregulates the levels of E2F mRNA and tumor suppressor p21, independently of p53
p‑RB1↓,
PARP↑, upregulation of Bax and cytochrome c, downregulation of Bcl-2, and activation of PARP, caspase-3, and caspase-9 cleavage
cl‑Casp3↑,
cl‑Casp9↑,
NRF2↑, withaferin A binding with Keap1 causes an increase in the nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels, which in turn, regulates the expression of antioxidant proteins that can protect the cells from oxidative stress.
ER-α36↓, Decreased ER-α
LDHA↓, inhibited growth, LDHA activity, and apoptotic induction
lipid-P↑, induction of oxidative stress, increased lipid peroxidation,
AP-1↓, anti-inflammatory qualities of withaferin A are specifically attributed to its inhibition of pro-inflammatory molecules, α-2 macroglobulin, NF-κB, activator protein 1 (AP-1), and cyclooxygenase-2 (COX-2) inhibition,
COX2↓,
RenoP↑, showing strong evidence of the renoprotective potential of withaferin A due to its anti-inflammatory activity
PDGFR-BB↓, attenuating the BB-(PDGF-BB) platelet growth factor
SIRT3↑, by increasing the sirtuin3 (SIRT3) expression
MMP2↓, withaferin A inhibits matrix metalloproteinase-2 (MMP-2) and MMP-9,
MMP9↓,
NADPH↑, but also provokes mRNA stimulation for a set of antioxidant genes, such as NADPH quinone dehydrogenase 1 (NQO1), glutathione-disulfide reductase (GSR), Nrf2, heme oxygenase 1 (HMOX1),
NQO1↑,
GSR↑,
HO-1↑,
*SOD2↑, cardiac ischemia-reperfusion injury model. Withaferin A triggered the upregulation of superoxide dismutase SOD2, SOD3, and peroxiredoxin 1(Prdx-1).
*Prx↑,
*Casp3?, and ameliorated cardiomyocyte caspase-3 activity
eff↑, combination with doxorubicin (DOX), is also responsible for the excessive generation of ROS
Snail↓, inhibition of EMT markers, such as Snail, Slug, β-catenin, and vimentin.
Slug↓,
Vim↓,
CSCs↓, highly effective in eliminating cancer stem cells (CSC) that expressed cell surface markers, such as CD24, CD34, CD44, CD117, and Oct4 while downregulating Notch1, Hes1, and Hey1 genes;
HEY1↓,
MMPs↓, downregulate the expression of MMPs and VEGF, as well as reduce vimentin, N-cadherin cytoskeleton proteins,
VEGF↓,
uPA↓, and protease u-PA involved in the cancer cell metastasis
*toxicity↓, A was orally administered to Wistar rats at a dose of 2000 mg/kg/day and had no adverse effects on the animals
CDK2↓, downregulated the activation of Bcl-2, CDK2, and cyclin D1
CDK4↓, Another study also demonstrated the inhibition of Hsp90 by withaferin A in a pancreatic cancer cell line through the degradation of Akt, cyclin-dependent kinase 4 Cdk4,
HSP90↓,

3156- Ash,    Withaferin A: From ayurvedic folk medicine to preclinical anti-cancer drug
- Review, Var, NA
MAPK↑, Figure 3
p38↑,
BAX↑,
BIM↑,
CHOP↑,
ROS↑,
DR5↑,
Apoptosis↑,
Ferroptosis↑,
GPx4↓,
BioAv↝, WA has a rapid oral absorption and reaches to peak plasma concentration of around 16.69 ± 4.02 ng/ml within 10 min after oral administration of Withania somnifera aqueous extract at dose of 1000 mg/kg, which is equivalent to 0.458 mg/kg of WA
HSP90↓, table 1 10uM) were found to inhibit the chaperone activity of HSP90
RET↓,
E6↓,
E7↓,
Akt↓,
cMET↓,
Glycolysis↓, by suppressing the glycolysis and tricarboxylic (TCA) cycle
TCA↓,
NOTCH1↓,
STAT3↓,
AP-1↓,
PI3K↓,
eIF2α↓,
HO-1↑,
TumCCA↑, WA (1--3 uM) have been reported to inhibit cell proliferation by inducing G2 and M phase cycle arrest inovarian, breast, prostate, gastric and myelodysplastic/leukemic cancer cells and osteosarcoma
CDK1↓, WA is able to decrease the cyclin-dependent kinase 1 (Cdk1) activity and prevent Cdk1/cyclin B1 complex formation, which are key steps in cell cycle progression
*hepatoP↑, A treatment (40 mg/kg) reduces acetaminophen-induced liver injury (AILI) in mouse models and decreases H 2O 2-induced glutathione (GSH) depletion and necrosis in hepatocyte
*GSH↑,
*NRF2↑, WA triggers an anti-oxidant response after acetaminophen overdose by enhancing hepatic transcription of the nuclear factor erythroid 2–related factor 2 (NRF2)-responsive gene
Wnt↓, indirectly inhibit Wnt
EMT↓, WA can also block tumor metastasis through reduced expression of epithelial mesenchymal transition (EMT) markers.
uPA↓, WA (700 nM) exert anti-meta-static activities in breast cancer cells through inhibition of the urokinase-type plasminogen activator (uPA) protease
CSCs↓, s WA (125-500 nM) suppress tumor sphere formation indicating that the self-renewal of CSC is abolished
Nanog↓, loss of these CSC-specific characteristics is reflected in the loss of typical stem cell markers such as ALDH1A, Nanog, Sox2, CD44 and CD24
SOX2↓,
CD44↓,
lactateProd↓, drop in lactate levels compared to control mice.
Iron↑, Furthermore, we found that WA elevates the levels of intracellular labile ferrous iron (Fe +2 ) through excessive activation of heme oxygenase-1 (HMOX1), which independently causes accumulation of toxic lipid radicals and ensuing ferroptosis
NF-kB↓, nhibition of NF-kB kinase signaling pathway

3155- Ash,    Overview of the anticancer activity of withaferin A, an active constituent of the Indian ginseng Withania somnifera
- Review, Var, NA
Half-Life↝, The pharmacokinetic study demonstrates that a dose of 4 mg/kg in mice results in 2 μM concentration in plasma (with a half-life of 1.3 h, in the breast cancer model of mice),
Inflam↓, WA has many biological activities: anti-inflammatory (Dubey et al. 2018), immunomodulatory (Davis and Girija 2000), antistress (Singh et al. 2016), antioxidant (Sumathi et al. 2007) and anti-angiogenesis
antiOx↓,
angioG↓,
ROS↑, WA induces oxidative stress (ROS) determining mitochondrial dysfunction as well as apoptosis in leukaemia cells
BAX↑, withaferin mediates apoptosis by ROS generation and activation of Bax/Bak.
Bak↑,
E6↓, The results of the study show that withaferin treatment downregulates the HPV E6 and E7 oncoprotein and induces accumulation of p53 result in the activation of various apoptotic markers (e.g. Bcl2, Bax, caspase-3 and cleaved PARP).
E7↓,
P53↑,
Casp3↑,
cl‑PARP↑,
STAT3↓, WA treatment also decreases the level of STAT3
eff↑, This study concludes that combination of DOX with WA can reduce the doses and side effects of the treatment which gives valuable possibilities for future research.
HSP90↓, by inhibiting the HSP90
TGF-β↓, WA inhibited TGFβ1 and TNFα- induced EMT;
TNF-α↓,
EMT↑,
mTOR↓, by downregulation of mTOR/STAT3 signalling.
NOTCH1↓, WA showed inhibition of pro-survival signalling markers (Notch1, pAKT and NFκB)
p‑Akt↓,
NF-kB↓,
Dose↝, WA dose escalation sets consisted of 72, 108, 144 and 216 mg, fractioned in 2-4 doses/day.


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 10

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

antiOx↓, 1,   ATF3↑, 1,   Ferroptosis↑, 1,   GPx↑, 1,   GPx4↓, 1,   GSR↑, 1,   HO-1↑, 4,   Iron↑, 1,   lipid-P↓, 1,   lipid-P↑, 1,   NQO1↑, 2,   NRF2↑, 2,   OXPHOS↓, 1,   ROS↓, 1,   ROS↑, 6,   SIRT3↑, 1,   SOD↓, 1,   SOD↑, 1,  

Mitochondria & Bioenergetics ⓘ

CDC2↓, 1,   CDC2↑, 1,   mitResp↓, 1,   MMP↓, 2,   XIAP↓, 1,  

Core Metabolism/Glycolysis ⓘ

ACLY↓, 1,   AMPK↑, 1,   cMyc↓, 1,   FASN↓, 1,   Glycolysis↓, 2,   lactateProd↓, 1,   LDH↓, 1,   LDHA↓, 1,   NADPH↑, 1,   TCA↓, 1,  

Cell Death ⓘ

Akt↓, 7,   Akt↑, 1,   p‑Akt↓, 2,   Apoptosis↑, 5,   Bak↑, 1,   BAX↑, 3,   Bcl-2↓, 2,   Bcl-2↑, 1,   BIM↑, 1,   Casp↑, 1,   Casp3↑, 3,   cl‑Casp3↑, 1,   cl‑Casp9↑, 1,   Chk2↓, 1,   Cyt‑c↑, 1,   DR5↑, 2,   Ferroptosis↑, 1,   HEY1↓, 1,   IAP1↓, 1,   JNK↑, 1,   MAPK↑, 2,   Mcl-1↓, 1,   p38↑, 2,   Proteasome↓, 1,   survivin↓, 1,   TumCD↑, 1,  

Kinase & Signal Transduction ⓘ

AMPKα↑, 1,   p70S6↓, 1,   RET↓, 1,   TSC2↑, 1,  

Transcription & Epigenetics ⓘ

H3↑, 1,   pRB↑, 1,  

Protein Folding & ER Stress ⓘ

CHOP↑, 3,   eIF2α↓, 1,   ER Stress↑, 2,   GRP94↑, 1,   HSF1↓, 1,   HSP70/HSPA5↑, 2,   HSP90↓, 6,   HSPs↑, 1,  

DNA Damage & Repair ⓘ

CHK1↓, 1,   DNAdam↑, 1,   P53↑, 4,   PARP↑, 1,   cl‑PARP↑, 1,   PCNA↓, 2,   γH2AX↑, 2,  

Cell Cycle & Senescence ⓘ

CDK1↓, 2,   CDK2↓, 1,   CDK4↓, 3,   cycA1/CCNA1↓, 1,   CycB/CCNB1↓, 1,   CycB/CCNB1↑, 1,   cycE/CCNE↓, 1,   P21↑, 2,   p‑RB1↓, 1,   TumCCA↑, 4,  

Proliferation, Differentiation & Cell State ⓘ

ALDH1A1↓, 1,   CD44↓, 1,   cMET↓, 1,   CSCs↓, 4,   EMT↓, 4,   EMT↑, 1,   ERK↓, 1,   FOXO↑, 1,   FOXO3↑, 2,   mTOR↓, 3,   Nanog↓, 1,   NOTCH↓, 1,   NOTCH1↓, 3,   NOTCH3↓, 1,   p85S6K↓, 1,   PI3K↓, 2,   SOX2↓, 1,   STAT3↓, 4,   TumCG↓, 1,   Wnt↓, 2,  

Migration ⓘ

AP-1↓, 2,   ER-α36↓, 2,   MMP2↓, 2,   MMP9↓, 1,   MMPs↓, 1,   N-cadherin↓, 2,   Slug↓, 2,   Snail↓, 2,   TGF-β↓, 1,   TumCI↓, 1,   TumCMig↓, 1,   TumCP↓, 3,   uPA↓, 2,   Vim↓, 3,   β-catenin/ZEB1↓, 4,  

Angiogenesis & Vasculature ⓘ

angioG↓, 2,   ATF4↑, 1,   PDGFR-BB↓, 1,   VEGF↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 2,   IL6↓, 2,   Inflam↓, 2,   NF-kB↓, 6,   TNF-α↓, 2,  

Drug Metabolism & Resistance ⓘ

BioAv↝, 1,   ChemoSen↑, 2,   Dose↝, 2,   eff↓, 1,   eff↑, 7,   Half-Life↝, 1,   RadioS↑, 3,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

E6↓, 4,   E7↓, 4,   IL6↓, 2,   LDH↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   AntiTum↑, 1,   chemoP↑, 1,   neuroP↑, 1,   RenoP↑, 1,  
Total Targets: 151

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

GSH↑, 1,   NRF2↑, 1,   Prx↑, 1,   ROS↓, 1,   ROS∅, 1,   SOD2↑, 2,  

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1,   p‑PPARγ↓, 1,  

Cell Death ⓘ

Casp3?, 1,  

Immune & Inflammatory Signaling ⓘ

IL18↓, 1,   IL1β↓, 1,   IL6↓, 1,   IL8↓, 1,   TNF-α↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↝, 1,   Dose↑, 1,   Half-Life↝, 2,  

Clinical Biomarkers ⓘ

IL6↓, 1,  

Functional Outcomes ⓘ

cardioP↑, 1,   chemoPv↑, 1,   hepatoP↑, 1,   toxicity↓, 1,  
Total Targets: 22

Scientific Paper Hit Count for: Akt, PKB-Protein kinase B
10 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#:4  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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