Cynara scolymus/Globe Artichoke/Artichoke Extract / NRF2 Cancer Research Results

CS, Cynara scolymus/Globe Artichoke/Artichoke Extract: Click to Expand ⟱
Features:

Cynara scolymus - Globe Artichoke / Artichoke Extract,, Artichoke leaf extract

Type: Botanical extract / polyphenol-rich medicinal plant

Active Constituents: Cynarin, chlorogenic acid, caffeoylquinic acids, luteolin, apigenin, and related flavonoids and phenolic compounds.

Function: Cynara scolymus exhibits antioxidant, anti-inflammatory, hepatoprotective, lipid-modulating, metabolic, and cytoprotective effects. Artichoke extracts can modulate oxidative stress, inflammatory signaling, apoptosis, and cellular metabolism.

Cancer: Experimental studies indicate antiproliferative, pro-apoptotic, antioxidant, and anti-inflammatory effects in multiple cancer cell models, with potential modulation of cell-cycle and survival pathways.

Alzheimer's Disease: Preclinical evidence suggests neuroprotective effects through antioxidant, anti-inflammatory, and cholinergic mechanisms, but the evidence base is less developed than for its metabolic and hepatic effects.


For supplements look for: standardized caffeoylquinic acids per capsule (example 5%, 25mg/capsule)

Cynara scolymus — globe artichoke, commonly used medicinally as artichoke leaf extract (ALE), is a polyphenol- and sesquiterpene-lactone-rich botanical preparation derived primarily from the leaves of Cynara cardunculus L. subsp. scolymus, historically also designated Cynara scolymus L. It is classified as a botanical extract / herbal medicinal product rather than a single defined drug. Common abbreviations are CS and ALE. Major constituents include chlorogenic acid and other caffeoylquinic acids, cynarin, luteolin glycosides, apigenin derivatives, and the sesquiterpene lactone cynaropicrin; their concentrations vary substantially with plant part, cultivar, extraction method, and standardization. Artichoke leaf preparations have established traditional gastrointestinal use and human clinical investigation for dyslipidemia and metabolic/liver disorders, whereas anticancer activity remains predominantly preclinical.

Primary mechanisms (ranked):

  1. Induction of mitochondrial apoptosis through ↑BAX, ↓BCL-2, mitochondrial dysfunction, and caspase-9/caspase activation.
  2. Cell-cycle arrest and durable growth suppression, including G2/M arrest and p16/p21-associated cellular senescence.
  3. Context-dependent pro-oxidant ROS accumulation in cancer cells, contributing to apoptosis, senescence, DNA damage, and chemosensitization.
  4. Suppression of proliferative and inflammatory survival signaling, including ↓NF-κB activity in susceptible cancer models.
  5. Suppression of cancer-cell invasion and metastatic phenotype in breast-cancer models.
  6. FEN1 downregulation and increased DNA-damage susceptibility, enhancing sensitivity to DNA-damaging chemotherapy such as paclitaxel in preclinical breast-cancer models.
  7. Antioxidant and cytoprotective activity in non-malignant tissues through polyphenol-mediated reduction of oxidative injury; this contrasts with the pro-oxidant response observed in some cancer models.

Bioavailability / PK relevance: Artichoke extract is a complex mixture rather than a single systemically delivered compound. Human pharmacokinetic studies demonstrate absorption and extensive metabolism of caffeoylquinic acids and flavonoids, with circulating metabolites such as caffeic/dihydrocaffeic-acid derivatives and conjugated flavonoids likely contributing to biological activity. Parent polyphenol exposure is relatively low and extensively transformed by intestinal, hepatic, and microbial metabolism. Extract composition and standardization are therefore major determinants of exposure.

In-vitro vs systemic exposure relevance: Many anticancer experiments use whole artichoke extracts at concentrations in the tens to hundreds of µg/mL range or prolonged cellular exposure. These conditions cannot be assumed to reproduce concentrations of intact extract constituents in human tumors after oral supplementation. Human circulating concentrations of individual absorbed polyphenols are generally in the submicromolar-to-low-micromolar range and are dominated by metabolites; consequently, direct extrapolation of cytotoxic in-vitro concentrations to oral systemic anticancer activity is not justified.

Clinical evidence status: Cancer: preclinical only; no established anticancer efficacy in humans and no validated role as cancer therapy or adjunct treatment. Non-cancer indications: multiple small randomized human trials and meta-analyses report effects on lipid parameters, and clinical studies have evaluated metabolic and hepatic outcomes. European herbal-medicine recognition is based principally on traditional use for dyspeptic gastrointestinal complaints rather than cancer treatment.

Safety / translation constraints: Artichoke leaf preparations are generally well tolerated in short-term human studies, but gastrointestinal adverse effects and allergic reactions can occur. Avoid in patients with hypersensitivity to artichoke or other Asteraceae plants. Because artichoke can stimulate bile secretion, bile-duct obstruction and cholangitis are important contraindications, and gallstones or other biliary disorders warrant medical assessment. Extract-to-extract chemical heterogeneity and the large exposure gap between many cell-culture experiments and oral human dosing are major constraints on anticancer translation.

Cancer-Relevant Mechanisms of Cynara scolymus Extract

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Mitochondrial apoptosis ↑ BAX, ↑ caspase-9, ↓ BCL-2, ↑ apoptosis ↔ / cytoprotective (context-dependent) R-G Programmed cancer-cell death Supported in oral squamous carcinoma and colorectal cancer models. Colon-cancer studies indicate activation of the mitochondrial-dependent apoptotic pathway.
2 Cell-cycle arrest and senescence ↑ G2/M arrest, ↑ p16, ↑ p21, ↑ senescence ↔ (model-dependent) G Suppression of proliferation G2/M arrest has been demonstrated in oral squamous carcinoma cells; prolonged low-dose exposure in MDA-MB-231 breast-cancer cells produces p16/p21-associated premature senescence.
3 ROS-mediated cancer stress ↑ ROS (dose-dependent), ↑ oxidative signaling ↓ oxidative stress P-G Apoptosis and senescence Artichoke polyphenols can behave as pro-oxidants in cancer cells while acting predominantly as antioxidants in non-malignant systems. NAC attenuation of growth inhibition supports a causal ROS component in breast-cancer models.
4 NF-κB and inflammatory survival signaling ↓ NF-κB, ↓ survival signaling ↓ excessive inflammatory signaling R-G Reduced proliferation and inflammation Artichoke leaf extract suppresses NF-κB activity in human leukemic-cell models, in part in association with AKR1B1 inhibition.
5 Invasion and metastatic phenotype ↓ invasion, ↓ metastatic phenotype G Reduced invasive behavior Polyphenolic artichoke extract reduces invasive potential in MDA-MB-231 breast-cancer cells. The precise molecular determinants appear extract- and model-dependent.
6 FEN1 and DNA damage response ↓ FEN1, ↑ DNA damage susceptibility Uncertain R-G Chemosensitization Artichoke polyphenols enhance chemotherapy response in breast-cancer cells through ROS-associated FEN1 downregulation and altered DNA-damage response.
7 Chemosensitization ↑ sensitivity to paclitaxel and DNA damage (model-dependent) Uncertain G Enhanced chemotherapy effect Observed preclinically with artichoke polyphenols plus paclitaxel; ROS/NRF2 and ERK signaling participate in the combination response. This has not been clinically validated.
8 NRF2 redox response NRF2 (context-dependent) ↑ antioxidant defense (context-dependent) P-R Redox adaptation NRF2 is involved in the ROS-dependent chemotherapy interaction described in breast-cancer cells but is not sufficiently consistent to classify as a universal primary anticancer mechanism of artichoke extract.
9 Antioxidant cytoprotection ↕ oxidative stress (context-dependent) ↓ ROS, ↓ oxidative injury, ↑ antioxidant capacity R-G Protection of non-malignant tissues Human and experimental non-cancer studies generally support antioxidant activity. This bidirectional redox behavior is important when interpreting apparently contradictory cancer and normal-tissue findings.
10 Clinical Translation Constraint In-vitro anticancer exposure often high Oral preparations generally well tolerated G Limits clinical inference Whole-extract concentrations used for cytotoxicity are not directly comparable with plasma exposure after oral ALE. Polyphenols undergo substantial metabolism, formulations vary chemically, and no clinical anticancer efficacy has been established.

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



NRF2, nuclear factor erythroid 2-related factor 2: Click to Expand ⟱
Source: TCGA
Type: Antiapoptotic
Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response.
-One way to estimate Nrf2 induction is through the expression of NQO1.
NQO1, the most potent inducer:
SFN 0.2 μM,
quercetin (2.5 μM),
curcumin (2.7 μM),
Silymarin (3.6 μM),
tamoxifen (5.9 μM),
genistein (6.2 μM ),
beta-carotene (7.2μM),
lutein (17 μM),
resveratrol (21 μM),
indol-3-carbinol (50 μM),
chlorophyll (250 μM),
alpha-cryptoxanthin (1.8 mM),
and zeaxanthin (2.2 mM)

1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects.
2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death.
3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress

-In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies.
-Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate.
Decreased Nrf2 expression: Skine, Liver, Pancreatic.
-Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer
- "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1.

Nrf2 Inhibitors and Activators
Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin
Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api
- potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany

Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue.
– In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis.
– In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity.
– This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming.
– Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies.
– High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types.
– While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression.

NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS).
-Brusatol: most cited natural inhibitors of Nrf2.
-Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent.
-Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent .
-Oridonin:
-Wogonin: although its effects might be cell‑ and dose‑specific.
- Withaferin A

Scientific Papers found: Click to Expand⟱
7412- CS,  Chemo,    Artichoke Polyphenols Sensitize Human Breast Cancer Cells to Chemotherapeutic Drugs via a ROS-Mediated Downregulation of Flap Endonuclease 1
- in-vitro, BC, MCF7 - in-vitro, BC, MDA-MB-231
Apoptosis↑, ROS↑, TumCP↓, DNAdam↑, FEN1↓, ChemoSen↑, NRF2↑,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


NA, unassigned(tgid=0)

FEN1↓, 1,  

Redox & Oxidative Stress(tgid=1)

NRF2↑, 1,   ROS↑, 1,  

Cell Death(tgid=5)

Apoptosis↑, 1,  

DNA Damage & Repair(tgid=10)

DNAdam↑, 1,  

Migration(tgid=13)

TumCP↓, 1,  

Drug Metabolism & Resistance(tgid=21)

ChemoSen↑, 1,  
Total Targets: 7

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: NRF2, nuclear factor erythroid 2-related factor 2
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#:443  Target#:226  State#:%  Dir#:%
wNotes=0 sortOrder:rid,rpid

 

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