Ivermectin / Hif1a 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):

PAK1 degradation with downstream AKT/mTOR suppression and induction of cytostatic/autophagic programs, particularly demonstrated in breast-cancer models.
Mitochondrial dysfunction with ↓ mitochondrial membrane potential, ↓ respiration and ↓ ATP, producing secondary ROS accumulation, oxidative damage and intrinsic apoptosis in several cancer models.
WNT/β-catenin-TCF pathway suppression, reducing WNT-dependent transcription, proliferation, cyclin D1 and cancer-cell growth in responsive models.
Hippo/YAP1 signaling suppression, including ↓ YAP1 expression/nuclear accumulation and ↓ downstream CTGF in susceptible tumor models.
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.
Chloride-channel-associated membrane effects, including chloride-dependent hyperpolarization/cytotoxicity demonstrated in leukemia cells.
Importin α/β-mediated nuclear transport inhibition, potentially affecting transcription factors and other cargo; mechanistically established but tumor relevance varies substantially by model.
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.

Hif1a, HIF1α/HIF1a: Click to Expand ⟱

Source:

Type:

Hypoxia-Inducible-Factor 1A (HIF1A gene, HIF1α, HIF-1α protein product)
-Dominantly expressed under hypoxia(low oxygen levels) in solid tumor cells
-HIF1A induces the expression of vascular endothelial growth factor (VEGF)
-High HIF-1α expression is associated with Poor prognosis
-Low HIF-1α expression is associated with Better prognosis

-Functionally, HIF-1α is reported to regulate glycolysis, whilst HIF-2α regulates genes associated with lipoprotein metabolism.
-Cancer cells produce HIF in response to hypoxia in order to generate more VEGF that promote angiogenesis

Key mediators of aerobic glycolysis regulated by HIF-1α.
-GLUT-1 → regulation of the flux of glucose into cells.
-HK2 → catalysis of the first step of glucose metabolism.
-PKM2 → regulation of rate-limiting step of glycolysis.
-Phosphorylation of PDH complex by PDK → blockage of OXPHOS and promotion of aerobic glycolysis.
-LDH (LDHA): Rapid ATP production, conversion of pyruvate to lactate;

HIF-1α Inhibitors:
-Curcumin: disruption of signaling pathways that stabilize HIF-1α (ie downregulate).
-Resveratrol: downregulate HIF-1α protein accumulation under hypoxic conditions.
-EGCG: modulation of upstream signaling pathways, leading to decreased HIF-1α activity.
-Emodin: reduce HIF-1α expression. (under hypoxia).
-Apigenin: inhibit HIF-1α accumulation.

Scientific Papers found: Click to Expand⟱

1166-

IVM,

The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

in-vitro,

NA,

importin α/β↓, Hif1a↓,

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:

DNA Damage & Repair(tgid=10) ⓘ

importin α/β↓, 1,

Angiogenesis & Vasculature(tgid=14) ⓘ

Hif1a↓, 1,
Total Targets: 2

Pathway results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: Hif1a, HIF1α/HIF1a

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