Ginseng / ROS Cancer Research Results

Gins, Ginseng: Click to Expand ⟱
Features:

Ginseng — a medicinal root from the genus Panax, principally Asian/Korean ginseng (Panax ginseng) and American ginseng (Panax quinquefolius). It is a botanical natural health product containing multiple pharmacologically active constituents, especially triterpenoid saponins called ginsenosides, including Rb1, Rb2, Rc, Rd, Re, Rg1 and, depending strongly on processing, Rg3, Rg5 and related compounds; intestinal metabolism also generates metabolites such as Compound K. Standard abbreviations include PG for Panax ginseng, KRG for Korean red ginseng and AG for American ginseng. White, red, fermented and heat-processed ginseng have substantially different ginsenoside profiles and should not be assumed mechanistically equivalent. Anticancer effects attributed to “ginseng” are predominantly derived from preclinical studies of specific ginsenosides such as Rg3 and Rh2 rather than conventional whole-root exposure.

Primary mechanisms (ranked):

  1. Suppression of oncogenic PI3K/Akt and related MAPK growth-survival signaling by selected ginsenosides, particularly Rg3 and Rh2.
  2. Induction of mitochondrial apoptosis through altered BCL-2/BAX balance, mitochondrial dysfunction and caspase activation.
  3. Suppression of tumor invasion, angiogenesis and metastatic signaling, including VEGF-related pathways, particularly by Rg3.
  4. Redox modulation: selected ginsenosides can increase mitochondrial ROS sufficiently to trigger apoptosis in cancer cells while ginseng/ginsenosides more commonly activate antioxidant defenses and reduce oxidative stress in nonmalignant tissues.
  5. Suppression of NF-κB-associated inflammatory and prosurvival signaling, with corresponding modulation of inflammatory cytokines.
  6. Chemo- and radiosensitization reported for selected ginsenosides, particularly Rg3, but predominantly at the preclinical level.
  7. Secondary NRF2/HO-1 antioxidant modulation, particularly relevant to normal-cell cytoprotection; its effect within tumors is context-dependent and may theoretically protect some malignant cells.

Bioavailability / PK relevance: Native ginsenosides generally have low and highly variable oral systemic exposure because of limited intestinal absorption and extensive gut-microbiota metabolism. Rb1 and related compounds can be converted sequentially to more readily absorbed metabolites including Compound K. Consequently, microbiome composition, ginseng species, processing and formulation strongly influence systemic exposure. Red or heat-processed ginseng contains substantially more Rg3/Rg5 than ordinary white ginseng.

In-vitro vs systemic exposure relevance: Many anticancer experiments with Rg3, Rh2 and related ginsenosides use approximately micromolar to tens-of-micromolar concentrations. Following conventional oral ginseng, circulating concentrations of many parent ginsenosides are substantially lower and exposure is frequently metabolite-driven. Therefore direct extrapolation of isolated-ginsenoside cancer-cell cytotoxicity to oral whole-root ginseng is weak. Pharmacologically enriched, fermented or purified ginsenoside products constitute materially different exposures.

Clinical evidence status: Direct anticancer efficacy of ordinary oral ginseng remains unestablished. A large phase III randomized trial supports American ginseng at 2 g/day for reduction of cancer-related fatigue, making supportive oncology its strongest cancer-related human evidence. Clinical literature on purified/enriched Rg3 combined with chemotherapy exists, particularly from China, but does not establish ordinary ginseng root as an anticancer therapy. Ginseng is marketed as a natural health/herbal product rather than an approved anticancer drug. Health Canada has specifically concluded that available evidence was insufficient to establish acceptable conditions for standardized Panax ginseng extract in supplemented foods when total ginsenoside intake would exceed 8 mg/day.

Ginseng (Panax ginseng) – This herb has been studied for its ability to enhance the immune system.
-Antioxidant Properties: Ginseng contains ginsenosides, which have antioxidant properties.
-Immune System Support
-Inhibition of Tumor Growth
-Chemopreventive Effects
-Synergistic Effects with Cancer Treatments: ginseng may enhance the effectiveness of certain cancer treatments, such as chemotherapy, and may help reduce side effect
Dose: Standardized Extract:
Dosage: extract containing 4-7% ginsenosides 200-400mg/d
Dried Root:1-2g/d
Tea: 1-2g dried root, 1-3x/d

Ginseng Cancer-Relevant Mechanisms

Rank Pathway / Axis Cancer Cells Normal Cells Primary Effect Notes / Interpretation
1 PI3K/Akt survival signaling ↓ ↔ / ↑ (context-dependent) Reduced proliferation and survival One of the most reproducible anticancer axes for Rg3 and Rh2. Evidence largely concerns isolated ginsenosides rather than conventional whole-root ginseng.
2 Mitochondrial apoptosis ↑ ↔ / ↓ injury Apoptotic cell death Selected ginsenosides increase BAX/BCL-2 ratio, mitochondrial dysfunction and caspase-9/caspase-3 activation. Usually concentration-dependent.
3 Angiogenesis and VEGF signaling ↓ ↔ Reduced tumor vascularization Particularly associated with Rg3; inhibition of VEGF signaling and endothelial responses has been demonstrated preclinically.
4 NF-κB inflammatory and survival signaling ↓ ↓ excessive activation Reduced inflammation and prosurvival signaling May suppress inflammatory cytokines, invasion and treatment resistance. Magnitude varies substantially among individual ginsenosides and preparations.
5 Mitochondrial ROS increase ↑ (dose-dependent) ↓ oxidative stress Oxidative apoptosis in cancer cells Rh2 can induce mitochondrial ROS and apoptosis. This should not be generalized to all ginseng preparations because antioxidant effects predominate in many normal-tissue models.
6 Migration and invasion ↓ ↔ Reduced metastatic phenotype Selected ginsenosides suppress migration, invasion and associated signaling in multiple experimental cancer models.
7 Chemosensitization ↑ treatment response ↔ / ↓ toxicity (model-dependent) Enhanced chemotherapy response Rg3 has enhanced responses to agents including 5-FU, cisplatin and doxorubicin in experimental systems. Evidence for whole-root ginseng is substantially weaker.
8 Radiosensitization ↑ (model-dependent) ↔ / radioprotection reported Enhanced radiation response Rg3 can enhance radiation-induced tumor-cell killing through pathways including NF-κB suppression, while other ginsenosides may protect normal tissue from radiation injury.
9 NRF2 antioxidant defense ↔ / ↑ (context-dependent) ↑ Antioxidant cytoprotection Secondary mechanism. Potentially beneficial in normal tissue but mechanistically ambiguous in cancer because NRF2 activation can also support tumor antioxidant defenses.
10 Clinical Translation Constraint — — Predominantly adjunctive use Species, processing and ginsenoside composition vary markedly. Oral parent-ginsenoside exposure is low and microbiome-dependent, while many anticancer experiments use purified Rg3/Rh2 at substantially higher concentrations. Direct tumor-control efficacy of ordinary oral ginseng has not been established.


Ginseng and Alzheimer’s disease: Panax ginseng, Korean red ginseng and individual ginsenosides have substantial preclinical neuroprotective evidence involving amyloid processing, tau phosphorylation, neuroinflammation, oxidative stress, synaptic signaling and neurotrophic pathways. Small Korean clinical studies have reported improvements in cognitive scores, but these studies were generally small, open-label or otherwise at substantial risk of bias. Current evidence is insufficient to classify ginseng as a disease-modifying treatment for Alzheimer’s disease.

Primary mechanisms (ranked):

  1. Reduction of amyloidogenic processing and Aβ accumulation through modulation of APP-processing enzymes and Aβ clearance pathways.
  2. Reduction of tau phosphorylation and aggregation through multiple kinase/phosphatase pathways.
  3. Enhancement of synaptic plasticity and neurotrophic signaling including BDNF/TrkB-related pathways.
  4. Suppression of microglial activation, NF-κB signaling and neuroinflammatory cytokine production.
  5. Reduction of neuronal oxidative stress and mitochondrial dysfunction through antioxidant pathways including NRF2.
  6. Cholinergic support and modulation of neurotransmission.

Clinical evidence status: Small human studies of Korean red ginseng have reported improvements in MMSE, ADAS-cog and related cognitive measures, but adequately powered modern blinded placebo-controlled Alzheimer trials are lacking. The evidence remains preliminary and does not establish prevention of neurodegeneration or disease modification.


Ginseng Alzheimer-Relevant Mechanisms

Rank Pathway / Axis Modulation Primary Effect Notes / Interpretation
1 Amyloid processing and Aβ burden ↓ Reduced amyloidogenic pathology Ginsenosides and processed ginseng can influence APP processing, BACE activity and Aβ clearance in preclinical systems.
2 Tau phosphorylation and aggregation ↓ Reduced tau pathology Multiple ginseng constituents have reduced tau phosphorylation in experimental systems; red ginseng can also interfere with tau aggregation in vitro.
3 BDNF and TrkB neuroplasticity ↑ Synaptic and neurotrophic support Ginsenosides can increase neurotrophic signaling and support learning and memory in experimental models.
4 Neuroinflammation and NF-κB ↓ Reduced microglial inflammatory signaling Associated with reductions in inflammatory cytokines and activated microglial responses in preclinical models.
5 NRF2 antioxidant defense ↑ Reduced oxidative neuronal injury Activation of antioxidant-response pathways contributes to neuronal protection in several ginseng and ginsenoside models.
6 Oxidative stress and ROS ↓ Reduced neuronal oxidative damage Generally antioxidant in neuronal and other nonmalignant tissues, unlike the pro-oxidant response produced by some ginsenosides in cancer cells at high concentrations.
7 Cholinergic signaling ↑ Improved neurotransmission Modulation of acetylcholine synthesis, release and degradation has been reported, although this mechanism is less clinically established than standard cholinesterase inhibition.
8 Clinical Translation Constraint — Preliminary human evidence Human Alzheimer studies are small and methodologically limited. Different species, red-ginseng processing and purified ginsenosides cannot be considered interchangeable.


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⟱
7283- Gins,    Ginsenoside-Rh2-induced mitochondrial depolarization and apoptosis are associated with reactive oxygen species- and Ca2+-mediated c-Jun NH2-terminal kinase 1 activation in HeLa cells
- in-vitro, Cerv, HeLa - in-vitro, BC, MCF-10AT - in-vitro, BC, MCF7
MMP↓, Casp↑, BAX↑, Ca+2↑, ROS↑, cJun↑,
7282- Gins,    Ginsenoside Rh2 stimulates the production of mitochondrial reactive oxygen species and induces apoptosis of cervical cancer cells by inhibiting mitochondrial electron transfer chain complex
- in-vitro, Cerv, NA
compI↓, compIII↓, ETC↓, ROS↑, Apoptosis↑, tumCV↓, selectivity↑, MMP↓, ATP↓, OXPHOS↓, ECAR↓, Glycolysis↓,

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) ⓘ

compI↓, 1,   OXPHOS↓, 1,   ROS↑, 2,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

ATP↓, 1,   compIII↓, 1,   ETC↓, 1,   MMP↓, 2,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

ECAR↓, 1,   Glycolysis↓, 1,  

Cell Death(tgid=5) ⓘ

Apoptosis↑, 1,   BAX↑, 1,   Casp↑, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

cJun↑, 1,   tumCV↓, 1,  

Migration(tgid=13) ⓘ

Ca+2↑, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

selectivity↑, 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#:219  Target#:275  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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