Ivermectin / mitResp 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.


mitResp, mitochondrial respiration: Click to Expand ⟱
Source:
Type:
Mitochondrial respiration plays a crucial role in the development and progression of cancer. Cancer cells often exhibit altered metabolic profiles, including changes in mitochondrial respiration, to support their rapid growth and proliferation.

In cancer cells, mitochondrial respiration is often downregulated, and instead, they rely on glycolysis for energy production, even in the presence of oxygen. This phenomenon is known as the "Warburg effect."

There are several key players involved in the regulation of mitochondrial respiration in cancer cells, including:

Pyruvate dehydrogenase (PDH): a critical enzyme that converts pyruvate into acetyl-CoA, which is then fed into the citric acid cycle.
Citrate synthase: an enzyme that catalyzes the first step of the citric acid cycle.
Succinate dehydrogenase (SDH): an enzyme that participates in both the citric acid cycle and the electron transport chain.
Cytochrome c oxidase (COX): the final enzyme in the electron transport chain, responsible for generating ATP.
Alterations in the expression and activity of these enzymes can impact mitochondrial respiration in cancer cells. For example, increased expression of PDH and citrate synthase can enhance mitochondrial respiration, while decreased expression of SDH and COX can impair it.

Additionally, various transcription factors and signaling pathways regulate mitochondrial respiration in cancer cells, including:

HIF-1α (hypoxia-inducible factor 1 alpha): a transcription factor that promotes glycolysis and suppresses mitochondrial respiration in response to hypoxia.
c-Myc: a transcription factor that regulates the expression of genes involved in mitochondrial respiration and biogenesis.
PI3K/Akt/mTOR: a signaling pathway that promotes cell growth and proliferation, in part by regulating mitochondrial respiration.
Scientific Papers found: Click to Expand⟱
8040- IVM,    Ivermectin, a potential anticancer drug derived from an antiparasitic drug
- Review, Var, NA
Akt↓, mTOR↓, TumAuto↑, TumCP↓, TumCCA↑, Wnt↓, YAP/TEAD↓, MMP↓, mitResp↓, ATP↓, eff↓, eff↑, ROS↑, ChemoSen↑, PAK1↓, MAPK↓, EMT↓, Beclin-1/ATG6↑, ATG5↑, CSCs↓, STAT3↝, P-gp/ABCB1↓, MDR1↓, HSP27↓, Chl↑, TFE3↑,
8046- IVM,    Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress
- in-vitro, CML, NA
TumCD↑, mtDam↑, ROS↓, selectivity↑, compI↓, mitResp↓, eff↓,
1175- IVM,  PDT,    Drug induced mitochondria dysfunction to enhance photodynamic therapy of hypoxic tumors
- in-vitro, Var, NA
Hypoxia↓, mitResp↓, ROS↑,
8022- IVM,    Antibiotic ivermectin preferentially targets renal cancer through inducing mitochondrial dysfunction and oxidative damage
- vitro+vivo, RCC, NA
AntiP↑, TumCP↓, Apoptosis↑, selectivity↑, TumCG↓, MMP↓, mitResp↓, ATP↓, ROS↑, eff↓,
8027- IVM,    Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin
- Review, Var, NA
*AntiP↑, TumCD↑, PAK1↑, TumAuto↑, Casp↑, ICD↑, TCF↝, Hippo↓, Akt↓, mTOR↓, angioG↓, CSCs↓, MMP↓, Cyt‑c↑, Apoptosis↑, BAX↑, P53↑, Bcl-2↓, cycE/CCNE↓, cycD1/CCND1↓, CDK2↓, CDK6↓, CDK4↓, YAP/TEAD↓, TFE3↑, mTORC1↓, mitResp↓, OCR↓, compI↓, MMP↓, ROS↑, SOD2↑, ATP↓, eff↓, mitA↓, P-gp/ABCB1↓, TumVol↓,

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) ⓘ

AntiP↑, 1,   TFE3↑, 2,  

Redox & Oxidative Stress(tgid=1) ⓘ

compI↓, 2,   ICD↑, 1,   ROS↓, 1,   ROS↑, 4,   SOD2↑, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

ATP↓, 3,   mitResp↓, 5,   MMP↓, 4,   mtDam↑, 1,   OCR↓, 1,  

Cell Death(tgid=5) ⓘ

Akt↓, 2,   Apoptosis↑, 2,   BAX↑, 1,   Bcl-2↓, 1,   Casp↑, 1,   Cyt‑c↑, 1,   Hippo↓, 1,   MAPK↓, 1,   TumCD↑, 2,   YAP/TEAD↓, 2,  

Protein Folding & ER Stress(tgid=8) ⓘ

HSP27↓, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

ATG5↑, 1,   Beclin-1/ATG6↑, 1,   TumAuto↑, 2,  

DNA Damage & Repair(tgid=10) ⓘ

P53↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

CDK2↓, 1,   CDK4↓, 1,   cycD1/CCND1↓, 1,   cycE/CCNE↓, 1,   mitA↓, 1,   TumCCA↑, 1,  

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

CSCs↓, 2,   EMT↓, 1,   mTOR↓, 2,   mTORC1↓, 1,   STAT3↝, 1,   TCF↝, 1,   TumCG↓, 1,   Wnt↓, 1,  

Migration(tgid=13) ⓘ

Chl↑, 1,   PAK1↓, 1,   PAK1↑, 1,   TumCP↓, 2,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 1,   Hypoxia↓, 1,  

Barriers & Transport(tgid=15) ⓘ

P-gp/ABCB1↓, 2,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

CDK6↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

ChemoSen↑, 1,   eff↓, 4,   eff↑, 1,   MDR1↓, 1,   selectivity↑, 2,  

Functional Outcomes(tgid=23) ⓘ

TumVol↓, 1,  
Total Targets: 55

Pathway results for Effect on Normal Cells:


NA, unassigned(tgid=0) ⓘ

AntiP↑, 1,  
Total Targets: 1

Scientific Paper Hit Count for: mitResp, mitochondrial respiration
5 Ivermectin
1 Photodynamic Therapy
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#:952  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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