iodine / ROS Cancer Research Results

iod, iodine: Click to Expand ⟱
Features:
Iodine deficiency can lead to thyroid enlargement (goiter) and hypothyroidism. In severe cases, longstanding iodine deficiency has been linked to an increased risk of developing certain thyroid disorders, including thyroid nodules and, less frequently, thyroid cancer.

-Preliminary clinical research have suggested that molecular iodine may have antioxidant properties, modulate cell differentiation, and even exert antiproliferative effects in certain tissues.
-"antineoplasic effect of I(2) in mammary cancer involves the intracellular formation of 6-IL. Mammary cancer cells are known to contain high concentrations of AA, which might explain why I(2) exerts apoptotic effects at lower concentrations only in tumoral cells."ref

Iodine — an essential halogen trace element required for thyroid-hormone synthesis and present biologically mainly as iodide (I−). For cancer-related research, the chemically distinct form with the strongest non-radioactive experimental evidence is molecular iodine (I2), whereas iodide and radioactive iodine (especially 131I) have substantially different pharmacology and therapeutic roles. Iodine is formally classified as an essential micronutrient/trace element; standard abbreviations include I, I− for iodide, I2 for molecular iodine, and 131I for radioactive iodine. Dietary iodine originates principally from iodized salt, seafood, dairy products, seaweed, and supplements. Molecular I2 has demonstrated antiproliferative and adjuvant effects particularly in mammary/breast cancer models, but this should not be generalized to ordinary dietary iodide.

Primary mechanisms (ranked):

  1. Formation of antineoplastic iodolipids, particularly 6-iodolactone from arachidonic acid, with subsequent PPARγ activation and differentiation/apoptotic signaling.
  2. Induction of mitochondrial apoptosis through mitochondrial membrane depolarization, Bax activation, Bcl-2 suppression, thiol depletion, and apoptosis-inducing factor signaling.
  3. Antiproliferative and cell-cycle effects, with preferential effects reported in mammary cancer cells relative to normal mammary cells at moderate I2 concentrations.
  4. Chemosensitization, including suppression of Bcl-2/MDR-related chemoresistance phenotypes and increased responsiveness to anthracycline-containing chemotherapy.
  5. Suppression of angiogenic and invasive signaling, including reductions in VEGF, vascular density, uPA, EMT-associated phenotypes, and invasive capacity in breast-cancer models.
  6. Modulation of the tumor immune microenvironment, including increased Th1-associated signaling, IFNγ/T-BET expression and immune-cell infiltration with suppression of TGF-β signaling in human breast tumors.
  7. Redox modulation: molecular iodine can perturb tumor-cell thiol/redox homeostasis and mitochondrial signaling while also showing antioxidant effects in some normal tissues and in-vivo models; the direction is strongly context-dependent.

Bioavailability / PK relevance: Dietary iodide is efficiently absorbed and distributed extracellularly, with substantial thyroid uptake through the sodium/iodide symporter and predominant renal elimination. Molecular I2 behaves differently from iodide in mammary tissue: experimental breast-cancer cells can take up I2 through a mechanism largely independent of NIS and incorporate iodine into lipids and proteins. The human breast-cancer studies used approximately 5 mg/day molecular I2, substantially above ordinary nutritional requirements and above the 1.1 mg/day adult tolerable upper intake level established for routine dietary exposure. Therefore anticancer-dose I2 should not be equated with nutritional iodine supplementation.

In-vitro vs systemic exposure relevance: Many mechanistic breast-cancer experiments use approximately 10–200 µM molecular I2, including 200 µM in chemoresistance experiments. Direct equivalence between these culture concentrations and plasma iodine concentrations after oral dosing is not established because I2 is chemically reactive, undergoes reduction and organification, and can generate tissue-localized iodolipids. Consequently, high-concentration in-vitro observations should not be assumed to represent achievable systemic free-I2 exposure. Human evidence instead comes from oral dosing of 5 mg/day I2 and tumor-tissue endpoints.

Clinical evidence status: Small human randomized/Phase II breast-cancer evidence plus substantial preclinical evidence. A randomized pilot study using 5 mg/day molecular I2 alone or with FEC/TE chemotherapy reported increased tumor responses, apoptosis and immune infiltration and reduced chemoresistance/toxicity signals, but the study was small and requires independent confirmation. ClinicalTrials.gov NCT03688958 remains listed with unknown status and has not been updated since 2018. Molecular iodine is not an established standard anticancer therapy. Separately, radioactive 131I is an established, regulated treatment for iodine-avid differentiated thyroid carcinoma; this is a fundamentally different therapeutic modality and should not be interpreted as evidence for non-radioactive iodine supplementation.

Iodine Cancer-Relevant Mechanisms

Rank Pathway / Axis Cancer Cells Normal Cells Primary Effect Notes / Interpretation
1 Iodolipid formation / 6-iodolactone / PPARγ ↑ 6-iodolactone; ↑ PPARγ; ↓ PPARα Lower 6-iodolactone formation reported in normal mammary tissue Antiproliferation, differentiation and apoptosis Central proposed mechanism for molecular I2 in mammary cancer. Tumor enrichment in arachidonic acid may favor local formation of 6-iodolactone.
2 Mitochondrial apoptosis / Bax / Bcl-2 / AIF ↑ Bax; ↓ Bcl-2; ↓ mitochondrial membrane potential; ↑ AIF nuclear translocation; ↑ apoptosis Less apoptosis at moderate concentrations; apoptosis can occur at higher concentrations Selective mitochondrial cell death Molecular iodine can initiate caspase-dependent or caspase-independent apoptosis depending on model and experimental conditions.
3 Proliferation / cell cycle ↓ proliferation; ↑ cell-cycle arrest; ↑ apoptosis ↑ G1 and G2/M arrest at moderate I2 exposure; apoptosis primarily at higher exposure Growth suppression Preferential tumor-cell cytotoxicity has been demonstrated in mammary models, but selectivity is concentration-dependent.
4 Chemosensitization / drug resistance ↓ Bcl-2; ↓ MDR-associated phenotype; ↑ doxorubicin retention; ↑ chemotherapy response Potential ↓ chemotherapy-associated tissue injury (model-dependent) Reduced chemoresistance Supported by breast-cancer cell, rodent, canine and small human studies; strongest evidence concerns anthracycline-containing regimens.
5 Angiogenesis / VEGF / uPA ↓ VEGF; ↓ vascular density; ↓ uPA Not established Antiangiogenic activity Demonstrated primarily in experimental mammary tumors.
6 EMT / invasion ↓ invasive phenotype; ↓ chemoresistant stem-like populations; ↓ EMT-associated phenotype Not established Reduced invasion and progression Observed particularly in doxorubicin-resistant breast-cancer models and human tumor analyses.
7 Tumor immune response / Th1 / IFNγ / TGF-β ↑ T-BET; ↑ IFNγ; ↑ Th1/Th17-associated signaling; ↑ B-cell infiltration; ↓ TGF-β Not established Shift toward antitumor immune activity Human tumor transcriptomic findings from the molecular-I2 breast-cancer study; clinical significance remains incompletely established.
8 Redox / cellular thiols / ROS ↓ cellular thiols; altered ROS signaling; ↑ mitochondrial stress (context-dependent) Antioxidant effects reported in several tissues; oxidative toxicity possible at high exposure Redox-dependent apoptosis and tissue protection Iodine should not be classified simply as either a ROS inducer or antioxidant. Redox direction depends on chemical form, dose, tissue and baseline oxidative state.
9 I2 uptake / NIS independence ↑ I2 uptake and incorporation into lipids/proteins; largely NIS-independent in mammary cells Lower uptake/retention in some normal-cell models Enables tissue-localized iodine signaling Distinct from iodide uptake through NIS and important when interpreting molecular-I2 studies.
10 Clinical Translation Constraint Human signal demonstrated primarily in breast cancer Excess iodine can cause thyroid dysfunction Limits generalization and unsupervised high-dose use Human I2 studies used 5 mg/day, above the routine adult dietary upper intake level. Susceptible individuals may develop iodine-induced hypothyroidism or hyperthyroidism. Evidence outside breast cancer is predominantly preclinical, and recent prostate models show potentially mixed anti- and pro-neoplastic effects.


ROS, Reactive Oxygen Species: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen and can lead to oxidative stress in cells. They play a dual role in cancer biology, acting as both promoters and suppressors of cancer.
ROS can cause oxidative damage to DNA, leading to mutations that may contribute to cancer initiation and progression. So normally you want to inhibit ROS to prevent cell mutations.
However excessive ROS can induce apoptosis (programmed cell death) in cancer cells, potentially limiting tumor growth. Chemotherapy typically raises ROS.
-mitochondria is the main source of reactive oxygen species (ROS) (and the ETC is heavily related)
ROS Homeostasis in Cancer Cells and Its Potential as a Therapeutic Target

"Reactive oxygen species (ROS) are two electron reduction products of oxygen, including superoxide anion, hydrogen peroxide, hydroxyl radical, lipid peroxides, protein peroxides and peroxides formed in nucleic acids 1. They are maintained in a dynamic balance by a series of reduction-oxidation (redox) reactions in biological systems and act as signaling molecules to drive cellular regulatory pathways."
"During different stages of cancer formation, abnormal ROS levels play paradoxical roles in cell growth and death 8. A physiological concentration of ROS that maintained in equilibrium is necessary for normal cell survival. Ectopic ROS accumulation promotes cell proliferation and consequently induces malignant transformation of normal cells by initiating pathological conversion of physiological signaling networks. Excessive ROS levels lead to cell death by damaging cellular components, including proteins, lipid bilayers, and chromosomes. Therefore, both scavenging abnormally elevated ROS to prevent early neoplasia and facilitating ROS production to specifically kill cancer cells are promising anticancer therapeutic strategies, in spite of their contradictoriness and complexity."
"ROS are the collection of derivatives of molecular oxygen that occur in biology, which can be categorized into two types, free radicals and non-radical species. The non-radical species are hydrogen peroxide (H 2O 2 ), organic hydroperoxides (ROOH), singlet molecular oxygen ( 1 O 2 ), electronically excited carbonyl, ozone (O3 ), hypochlorous acid (HOCl, and hypobromous acid HOBr). Free radical species are super-oxide anion radical (O 2•−), hydroxyl radical (•OH), peroxyl radical (ROO•) and alkoxyl radical (RO•) [130]. Any imbalance of ROS can lead to adverse effects. H2 O 2 and O 2 •− are the main redox signalling agents. The cellular concentration of H2 O 2 is about 10−8 M, which is almost a thousand times more than that of O2 •−".
"Radicals are molecules with an odd number of electrons in the outer shell [393,394]. A pair of radicals can be formed by breaking a chemical bond or electron transfer between two molecules."

Recent investigations have documented that polyphenols with good antioxidant activity may exhibit pro-oxidant activity in the presence of copper ions, which can induce apoptosis in various cancer cell lines but not in normal cells. "We have shown that such cell growth inhibition by polyphenols in cancer cells is reversed by copper-specific sequestering agent neocuproine to a significant extent whereas iron and zinc chelators are relatively ineffective, thus confirming the role of endogenous copper in the cytotoxic action of polyphenols against cancer cells. Therefore, this mechanism of mobilization of endogenous copper." > Ions could be one of the important mechanisms for the cytotoxic action of plant polyphenols against cancer cells and is possibly a common mechanism for all plant polyphenols. In fact, similar results obtained with four different polyphenolic compounds in this study, namely apigenin, luteolin, EGCG, and resveratrol, strengthen this idea.
Interestingly, the normal breast epithelial MCF10A cells have earlier been shown to possess no detectable copper as opposed to breast cancer cells [24], which may explain their resistance to polyphenols apigenin- and luteolin-induced growth inhibition as observed here (Fig. 1). We have earlier proposed [25] that this preferential cytotoxicity of plant polyphenols toward cancer cells is explained by the observation made several years earlier, which showed that copper levels in cancer cells are significantly elevated in various malignancies. Thus, because of higher intracellular copper levels in cancer cells, it may be predicted that the cytotoxic concentrations of polyphenols required would be lower in these cells as compared to normal cells."

Majority of ROS are produced as a by-product of oxidative phosphorylation, high levels of ROS are detected in almost all cancers.
-It is well established that during ER stress, cytosolic calcium released from the ER is taken up by the mitochondrion to stimulate ROS overgeneration and the release of cytochrome c, both of which lead to apoptosis.

Note: Products that may raise ROS can be found using this database, by:
Filtering on the target of ROS, and selecting the Effect Direction of ↑

Targets to raise ROS (to kill cancer cells):
• NADPH oxidases (NOX): NOX enzymes are involved in the production of ROS.
    -Targeting NOX enzymes can increase ROS levels and induce cancer cell death.
    -eNOX2 inhibition leads to a high NADH/NAD⁺ ratio which can lead to increased ROS
• Mitochondrial complex I: Inhibiting can increase ROS production
• P53: Activating p53 can increase ROS levels(by inducing the expression of pro-oxidant genes)
• Nrf2 inhibition: regulates the expression of antioxidant genes. Inhibiting Nrf2 can increase ROS levels
• Glutathione (GSH): an antioxidant. Depleting GSH can increase ROS levels
• Catalase: Catalase converts H2O2 into H2O+O. Inhibiting catalase can increase ROS levels
• SOD1: converts superoxide into hydrogen peroxide. Inhibiting SOD1 can increase ROS levels
• PI3K/AKT pathway: regulates cell survival and metabolism. Inhibiting can increase ROS levels
• HIF-1α inhibition: regulates genes involved in metabolism and angiogenesis. Inhibiting HIF-1α can increase ROS
• Glycolysis: Inhibiting glycolysis can increase ROS levels • Fatty acid oxidation: Cancer cells often rely on fatty acid oxidation for energy production.
-Inhibiting fatty acid oxidation can increase ROS levels
• ER stress: Endoplasmic reticulum (ER) stress can increase ROS levels
• Autophagy: process by which cells recycle damaged organelles and proteins.
-Inhibiting autophagy can increase ROS levels and induce cancer cell death.
• KEAP1/Nrf2 pathway: regulates the expression of antioxidant genes.
    -Inhibiting KEAP1 or activating Nrf2 can increase ROS levels and induce cancer cell death.
• DJ-1: regulates the expression of antioxidant genes. Inhibiting DJ-1 can increase ROS levels
• PARK2: regulates the expression of antioxidant genes. Inhibiting PARK2 can increase ROS levels
• SIRT1 inhibition:regulates the expression of antioxidant genes. Inhibiting SIRT1 can increase ROS levels
• AMPK activation: regulates energy metabolism and can increase ROS levels when activated.
• mTOR inhibition: regulates cell growth and metabolism. Inhibiting mTOR can increase ROS levels
• HSP90 inhibition: regulates protein folding and can increase ROS levels when inhibited.
• Proteasome: degrades damaged proteins. Inhibiting the proteasome can increase ROS levels
• Lipid peroxidation: a process by which lipids are oxidized, leading to the production of ROS.
    -Increasing lipid peroxidation can increase ROS levels
• Ferroptosis: form of cell death that is regulated by iron and lipid peroxidation.
    -Increasing ferroptosis can increase ROS levels
• Mitochondrial permeability transition pore (mPTP): regulates mitochondrial permeability.
    -Opening the mPTP can increase ROS levels
• BCL-2 family proteins: regulate apoptosis and can increase ROS levels when inhibited.
• Caspase-independent cell death: a form of cell death that is regulated by ROS.
    -Increasing caspase-independent cell death can increase ROS levels
• DNA damage response: regulates the repair of DNA damage. Increasing DNA damage can increase ROS
• Epigenetic regulation: process by which gene expression is regulated.
    -Increasing epigenetic regulation can increase ROS levels

-PKM2, but not PKM1, can be inhibited by direct oxidation of cysteine 358 as an adaptive response to increased intracellular reactive oxygen species (ROS)

ProOxidant Strategy:(inhibit the Mevalonate Pathway (likely will also inhibit GPx)
-HydroxyCitrate (HCA) found as supplement online and typically used in a dose of about 1.5g/day or more
-Atorvastatin typically 40-80mg/day, -Dipyridamole typically 200mg 2x/day Combined effect research
-Lycopene typically 100mg/day range (note debatable as it mainly lowers NRF2)

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy 
ROS-Inducing Interventions in Cancer — Canonical + Mechanistic Reference
-generated from AI and Cancer database
ROS rating:  +++ strong | ++ moderate | + weak | ± mixed | 0 none
NRF2:        ↓ suppressed | ↑ activated | ± mixed | 0 none
Conditions:  [D] dose  [Fe] metal  [M] metabolic  [O₂] oxygen
             [L] light [F] formulation [T] tumor-type [C] combination




Item ROS↑ NRF2 Condition Mechanism Class Remarks 



ROS">Piperlongumine
+++ ↓ [D][T] ROS-dominant






ROS">Shikonin
+++↓/±[D][T]ROS-dominant






ROS">Vitamin K3 (menadione)
+++↓[D]ROS-dominant






ROS">Copper (ionic / nano)
+++↓[Fe][F]ROS-dominant






ROS">Sodium Selenite
+++↓[D]ROS-dominant






ROS">Juglone
+++↓[D]ROS-dominant






ROS">Auranofin
+++↓[D]ROS-dominant






ROS">Photodynamic Therapy (PDT)
+++0[L][O₂]ROS-dominant






ROS">Radiotherapy / Radiation
+++0[O₂]ROS-dominant






ROS">Doxorubicin
+++↓[D]ROS-dominant






ROS">Cisplatin
++↓[D][T]ROS-dominant






ROS">Salinomycin
++↓[D][T]ROS-dominant






ROS">Artemisinin / DHA
++↓[Fe][T]ROS-dominant






ROS">Sulfasalazine
++↓[C][T]ROS-dominant






ROS">FMD / fasting
++↓[M][C][O₂]ROS-dominant






ROS">Vitamin C (pharmacologic)
++↓[Fe][D]ROS-dominant






ROS">Silver nanoparticles
++±[F][D]ROS-dominant






ROS">Gambogic acid
++↓[D][T]ROS-dominant






ROS">Parthenolide
++↓[D][T]ROS-dominant






ROS">Plumbagin
++↓[D]ROS-dominant






ROS">Allicin
++↓[D]ROS-dominant






ROS">Ashwagandha (Withaferin A)
++↓[D][T]ROS-dominant






ROS">Berberine
++↓[D][M]ROS-dominant






ROS">PEITC
++↓[D][C]ROS-dominant






ROS">Methionine restriction
+↓[M][C][T]ROS-secondary






ROS">DCA
+±[M][T]ROS-secondary






ROS">Capsaicin
+±[D][T]ROS-secondary






ROS">Galloflavin
+0[D]ROS-secondary






ROS">Piperine
+±[D][F]ROS-secondary






ROS">Propyl gallate
+↓[D]ROS-secondary






ROS">Scoulerine
+?[D][T]ROS-secondary






ROS">Thymoquinone
±±[D][T]Dual redox






ROS">Emodin
±±[D][T]Dual redox






ROS">Alpha-lipoic acid (ALA)
±↑[D][M]NRF2-dominant






ROS">Curcumin
±↑/↓[D][F]NRF2-dominant






ROS">EGCG
±↑/↓[D][O₂]NRF2-dominant






ROS">Quercetin
±↑/↓[D][Fe]NRF2-dominant






ROS">Resveratrol
±↑[D][M]NRF2-dominant






ROS">Sulforaphane
±↑↑[D]NRF2-dominant






ROS">Lycopene
0↑—Antioxidant






ROS">Rosmarinic acid
0↑—Antioxidant






ROS">Citrate
00—Neutral


Scientific Papers found: Click to Expand⟱
7688- iod,  CEL,    Iodine prevents the increase of testosterone-induced oxidative stress in a model of rat prostatic hyperplasia
- in-vivo, Pca, NA
TumCP↓, ROS↓, NOS2↓, COX2/PTGS2↓,
7674- iod,    Molecular iodine induces caspase-independent apoptosis in human breast carcinoma cells involving the mitochondria-mediated pathway
- in-vitro, BC, NA
AntiTum↑, selectivity↑, MMP↓, antiOx↑, Thiols↓, Bcl-2↓, BAX↑, eff↓, Casp↑, ROS↓, ROS↑, Cyt‑c↑, AIF↑,

Showing Research Papers: 1 to 2 of 2

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↑, 1,   ROS↓, 2,   ROS↑, 1,   Thiols↓, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

AIF↑, 1,   MMP↓, 1,  

Cell Death(tgid=5) ⓘ

BAX↑, 1,   Bcl-2↓, 1,   Casp↑, 1,   Cyt‑c↑, 1,  

Migration(tgid=13) ⓘ

TumCP↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2/PTGS2↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

eff↓, 1,   selectivity↑, 1,  

Clinical Biomarkers(tgid=22) ⓘ

NOS2↓, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiTum↑, 1,  
Total Targets: 16

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species
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#:310  Target#:275  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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