itraconazole / P-gp/ABCB1 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
P-gp/ABCB1, permeability-glycoprotein: Click to Expand ⟱
Source:
Type:
P-glycoprotein (P-gp), also known as multidrug resistance protein 1 (MDR1), is a membrane protein that plays a crucial role in the transport of various substances across cellular membranes. It is part of the ATP-binding cassette (ABC) transporter family.
P-glycoprotein is often overexpressed in a variety of cancers, including breast cancer, lung cancer, leukemia, and ovarian cancer.

- The overexpression of P-glycoprotein (P-gp), is widely considered as an important reason for the MDR (multidrug resistance).

ABCB1 - ATP-Binding Cassette Subfamily B Member 1 / P-Glycoprotein

Abbreviation: ABCB1, P-gp, P-glycoprotein, MDR1

Type: ATP-dependent membrane efflux transporter / multidrug resistance protein

Function: ABCB1 encodes P-glycoprotein, an ATP-binding cassette transporter that exports a broad range of drugs, xenobiotics, lipids, and other substrates across cellular membranes. It is highly expressed in barrier tissues including the intestine, liver, kidney, placenta, and blood-brain barrier, where it limits tissue accumulation of potentially harmful compounds.

Cancer: ↑ Frequently overexpressed or functionally activated in drug-resistant tumors. Increased ABCB1 lowers intracellular concentrations of many anticancer agents by actively transporting them out of cancer cells, producing multidrug resistance and reducing chemotherapy effectiveness.

Alzheimer's Disease: ↓ Reduced ABCB1/P-glycoprotein expression or transport activity at the blood-brain barrier is associated with impaired amyloid-β clearance from the brain. Lower P-gp function correlates with increased cerebral Aβ accumulation and may contribute to Alzheimer's disease progression.
Scientific Papers found: Click to Expand⟱
8001- itraC,    Repurposing itraconazole as an anticancer agent
- Review, Var, NA
*AntiFungal↑, AntiCan↑, P-gp/ABCB1↓, HH↓, mTOR↓, Wnt↓, β-catenin/ZEB1↓, angioG↓, LymphAG↓, ChemoSen↑, OS↑, Gli1↓, Ki-67↓, CSCs↓,
8016- itraC,    Impact of combination chemotherapy with itraconazole on survival for patients with recurrent or persistent ovarian clear cell carcinoma
- Human, Ovarian, NA
P-gp/ABCB1↓, angioG↓, HH↓, OS↑, Dose↝,
2179- itraC,    Repurposing itraconazole for the treatment of cancer
- Review, Var, NA
HH↓, angioG↓, TumCCA↑, MDR1↓, P-gp/ABCB1↓, mTOR↓, VEGF↓, Smo↓, Gli1↓, OS↑, PSA↓,
7990- itraC,    A Novel Approach to Reducing Chemoresistance in Advanced Ovarian Cancer: The Effect of Itraconazole-A Single-Institution Randomized Placebo-Controlled Trial
- Trial, Ovarian, NA
Dose↝, DCR↑, PFS↑, CA125↓, P-gp/ABCB1↓, VEGFR2/KDR/Flk1↑, toxicity↓, QoL↑, toxicity↝,
7992- itraC,    Cellular pharmacokinetic aspects of reversal effect of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs
P-gp/ABCB1↓, BioEnh↑,

Showing Research Papers: 1 to 5 of 5

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 5

Pathway results for Effect on Cancer / Diseased Cells:


NA, unassigned(tgid=0) ⓘ

DCR↑, 1,   PFS↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

TumCCA↑, 1,  

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

CSCs↓, 1,   Gli1↓, 2,   HH↓, 3,   mTOR↓, 2,   Smo↓, 1,   Wnt↓, 1,  

Migration(tgid=13) ⓘ

Ki-67↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 3,   LymphAG↓, 1,   VEGF↓, 1,   VEGFR2/KDR/Flk1↑, 1,  

Barriers & Transport(tgid=15) ⓘ

P-gp/ABCB1↓, 5,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

PSA↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioEnh↑, 1,   ChemoSen↑, 1,   Dose↝, 2,   MDR1↓, 1,  

Clinical Biomarkers(tgid=22) ⓘ

CA125↓, 1,   Ki-67↓, 1,   PSA↓, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiCan↑, 1,   OS↑, 3,   QoL↑, 1,   toxicity↓, 1,   toxicity↝, 1,  
Total Targets: 29

Pathway results for Effect on Normal Cells:


Infection & Microbiome(tgid=24) ⓘ

AntiFungal↑, 1,  
Total Targets: 1

Scientific Paper Hit Count for: P-gp/ABCB1, permeability-glycoprotein
5 itraconazole
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#:232  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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