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tid		Target	ROS	Cancers General Effect on Target

Name	Reactive Oxygen Species
Source	HalifaxProj (inhibit)
Type

Reactive Oxygen Species

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)

"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  

Piperlongumine
+++  ↓  [D][T]  ROS-dominant
Selective ROS stressor, Prevents compensatory upregulation of NRF2, ie GSH↓



Shikonin
+++ ↓/± [D][T] ROS-dominant
ROS + glycolysis + GPX4 inhibition



Vitamin K3 (menadione)
+++ ↓ [D] ROS-dominant
Quinone redox cycler; toxicity limits use



Copper (ionic / nano)
+++ ↓ [Fe][F] ROS-dominant
Fenton-type redox chemistry



Sodium Selenite
+++ ↓ [D] ROS-dominant
Pro-oxidant, depletes GSH



Juglone
+++ ↓ [D] ROS-dominant
Strong quinone ROS chemistry



Auranofin
+++ ↓ [D] ROS-dominant
TrxR inhibition → redox collapse



Photodynamic Therapy (PDT)
+++ 0 [L][O₂] ROS-dominant
Singlet oxygen is core cytotoxic mechanism



Radiotherapy / Radiation
+++ 0 [O₂] ROS-dominant
DNA damage largely via ROS



Doxorubicin
+++ ↓ [D] ROS-dominant
Chemo; redox cycling + mitochondrial ROS



Cisplatin
++ ↓ [D][T] ROS-dominant
ROS contributes to DNA/protein damage



Salinomycin
++ ↓ [D][T] ROS-dominant
ROS-mediated CSC toxicity



Artemisinin / DHA
++ ↓ [Fe][T] ROS-dominant
Iron-activated radical generation



Sulfasalazine
++ ↓ [C][T] ROS-dominant
Ferroptosis; xCT inhibition → lipid ROS



FMD / fasting
++ ↓ [M][C][O₂] ROS-dominant
Metabolic stress → mitochondrial ROS



Vitamin C (pharmacologic)
++ ↓ [Fe][D] ROS-dominant
Extracellular H₂O₂ at high dose



Silver nanoparticles
++ ± [F][D] ROS-dominant
ROS common; selectivity unreliable



Gambogic acid
++ ↓ [D][T] ROS-dominant
ROS-mediated apoptosis



Parthenolide
++ ↓ [D][T] ROS-dominant
ROS + NF-κB suppression



Plumbagin
++ ↓ [D] ROS-dominant
Quinone ROS driver



Allicin
++ ↓ [D] ROS-dominant
Thiol-reactive oxidative stress



Ashwagandha (Withaferin A)
++ ↓ [D][T] ROS-dominant
ROS-mediated apoptosis



Berberine
++ ↓ [D][M] ROS-dominant
Mitochondrial ROS induction



PEITC
++ ↓ [D][C] ROS-dominant
GSH depletion + ROS



Methionine restriction
+ ↓ [M][C][T] ROS-secondary
Redox vulnerability increased; ROS indirect



DCA
+ ± [M][T] ROS-secondary
ROS via forced OXPHOS



Capsaicin
+ ± [D][T] ROS-secondary
Ca²⁺ stress → ROS



Galloflavin
+ 0 [D] ROS-secondary
ROS not primary driver



Piperine
+ ± [D][F] ROS-secondary
Weak ROS induction



Propyl gallate
+ ↓ [D] ROS-secondary
Pro-oxidant at high dose



Scoulerine
+ ? [D][T] ROS-secondary
Sparse ROS data



Thymoquinone
± ± [D][T] Dual redox
Antioxidant ↔ pro-oxidant switch



Emodin
± ± [D][T] Dual redox
Not cancer-exclusive



Alpha-lipoic acid (ALA)
± ↑ [D][M] NRF2-dominant
Antioxidant at low dose



Curcumin
± ↑/↓ [D][F] NRF2-dominant
Hormetic redox behavior



EGCG
± ↑/↓ [D][O₂] NRF2-dominant
Auto-oxidation artifacts common



Quercetin
± ↑/↓ [D][Fe] NRF2-dominant
GSH-dependent cycling



Resveratrol
± ↑ [D][M] NRF2-dominant
ROS only at high dose



Sulforaphane
± ↑↑ [D] NRF2-dominant
Strong NRF2 activator



Lycopene
0 ↑ — Antioxidant
Consistently antioxidant



Rosmarinic acid
0 ↑ — Antioxidant
Primarily antioxidant



Citrate
0 0 — Neutral
Metabolic; not a ROS agent

Item	ROS↑	NRF2	Condition	Mechanism Class	Remarks
Piperlongumine	+++	↓	[D][T]	ROS-dominant	Selective ROS stressor, Prevents compensatory upregulation of NRF2, ie GSH↓
Shikonin	+++	↓/±	[D][T]	ROS-dominant	ROS + glycolysis + GPX4 inhibition
Vitamin K3 (menadione)	+++	↓	[D]	ROS-dominant	Quinone redox cycler; toxicity limits use
Copper (ionic / nano)	+++	↓	[Fe][F]	ROS-dominant	Fenton-type redox chemistry
Sodium Selenite	+++	↓	[D]	ROS-dominant	Pro-oxidant, depletes GSH
Juglone	+++	↓	[D]	ROS-dominant	Strong quinone ROS chemistry
Auranofin	+++	↓	[D]	ROS-dominant	TrxR inhibition → redox collapse
Photodynamic Therapy (PDT)	+++	0	[L][O₂]	ROS-dominant	Singlet oxygen is core cytotoxic mechanism
Radiotherapy / Radiation	+++	0	[O₂]	ROS-dominant	DNA damage largely via ROS
Doxorubicin	+++	↓	[D]	ROS-dominant	Chemo; redox cycling + mitochondrial ROS
Cisplatin	++	↓	[D][T]	ROS-dominant	ROS contributes to DNA/protein damage
Salinomycin	++	↓	[D][T]	ROS-dominant	ROS-mediated CSC toxicity
Artemisinin / DHA	++	↓	[Fe][T]	ROS-dominant	Iron-activated radical generation
Sulfasalazine	++	↓	[C][T]	ROS-dominant	Ferroptosis; xCT inhibition → lipid ROS
FMD / fasting	++	↓	[M][C][O₂]	ROS-dominant	Metabolic stress → mitochondrial ROS
Vitamin C (pharmacologic)	++	↓	[Fe][D]	ROS-dominant	Extracellular H₂O₂ at high dose
Silver nanoparticles	++	±	[F][D]	ROS-dominant	ROS common; selectivity unreliable
Gambogic acid	++	↓	[D][T]	ROS-dominant	ROS-mediated apoptosis
Parthenolide	++	↓	[D][T]	ROS-dominant	ROS + NF-κB suppression
Plumbagin	++	↓	[D]	ROS-dominant	Quinone ROS driver
Allicin	++	↓	[D]	ROS-dominant	Thiol-reactive oxidative stress
Ashwagandha (Withaferin A)	++	↓	[D][T]	ROS-dominant	ROS-mediated apoptosis
Berberine	++	↓	[D][M]	ROS-dominant	Mitochondrial ROS induction
PEITC	++	↓	[D][C]	ROS-dominant	GSH depletion + ROS
Methionine restriction	+	↓	[M][C][T]	ROS-secondary	Redox vulnerability increased; ROS indirect
DCA	+	±	[M][T]	ROS-secondary	ROS via forced OXPHOS
Capsaicin	+	±	[D][T]	ROS-secondary	Ca²⁺ stress → ROS
Galloflavin	+	0	[D]	ROS-secondary	ROS not primary driver
Piperine	+	±	[D][F]	ROS-secondary	Weak ROS induction
Propyl gallate	+	↓	[D]	ROS-secondary	Pro-oxidant at high dose
Scoulerine	+	?	[D][T]	ROS-secondary	Sparse ROS data
Thymoquinone	±	±	[D][T]	Dual redox	Antioxidant ↔ pro-oxidant switch
Emodin	±	±	[D][T]	Dual redox	Not cancer-exclusive
Alpha-lipoic acid (ALA)	±	↑	[D][M]	NRF2-dominant	Antioxidant at low dose
Curcumin	±	↑/↓	[D][F]	NRF2-dominant	Hormetic redox behavior
EGCG	±	↑/↓	[D][O₂]	NRF2-dominant	Auto-oxidation artifacts common
Quercetin	±	↑/↓	[D][Fe]	NRF2-dominant	GSH-dependent cycling
Resveratrol	±	↑	[D][M]	NRF2-dominant	ROS only at high dose
Sulforaphane	±	↑↑	[D]	NRF2-dominant	Strong NRF2 activator
Lycopene	0	↑	—	Antioxidant	Consistently antioxidant
Rosmarinic acid	0	↑	—	Antioxidant	Primarily antioxidant
Citrate	0	0	—	Neutral	Metabolic; not a ROS agent

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