Ivermectin / TumCI Cancer Research Results

IVM, Ivermectin: Click to Expand ⟱
Features:

Ivermectin — a semisynthetic avermectin-derived macrocyclic lactone and prescription antiparasitic drug, commonly abbreviated IVM and marketed orally as Stromectol. It is formally an anthelmintic/antiparasitic agent derived from avermectins originally isolated from Streptomyces avermitilis. Its established therapeutic action is activation/modulation of invertebrate glutamate-gated chloride channels, producing paralysis and death of susceptible parasites. In oncology, ivermectin is an investigational drug-repurposing candidate rather than an approved anticancer therapy. Preclinical cancer models report multiple effects including PAK1/AKT/mTOR suppression, mitochondrial dysfunction and oxidative stress, WNT-TCF inhibition, Hippo/YAP1 suppression, chloride-dependent cytotoxicity, and immunogenic cell-death/immune modulation.

Primary mechanisms (ranked):

  1. PAK1 degradation with downstream AKT/mTOR suppression and induction of cytostatic/autophagic programs, particularly demonstrated in breast-cancer models.
  2. Mitochondrial dysfunction with ↓ mitochondrial membrane potential, ↓ respiration and ↓ ATP, producing secondary ROS accumulation, oxidative damage and intrinsic apoptosis in several cancer models.
  3. WNT/β-catenin-TCF pathway suppression, reducing WNT-dependent transcription, proliferation, cyclin D1 and cancer-cell growth in responsive models.
  4. Hippo/YAP1 signaling suppression, including ↓ YAP1 expression/nuclear accumulation and ↓ downstream CTGF in susceptible tumor models.
  5. ATP/P2X4/P2X7 signaling modulation and immunogenic cancer-cell death, with increased antitumor T-cell activity and reduced immunosuppressive populations in preclinical breast-cancer models; this provides the rationale for current immune-checkpoint-inhibitor combination trials.
  6. Chloride-channel-associated membrane effects, including chloride-dependent hyperpolarization/cytotoxicity demonstrated in leukemia cells.
  7. Importin α/β-mediated nuclear transport inhibition, potentially affecting transcription factors and other cargo; mechanistically established but tumor relevance varies substantially by model.
  8. JAK/STAT, glycolytic and other metabolic suppression in selected tumor models; these are context-dependent rather than universal ivermectin mechanisms.

Bioavailability / PK relevance: Oral ivermectin is highly lipophilic and poorly water-soluble. After a fasting 12-mg oral dose, reported mean peak plasma concentrations are approximately 31–47 ng/mL at about 4 hours, with a plasma half-life of approximately 18 hours. It is primarily metabolized by CYP3A4 and eliminated predominantly in feces. A high-fat meal can increase systemic bioavailability approximately 2.5-fold. P-glycoprotein-mediated efflux is important in limiting CNS exposure; disruption or inhibition of this protective transport mechanism can increase neurotoxicity risk. Drug interactions and altered hepatic metabolism become particularly important when considering nonstandard high or repeated oncology dosing.

In-vitro vs systemic exposure relevance: A major translational limitation is the exposure gap. Standard antiparasitic dosing produces peak circulating concentrations in the tens of ng/mL, corresponding to only roughly 0.04–0.06 µM, whereas many direct anticancer experiments use approximately 2.5–20 µM or higher ivermectin. Thus, common in-vitro anticancer concentrations can exceed conventional human systemic exposure by tens to several hundred-fold. Some tumor-selective or immune-modulatory effects may occur at lower exposures, and oncology trials are testing repeated dosing, but direct extrapolation of micromolar cell-culture cytotoxicity to standard oral dosing is not justified.

Clinical evidence status: Approved antiparasitic; oncology investigational. The anticancer evidence remains predominantly preclinical, with substantial cell-culture, organoid, xenograft and immunologic evidence but very limited human efficacy data. A Phase I/II study of ivermectin plus pembrolizumab or balstilimab in metastatic triple-negative breast cancer is recruiting, and a separate randomized Phase II ICONIC study is planned to evaluate ivermectin with standard immune-checkpoint inhibition in solid tumors. No completed large randomized controlled trial has established ivermectin as an effective cancer treatment, and it has no FDA or Health Canada oncology indication.

Ivermectin Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells Primary Effect Notes / Interpretation
1 PAK1 / AKT / mTOR PAK1 ↓
AKT ↓
mTOR ↓
Autophagic flux ↑		 ↔ / not established Cytostatic autophagy and reduced proliferation Strong mechanistic evidence in breast-cancer models; ivermectin promotes ubiquitination-mediated degradation of PAK1 with subsequent suppression of AKT/mTOR signaling.
2 Mitochondrial bioenergetics Mitochondrial membrane potential ↓
Mitochondrial respiration ↓
ATP ↓		 ↔ / ↓ (high exposure) Bioenergetic failure and apoptosis Demonstrated particularly in renal, colorectal and esophageal cancer models. Preferential effects over corresponding normal cells have been reported in some models but should not be generalized to all tissues.
3 Mitochondrial ROS and oxidative damage ROS ↑ (dose-dependent) ↔ / ↑ (high exposure) Oxidative stress and intrinsic apoptosis ROS is principally a downstream consequence of mitochondrial dysfunction rather than a universal primary molecular target. NAC or mitochondrial metabolic rescue can attenuate ivermectin cytotoxicity in several experimental systems.
4 WNT / β-catenin / TCF WNT-TCF transcription ↓
β-catenin signaling ↓
CCND1 ↓		 ↔ / not established Reduced proliferation and WNT-dependent tumor growth Well-characterized preclinical repurposing mechanism, particularly relevant to tumors dependent on canonical WNT-TCF signaling.
5 Hippo / YAP1 / CTGF YAP1 ↓
YAP1 nuclear localization ↓
CTGF ↓ (model-dependent)		 ↔ / not established Reduced oncogenic transcription and proliferation Demonstrated in gastric and other YAP-dependent cancer models. Sensitivity is heterogeneous, and recent organoid work indicates substantial tumor-to-tumor and time-dependent variation.
6 ATP / P2X4 / P2X7 immune signaling Immunogenic cell death ↑ Antitumor T-cell activity ↑
Immunosuppressive populations ↓ (model-dependent)		 Conversion toward an immunologically active tumor microenvironment Preclinical breast-cancer studies provide the rationale for combining ivermectin with PD-1 pathway inhibition. Human therapeutic benefit remains unproven.
7 Chloride-dependent membrane signaling Intracellular Cl⁻ ↑
Membrane hyperpolarization ↑
Cell death ↑		 Lower effect (model-dependent) Preferential leukemia-cell cytotoxicity One of the earliest experimentally demonstrated anticancer mechanisms. Evidence is strongest in leukemia and should not be assumed to be dominant in solid tumors.
8 JAK / STAT signaling JAK2 ↓
p-STAT3 ↓
p-STAT5 ↓ (model-dependent)		 ↔ / not established Reduced survival and metabolic signaling Demonstrated in selected models including glioma; not established as a universal ivermectin target across cancer types.
9 Glycolytic metabolism GLUT4 ↓
HK2 ↓
PFK1 ↓
Pyruvate ↓
ATP ↓ (model-dependent)		 ↔ / ↓ (high concentration only) Reduced glycolytic capacity and enhanced metabolic stress Strongly demonstrated in particular glioma models through GLUT4/JAK/STAT signaling, but insufficient evidence supports treating glycolysis as a universal primary ivermectin mechanism.
10 Intrinsic apoptosis Bax ↑
Bcl-2 ↓
Caspase activity ↑
PARP cleavage ↑		 ↔ / ↑ (high exposure) Programmed tumor-cell death Common downstream phenotype following mitochondrial dysfunction, ROS accumulation and signaling disruption.
11 Importin α / β nuclear transport Importin-dependent nuclear transport ↓ ↓ (exposure-dependent) Reduced nuclear localization of susceptible cargo Biochemically important ivermectin activity, but it is not cancer-cell-specific and its contribution to antitumor effects varies by substrate and tumor context.
12 HIF hypoxia signaling HIF-1α nuclear localization ↓
HIF transcription ↓ (model-dependent)		 ↓ (context-dependent) Reduced cellular hypoxia-response transcription Likely linked partly to importin α/β inhibition. Relevant in hypoxic models but not sufficiently universal to rank as a core ivermectin anticancer mechanism.
13 Cancer stemness and invasion Stemness ↓
Migration ↓
Invasion ↓ (model-dependent)		 ↔ / not established Reduced aggressive tumor phenotype Reported across several preclinical systems and probably reflects convergence of WNT, YAP, AKT and related pathways rather than a single direct target.
14 NRF2 antioxidant response ↔ / context-dependent ↔ / context-dependent Not established as a core ivermectin mechanism Evidence is insufficient to assign a consistent ivermectin-induced NRF2 direction across cancers. It should not currently be presented as a standard ivermectin pathway.
15 Clinical Translation Constraint Effective experimental exposure often exceeds standard human exposure Neurotoxicity and systemic toxicity risk ↑ with excessive exposure Limits translation of direct in-vitro cytotoxicity Standard oral dosing produces approximately 0.04–0.06 µM peak plasma concentrations, whereas many cancer-cell experiments use several µM. CYP3A4 metabolism, food-dependent exposure, P-glycoprotein-mediated CNS protection, concomitant drugs and repeated high dosing are important clinical constraints. Current oncology studies are investigational and efficacy remains unconfirmed.


TumCI, Tumor Cell invasion: Click to Expand ⟱
Source:
Type:
Tumor cell invasion is a critical process in cancer progression and metastasis, where cancer cells spread from the primary tumor to surrounding tissues and distant organs. This process involves several key steps and mechanisms:

1.Epithelial-Mesenchymal Transition (EMT): Many tumors originate from epithelial cells, which are typically organized in layers. During EMT, these cells lose their epithelial characteristics (such as cell-cell adhesion) and gain mesenchymal traits (such as increased motility). This transition is crucial for invasion.

2.Degradation of Extracellular Matrix (ECM): Tumor cells secrete enzymes, such as matrix metalloproteinases (MMPs), that degrade the ECM, allowing cancer cells to invade surrounding tissues. This degradation facilitates the movement of cancer cells through the tissue.

3.Cell Migration: Once the ECM is degraded, cancer cells can migrate. They often use various mechanisms, including amoeboid movement and mesenchymal migration, to move through the tissue. This migration is influenced by various signaling pathways and the tumor microenvironment.

4.Angiogenesis: As tumors grow, they require a blood supply to provide nutrients and oxygen. Tumor cells can stimulate the formation of new blood vessels (angiogenesis) through the release of growth factors like vascular endothelial growth factor (VEGF). This not only supports tumor growth but also provides a route for cancer cells to enter the bloodstream.

5.Invasion into Blood Vessels (Intravasation): Cancer cells can invade nearby blood vessels, allowing them to enter the circulatory system. This step is crucial for metastasis, as it enables cancer cells to travel to distant sites in the body.

6.Survival in Circulation: Once in the bloodstream, cancer cells must survive the immune response and the shear stress of blood flow. They can form clusters with platelets or other cells to evade detection.

7.Extravasation and Colonization: After traveling through the bloodstream, cancer cells can exit the circulation (extravasation) and invade new tissues. They may then establish secondary tumors (metastases) in distant organs.

8.Tumor Microenvironment: The surrounding microenvironment plays a significant role in tumor invasion. Factors such as immune cells, fibroblasts, and signaling molecules can either promote or inhibit invasion and metastasis.
Scientific Papers found: Click to Expand⟱
8043- IVM,    Ivermectin suppresses tumour growth and metastasis through degradation of PAK1 in oesophageal squamous cell carcinoma
- vitro+vivo, ESCC, KYSE-30 - in-vitro, ESCC, KYSE70 - in-vitro, ESCC, KYSE150
tumCV↓, Apoptosis↑, TumCMig↓, TumCI↓, MMP2↓, MMP9↓, PAK1↓, ChemoSen↑, cl‑PARP↑, Casp3↑, TumMeta↓,

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,   Casp3↑, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

tumCV↓, 1,  

DNA Damage & Repair(tgid=10) ⓘ

cl‑PARP↑, 1,  

Migration(tgid=13) ⓘ

MMP2↓, 1,   MMP9↓, 1,   PAK1↓, 1,   TumCI↓, 1,   TumCMig↓, 1,   TumMeta↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

ChemoSen↑, 1,  
Total Targets: 11

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: TumCI, Tumor Cell invasion
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#:10  Target#:324  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

Home Page