itraconazole / Smo Cancer Research Results

itraC, itraconazole: Click to Expand ⟱
Features:

Itraconazole — a synthetic, highly lipophilic triazole antifungal drug with substantial drug-repurposing interest in oncology. Standard abbreviations include ITZ and ITRA; Sporanox is a major brand name. Its approved pharmacologic function is inhibition of fungal lanosterol 14α-demethylase, disrupting ergosterol synthesis. Its anticancer activity is mechanistically distinct and appears to be multitargeted, involving direct inhibition of NPC1-dependent lysosomal cholesterol export, VDAC1-dependent metabolic signaling, mTOR suppression, inhibition of VEGFR2 maturation/angiogenesis, and inhibition of Hedgehog signaling through SMO. Itraconazole remains an approved antifungal rather than an approved anticancer drug.

Primary mechanisms (ranked):

  1. ↓ NPC1-mediated lysosomal cholesterol export, causing endolysosomal cholesterol accumulation and downstream disruption of growth and angiogenic signaling.
  2. ↓ Hedgehog signaling through inhibition of SMO trafficking/activation and downstream GLI signaling, particularly relevant to Hedgehog-dependent tumors such as basal cell carcinoma.
  3. ↓ Angiogenesis through impaired VEGFR2 glycosylation, trafficking and signaling, with reduced endothelial proliferation.
  4. ↓ mTORC1 signaling through complementary NPC1/cholesterol-trafficking and VDAC1/AMPK mechanisms.
  5. ↓ VDAC1-dependent mitochondrial metabolite transport, producing an increased AMP:ATP ratio, ↑ AMPK and ↓ mTOR signaling in endothelial models.
  6. ↓ P-glycoprotein/BCRP transporter activity and MDR-associated drug efflux, potentially contributing to chemosensitization; this is also a clinically important source of pharmacokinetic drug interactions.
  7. ↓ Glycolysis through the CEBPB–ENO1 axis in colorectal-cancer models, with decreases in glycolytic enzymes, glucose utilization, ECAR and tumor growth; this appears tumor- and model-dependent rather than a universal itraconazole mechanism.
  8. ↑ Autophagy and growth arrest in selected tumor models, frequently downstream of impaired cholesterol trafficking and AKT/mTOR signaling.
  9. ↑ Apoptosis and cell-cycle arrest in responsive tumor models as downstream phenotypes rather than primary direct molecular targets.

Bioavailability / PK relevance: Itraconazole has nonlinear, formulation-dependent pharmacokinetics and very low aqueous solubility. Conventional capsule absolute oral bioavailability is approximately 55%, is maximal immediately after a full meal, and decreases with reduced gastric acidity or acid-suppressive therapy. Capsule and oral-solution formulations are not pharmacokinetically interchangeable; systemic exposure is generally greater with oral solution at the same dose. After repeated capsule dosing, reported steady-state Cmax values are approximately 0.5, 1.1 and 2.0 µg/mL after 100 mg once daily, 200 mg once daily and 200 mg twice daily, respectively. Itraconazole is approximately 99.8% plasma-protein bound, extensively tissue distributed, metabolized predominantly through CYP3A4, and has an active hydroxy-itraconazole metabolite. Strong CYP3A4, P-glycoprotein and BCRP inhibition produces a major drug–drug interaction burden.

In-vitro vs systemic exposure relevance: Several experimentally important anticancer effects occur around the low-micromolar range, which overlaps total plasma concentrations achievable with high-dose clinical regimens, but free circulating itraconazole is far lower because protein binding approaches 99.8%. Tissue accumulation can exceed plasma concentrations, while exposure varies markedly among patients and formulations. Consequently, mechanistic plausibility is relatively strong for NPC1, VDAC1/mTOR and endothelial targets, but translation of individual in-vitro concentration-response findings should not be assumed without pharmacokinetic confirmation.

Clinical evidence status: Approved antifungal; oncology repurposing remains investigational. Human anticancer evidence includes phase II studies in basal cell carcinoma and prostate cancer, window-of-opportunity studies in NSCLC, and small combination studies in several malignancies. A recent randomized double-blind placebo-controlled study in 60 patients with advanced epithelial ovarian cancer reported improved response and progression-free outcomes when itraconazole was added to paclitaxel/carboplatin, but this remains a small single-institution study and does not establish an approved oncology indication. A recent perioperative phase II BCC study also showed a modest reduction in tumor diameter together with decreased CD105-associated angiogenesis. Important translational limitations include substantial interpatient PK variability, CYP3A4-mediated oncology drug interactions, a boxed warning concerning congestive heart failure/negative inotropy, and rare serious hepatotoxicity.



Itraconazole Mechanistic Pathway Map

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 NPC1 and lysosomal cholesterol trafficking ↓ NPC1 activity
↑ lysosomal cholesterol		 ↓ NPC1 activity
↑ lysosomal cholesterol		 R/G Disrupts cholesterol export and growth signaling Direct itraconazole binding to NPC1 is structurally and functionally supported. This mechanism can contribute to ↓ mTOR signaling and altered membrane-associated signaling. It is not intrinsically cancer-selective.
2 Hedgehog SMO GLI signaling ↓ SMO
↓ GLI1
↓ Hedgehog signaling		 ↓ (context-dependent) R/G Reduced Hedgehog-dependent proliferation One of the strongest tumor-directed repurposing mechanisms. Most relevant where Hedgehog signaling is oncogenic, particularly basal cell carcinoma. Clinical pharmacodynamic suppression has been demonstrated.
3 VEGFR2 maturation and angiogenesis ↓ vascular support ↓ VEGFR2 glycosylation
↓ VEGFR2 trafficking
↓ endothelial proliferation		 R/G Anti-angiogenic activity Itraconazole impairs VEGFR2 N-glycosylation and surface trafficking in endothelial cells. This is primarily an effect on tumor-supporting vasculature rather than direct killing of malignant cells.
4 VDAC1 AMPK mTOR axis ↑ AMPK
↓ mTOR (model-dependent)		 ↓ VDAC1 function
↑ AMP:ATP
↑ AMPK
↓ mTOR		 P/R Energetic stress and suppression of anabolic signaling VDAC1 is a direct itraconazole target in endothelial models. AMPK activation can occur within minutes and precedes mTOR inhibition.
5 mTORC1 growth signaling ↓ (model-dependent) ↓ (endothelium) R/G Reduced protein synthesis, proliferation and angiogenic signaling Mechanistically convergent downstream effect of both NPC1-mediated cholesterol sequestration and VDAC1-mediated AMPK activation.
6 P-glycoprotein and multidrug resistance ↓ P-gp activity
↓ drug efflux		 ↓ P-gp activity P/R Chemosensitization and altered drug disposition Itraconazole inhibits P-glycoprotein and can increase intracellular exposure to P-gp substrates. Therapeutically interesting for resistant tumors but clinically hazardous because the same transporter and CYP3A4 inhibition can markedly alter concomitant anticancer-drug exposure.
7 CEBPB ENO1 glycolysis axis ↓ CEBPB
↓ ENO1
↓ glycolysis
↓ ECAR		 Not established G Reduced glycolytic metabolism and tumor growth Demonstrated recently in colorectal-cancer models. ENO1, LDHA, PKM2 and GAPDH-related metabolic changes were reported, but this should currently be treated as tumor-specific rather than a universal itraconazole mechanism.
8 Autophagy and lysosomal stress ↑ autophagy (model-dependent) ↑ (stress-dependent) G Autophagic growth suppression or cell death Frequently follows cholesterol-trafficking and AKT/mTOR disruption. Biological outcome varies by tumor type and can be cytostatic or cytotoxic.
9 Cell cycle and apoptosis ↑ arrest
↑ apoptosis (model-dependent)		 ↔ / ↑ (high exposure) G Reduced proliferation and programmed cell death Downstream phenotype reported in multiple tumor systems rather than a single direct molecular target.
10 Clinical Translation Constraint ↓ usable therapeutic window ↓ tolerability margin G PK variability, DDIs and toxicity constrain oncology use Capsule absorption depends strongly on food and gastric acidity; exposure is formulation-dependent and variable. Itraconazole and hydroxy-itraconazole are potent CYP3A4 inhibitors and itraconazole inhibits P-gp/BCRP. Major concerns include numerous anticancer-drug interactions, negative inotropy/CHF risk and rare serious hepatotoxicity.

TSF legend: P: 0–30 min     R: 30 min–3 hr     G: >3 hr
Smo, G-protein-coupled receptor-like 7-pass transmembrane protein Smoothened: Click to Expand ⟱
Source: CGL-Driver Genes
Type: HH Oncogene
Smoothened homolog (Drosophila)
SMO, or Smoothened, is a protein that plays a crucial role in the Hedgehog signaling pathway, which is important for cell growth, differentiation, and tissue patterning during embryonic development. Inhibitors of SMO, such as vismodegib and sonidegib, have been developed as targeted therapies for cancers associated with aberrant Hedgehog signaling.
SMO (Smoothened):
- A G protein-coupled receptor (GPCR)-like protein that is a critical component of the Hedgehog (Hh) signaling pathway.
- Functions in transmitting the Hedgehog signal from the cell surface to intracellular effectors, culminating in changes in gene expression.
Aberrant Activation of the Hedgehog Pathway:
- In many cancers, mutations or dysregulations in pathway components lead to ligand-independent or ligand-dependent activation of SMO.
- This inappropriate activation can result in enhanced cell proliferation, survival, and stem cell-like
Several cancers exhibit overexpression of SMO or activating mutations leading to Hedgehog pathway activation.
Smoothened (SMO) is a critical mediator of the Hedgehog signaling pathway, with aberrant activation contributing to tumor growth, progression, and resistance to therapy. High expression or activating mutations in SMO are linked with a poor prognosis in certain cancer types, particularly in cancers that are dependent on Hedgehog pathway signaling such as basal cell carcinoma and medulloblastoma. By targeting SMO with specific inhibitors, researchers and clinicians are addressing one of the key drivers of tumorigenesis in these settings.
Scientific Papers found: Click to Expand⟱
8010- itraC,    Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells
- vitro+vivo, GC, MKN45
TumCP↓, ChemoSen↑, TumCCA↑, Apoptosis↑, Gli1↓, TumCG↓, HH↓, Smo∅,

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:


Cell Death(tgid=5) ⓘ

Apoptosis↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

TumCCA↑, 1,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

Gli1↓, 1,   HH↓, 1,   Smo∅, 1,   TumCG↓, 1,  

Migration(tgid=13) ⓘ

TumCP↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

ChemoSen↑, 1,  
Total Targets: 8

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: Smo, G-protein-coupled receptor-like 7-pass transmembrane protein Smoothened
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#:287  State#:%  Dir#:6
  wNotes=0  sortOrder:rid,rpid

 

Home Page