itraconazole / PKM2 Cancer Research Results

itraC, itraconazole: Click to Expand ⟱
Features:
Itraconazole is a medication used in the management and treatment of fungal infections.

Itraconazole (ITZ; brand Sporanox) — oral triazole antifungal (drug). Oncology relevance is mainly repurposing research (not an approved anticancer indication).

Primary mechanisms (conceptual rank):
1) ↓ Ergosterol synthesis via fungal CYP51 inhibition (primary approved antifungal MoA)
2) ↓ Hedgehog signaling (SMO pathway inhibition; anticancer repurposing)
3) ↓ Angiogenesis / endothelial signaling (anti-angiogenic effects reported; AKT/mTOR signaling suppression in endothelium models)
4) ↑ Autophagy / cell-cycle arrest (model-dependent anticancer phenotypes)

Bioavailability / PK relevance: Oral bioavailability ~55%; capsules absorb best with a full meal; reduced by low gastric acidity (PPIs/H2 blockers). Strong CYP3A4 inhibitor with major drug–drug interaction burden; boxed warning/avoid in ventricular dysfunction/CHF except for serious infections.

In-vitro vs oral exposure: Many anticancer in-vitro effects occur at concentrations that may exceed (or sit near the upper range of) achievable systemic exposure; clinical relevance is formulation/PK-limited and indication-specific.

Clinical evidence status: Approved antifungal; oncology evidence is preclinical + small human/phase II repurposing signals (no oncology RCT approval).


Cancer pathways:
-inhibit VEGF
-inhibit Hedghog Signaling Pathway
-P-glycoprotein Inhibition
-mTOR Pathway

Itraconazole — Cancer vs Normal Cell Pathway Map

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Hedgehog (SMO → GLI) ↓ (model-dependent) ↔ R/G Reduced HH-driven proliferation Repurposing core: inhibits SMO/HH signaling in HH-dependent tumors (e.g., BCC contexts); not an approved oncology indication.
2 Angiogenesis (endothelial growth signaling) ↓ vascular support ↓ endothelial proliferation (context-dependent) R/G Anti-angiogenic effect Identified in repurposing screens as anti-angiogenic; often framed via endothelial signaling suppression (AKT/mTOR in some models).
3 AKT / mTOR ↓ (model-dependent) ↓ (endothelium; context-dependent) R/G Reduced anabolic/survival signaling Reported in endothelial and some tumor models; often tied to growth inhibition and vascular effects.
4 Autophagy ↑ (model-dependent) ↔ / ↑ (stress-dependent) R/G Stress adaptation / growth arrest Often described as autophagic growth arrest; can be cytostatic or contribute to death depending on context.
5 Cell cycle ↓ proliferation ↔ G Checkpoint arrest Phenotype reported across models; typically requires sustained exposure.
6 Apoptosis (intrinsic; caspases) ↑ (model-dependent) ↔ / ↑ (high exposure) R/G Programmed cell death Usually secondary to pathway inhibition / metabolic stress; varies by tumor type and exposure.
7 ROS ↔ (not primary) ↔ P/R No dominant redox program ROS is not a canonical primary ITZ mechanism versus HH/angiogenesis; include only with model-specific evidence.
8 NRF2 ↔ ↔ R/G No primary modulation No consistent NRF2-first mechanism at therapeutic exposure in the repurposing literature.
9 Ferroptosis ↔ (insufficiently established) ↔ R/G Not a canonical ITZ axis Not a standard mechanistic claim for ITZ; treat as investigational unless a specific study supports it.
10 HIF-1α ↓ (indirect; context-dependent) ↔ G Hypoxia/angiogenesis coupling reduction Primarily indirect via anti-angiogenic effects; tumor hypoxia biology can be complex.
11 Ca²⁺ signaling ↔ ↔ P/R No primary role Not a recognized primary ITZ axis.
12 Clinical Translation Constraint ↓ (constraint) ↓ (constraint) — DDIs + exposure variability Major constraints: CYP3A4 inhibition (drug–drug interactions), absorption dependence on meal/acidity, CHF/ventricular dysfunction warning, and repurposing effects that may require higher exposure or specific tumor dependence (HH).

TSF legend: P: 0–30 min (direct target engagement); R: 30 min–3 hr (acute signaling shifts); G: >3 hr (gene-regulatory/phenotype outcomes)
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⟱
2178- itraC,    Itraconazole inhibits tumor growth via CEBPB-mediated glycolysis in colorectal cancer
- in-vivo, CRC, HCT116
TumCG↓, Glycolysis↓, CEBPB?, ENO1↓, LDHA↓, PKM2↓, GAPDH↓, ECAR↓, OCR↓,

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:


Mitochondria & Bioenergetics ⓘ

OCR↓, 1,  

Core Metabolism/Glycolysis ⓘ

ECAR↓, 1,   ENO1↓, 1,   GAPDH↓, 1,   Glycolysis↓, 1,   LDHA↓, 1,   PKM2↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

CEBPB?, 1,   TumCG↓, 1,  
Total Targets: 9

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#:312  Target#:772  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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