flavonoids / PKM2 Cancer Research Results

Flav, flavonoids: Click to Expand ⟱
Features:

Flavonoids — a large class of plant polyphenols (natural products) including flavonols (quercetin, kaempferol), flavones (apigenin, luteolin), flavanones (naringenin), isoflavones (genistein), flavan-3-ols (EGCG/catechins), and anthocyanins. Sources: fruits/berries, tea/cocoa, legumes, herbs, and standardized extracts.

Primary mechanisms (conceptual rank):
1) Redox signaling modulation (often hormetic: low-dose NRF2 ↑; high-dose ROS ↑ in cancer)
2) Anti-inflammatory transcription suppression (NF-κB ↓; cytokines ↓)
3) Kinase signaling modulation (PI3K/AKT/mTOR ↓; MAPK context-dependent)
4) Mitochondrial stress → apoptosis (cancer; often high concentration only)
5) Iron/copper chelation + lipid-peroxidation effects (ferroptosis overlap in select contexts)

Bioavailability / PK relevance: Many flavonoids have low oral bioavailability (rapid phase II conjugation: glucuronidation/sulfation; microbiome-derived metabolites). Plasma free aglycone levels are typically low; tissue effects often reflect metabolites and chronic exposure.

In-vitro vs oral exposure: Many “anti-cancer” cytotoxic effects occur at micromolar aglycone concentrations exceeding typical systemic exposure from diet/supplements (high concentration only), unless specialized formulations or local GI exposure is the intent.

Clinical evidence status: Broad epidemiology + small human trials for cardiometabolic/inflammatory endpoints; oncology evidence mostly preclinical/adjunct-hypothesis; no class-wide RCT oncology approval.


Flavonoids are classified into seven structural classes:
1.flavanones
-Nargenin, Naringin, Hesperetin, Isosakuranetin, Eriodictyol, Taxifolin
2.flavonols
-Quercetin, Myrcetin, Fisetin, Rutin Morin, Kaempferol
3.chalcones
-Butein, Xanthohumol, Isoliquintigenin, Cardamonin, Bavachalone, Xanthohumol, Phloretin
4.flavanols
-Catechin, Gallocatechin, Epicatechin, Epigallocatechin-3-galate
5.anthocyanidins
-Cyanidin
6.flavones
-Chrysin, Apigenin, Luteolin, Vitexin, Orientin, Bacalein, Wogonin, Oroxylin A, Saponarin
7.isoflavonoids
-Daidzein, Genistein, Glycitein

Flavonoids — Cancer vs Normal Cell Pathway Map (Class-Level)

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 ROS ↑ or ↓ (dose-dependent) ↓ (physiologic / adaptive) P/R Redox reprogramming Class hallmark: hormesis. Low–moderate exposure often antioxidant/mitochondrial-protective; high exposure can be pro-oxidant/cytotoxic in cancer models.
2 NRF2 (stress-defense; resistance role) ↑ (context-dependent) ↑ R/G Antioxidant gene induction Normal: cytoprotection. Cancer: NRF2 ↑ can reduce therapy sensitivity in some contexts (double-edged).
3 NF-κB / inflammatory cytokine programs ↓ ↓ R/G Anti-inflammatory transcription suppression One of the most consistent class-level effects across models.
4 PI3K/AKT/mTOR ↓ (model-dependent) ↔ / ↓ (metabolic/inflammatory improvement) R/G Reduced anabolic survival signaling Frequently reported but not uniform; often secondary to redox/inflammation changes.
5 MAPK (ERK/JNK/p38) ↑ stress MAPKs; ↓ ERK (context-dependent) ↔ P/R Stress-response tuning JNK/p38 often ↑ with pro-apoptotic stress; ERK effects vary by compound/model.
6 Intrinsic apoptosis (mitochondrial; caspases) ↑ (high concentration only) ↔ R/G Experimental tumor cytotoxicity Common in vitro endpoint; translation limited by PK and achievable free aglycone levels.
7 Cell-cycle checkpoints ↓ proliferation (model-dependent) ↔ G Checkpoint enforcement Often downstream of kinase/redox modulation.
8 Ferroptosis (iron/lipid peroxidation contexts) ↑ or ↓ (compound-dependent) ↔ R/G Lipid-ROS vulnerability shift Some flavonoids chelate iron (anti-ferroptotic) while others promote lipid peroxidation under stress (pro-ferroptotic); not class-uniform.
9 HIF-1α / Warburg coupling ↓ (model-dependent; high concentration only) ↔ G Reduced hypoxia-adaptation signaling Reported in some models (often via PI3K/mTOR or ROS), but not a universal class mechanism at dietary exposure.
10 Ca²⁺ / ER stress coupling ↑ or ↔ (stress-dependent) ↔ P/R UPR/excitability modulation Relevant mainly when apoptosis/UPR/excitotoxicity endpoints are measured; not a core class axis.
11 Clinical Translation Constraint ↓ (constraint) ↓ (constraint) — PK + heterogeneity Major constraints: low bioavailability, metabolite-dominant exposure, large heterogeneity across subclasses, and frequent in-vitro concentration gaps.

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



Flavonoids — AD relevance: Flavonoid-rich diets and select supplements are studied for neuroprotection via antioxidant/anti-inflammatory effects, cerebrovascular support, and synaptic plasticity signaling. Effects are generally supportive and exposure/metabolite dependent.

Primary mechanisms (conceptual rank):
1) ↓ Oxidative stress (ROS ↓; lipid peroxidation ↓)
2) ↓ Neuroinflammation (NF-κB/cytokines ↓; microglial tone ↓)
3) ↑ Synaptic plasticity signaling (BDNF/CREB ↑; network efficiency; chronic adaptation)
4) Vascular/endothelial support (NO signaling; perfusion coupling)
5) Secondary Aβ/tau pathway modulation (preclinical; not class-uniform)

Bioavailability / PK relevance: Brain effects likely mediated by metabolites and chronic intake; large variability by subclass and microbiome.

Clinical evidence status: Signals in small human trials (often with specific subclasses like cocoa flavanols/anthocyanins); AD disease-modification not established.

Flavonoids — AD / Neurodegeneration Pathway Map (Class-Level)

Rank Pathway / Axis Cells TSF Primary Effect Notes / Interpretation
1 ROS / lipid peroxidation ↓ P/R Reduced oxidative burden Core neuroprotection rationale; effect depends on subclass/metabolites and baseline oxidative stress.
2 Neuroinflammation (NF-κB, cytokines) ↓ R/G Lower inflammatory stress Common class-level effect; relevant to microglial activation tone.
3 NRF2 axis ↑ (adaptive; context-dependent) R/G Stress-defense upshift Often supports antioxidant enzymes; magnitude varies widely by compound and exposure.
4 BDNF / CREB / synaptic plasticity ↑ (supportive) G Plasticity and learning support Frequently invoked across flavonoid cognition studies; typically requires weeks–months intake.
5 Vascular/endothelial function (NO coupling) ↑ (supportive) R/G Perfusion and neurovascular support Often attributed to flavanols/anthocyanins; supports “vascular cognitive impairment” framing.
6 Aβ / tau-associated pathology ↔ / ↓ (preclinical; compound-dependent) G Pathology modulation (hypothesis) Not class-uniform; strongest evidence is preclinical, with limited biomarker-confirmed human replication.
7 Ca²⁺ homeostasis / excitotoxic vulnerability ↔ / stabilized (indirect) P/R Excitotoxic buffering Secondary to antioxidant/mitochondrial support; include as primary only with explicit Ca²⁺ endpoints.
8 Clinical Translation Constraint ↓ (constraint) — Heterogeneity + metabolite dependence Large differences across subclasses, dosing, and microbiome; effects generally supportive, not disease-modifying.

TSF legend: P: 0–30 min; R: 30 min–3 hr; G: >3 hr
PKM2, Pyruvate Kinase, Muscle 2: Click to Expand ⟱
Source:
Type: enzyme
PKM2 (Pyruvate Kinase, Muscle 2) is an enzyme that plays a crucial role in glycolysis, the process by which cells convert glucose into energy. PKM2 is a key regulatory enzyme in the glycolytic pathway, and it is primarily expressed in various tissues, including muscle, brain, and cancer cells.
-C-myc is a common oncogene that enhances aerobic glycolysis in the cancer cells by transcriptionally activating GLUT1, HK2, PKM2 and LDH-A
-PKM2 has been shown to be overexpressed in many types of tumors, including breast, lung, and colon cancer. This overexpression may contribute to the development and progression of cancer by promoting glycolysis and energy production in cancer cells.
-inhibition of PKM2 may cause ATP depletion and inhibiting glycolysis.
-PK exists in four isoforms: PKM1, PKM2, PKR, and PKL
-PKM2 plays a role in the regulation of glucose metabolism in diabetes.
-PKM2 is involved in the regulation of cell proliferation, apoptosis, and autophagy.
– Pyruvate kinase catalyzes the final, rate-limiting step of glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate with the production of ATP.
– The PKM2 isoform is uniquely regulated and can exist in both highly active tetrameric and less active dimeric forms.
– Cancer cells often favor the dimeric form of PKM2 to slow pyruvate production, thereby accumulating upstream glycolytic intermediates that can be diverted into anabolic pathways to support cell growth and proliferation.
– Under low oxygen conditions, cancer cells rely on altered metabolic pathways in which PKM2 is a key player. – The shift to aerobic glycolysis (Warburg effect) orchestrated in part by PKM2 helps tumor cells survive and grow in hypoxic conditions.

– Elevated expression of PKM2 is frequently observed in many cancer types, including lung, breast, colorectal, and pancreatic cancers.
– High levels of PKM2 are often correlated with enhanced tumor aggressiveness, poor differentiation, and advanced clinical stage.

PKM2 in carcinogenesis and oncotherapy

Inhibitors of PKM2:
-Shikonin, Resveratrol, Baicalein, EGCG, Apigenin, Curcumin, Ursolic Acid, Citrate (best known as an allosteric inhibitor of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme in glycolysis) potential to directly inhibit or modulate PKM2 is less well established

Full List of PKM2 inhibitors from Database
-key connected observations: Glycolysis↓, lactateProd↓, ROS↑ in cancer cell, while some result for opposite effect on normal cells.
Tumor pyruvate kinase M2 modulators

Flavonoids effect on PKM2
Compounds name IC50/AC50uM Effect
Flavonols
1. Fisetin 0.90uM Inhibition
2. Rutin 7.80uM Inhibition
3. Galangin 8.27uM Inhibition
4. Quercetin 9.24uM Inhibition
5. Kaempferol 9.88uM Inhibition
6. Morin hydrate 37.20uM Inhibition
7. Myricetin 0.51uM Activation
8. Quercetin 3-b- D-glucoside 1.34uM Activation
9. Quercetin 3-D -galactoside 27-107uM Ineffective
Flavanons
10. Neoeriocitrin 0.65uM Inhibition
11. Neohesperidin 14.20uM Inhibition
12. Naringin 16.60uM Inhibition
13. Hesperidin 17.30uM Inhibition
14. Hesperitin 29.10uM Inhibition
15. Naringenin 70.80uM Activation
Flavanonols
16. (-)-Catechin gallateuM 0.85 Inhibition
17. (±)-Taxifolin 1.16uM Inhibition
18. (-)-Epicatechin 1.33uM Inhibition
19. (+)-Gallocatechin 4-16uM Ineffective
Phenolic acids
20. Ferulic 11.4uM Inhibition
21. Syringic and 13.8uM Inhibition
22. Caffeic acid 36.3uM Inhibition
23. 3,4-Dihydroxybenzoic acid 78.7uM Inhibition
24. Gallic acid 332.6uM Inhibition
25. Shikimic acid 990uM Inhibition
26. p-Coumaric acid 22.2uM Activation
27. Sinapinic acids 26.2uM Activation
28. Vanillic 607.9uM Activation


Scientific Papers found: Click to Expand⟱
2313- Flav,    Flavonoids against the Warburg phenotype—concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism
- Review, Var, NA
Warburg↓, antiOx↑, angioG↓, Glycolysis↓, PKM2↓, PKM2:PKM1↓, β-catenin/ZEB1↓, cMyc↓, HK2↓, Akt↓, mTOR↓, GLUT1↓, Hif1a↓,
2401- Flav,    In vitro effects of some flavonoids and phenolic acids on human pyruvate kinase isoenzyme M2
- in-vitro, Nor, NA
PKM2↓,

Showing Research Papers: 1 to 2 of 2

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 1,   Glycolysis↓, 1,   HK2↓, 1,   PKM2↓, 2,   PKM2:PKM1↓, 1,   Warburg↓, 1,  

Cell Death ⓘ

Akt↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

mTOR↓, 1,  

Migration ⓘ

β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   Hif1a↓, 1,  

Barriers & Transport ⓘ

GLUT1↓, 1,  
Total Targets: 13

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: PKM2, Pyruvate Kinase, Muscle 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#:227  Target#:772  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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