Geraniol / ROS Cancer Research Results

Ger, Geraniol: Click to Expand ⟱
Features:

Geraniol — an acyclic monoterpene alcohol and fragrance compound found in citronella, palmarosa, rose, lemongrass, rose-geranium, and several other essential oils. It is formally classified as a plant-derived monoterpenoid natural product; Citronella oil is not equivalent to geraniol: it is a variable multi-component essential oil distilled primarily from Cymbopogon winterianus or Cymbopogon nardus, with citronellal, geraniol, citronellol, geranyl acetate, limonene, and other terpenes as principal constituents.

Primary mechanisms (ranked):

  1. Induction of intrinsic and caspase-dependent apoptosis through mitochondrial dysfunction, altered BAX/BCL-2 balance, cytochrome-c release, and caspase activation.
  2. Suppression of PI3K/AKT/mTOR survival and growth signalling.
  3. Disruption of mevalonate and lipid metabolism, including inhibition of HMG-CoA reductase activity and reduced availability of intermediates required for membrane synthesis and protein prenylation.
  4. Suppression of NF-κB, inflammatory cytokine, MAPK, and JAK/STAT3 signalling in responsive cancer models.
  5. Cell-cycle arrest and inhibition of DNA synthesis, proliferation, migration, invasion, and epithelial–mesenchymal transition.
  6. Chemosensitization, particularly enhancement of 5-fluorouracil activity in colorectal-cancer models.
  7. Redox modulation, with pro-oxidant mitochondrial stress reported in some cancer models but antioxidant and NRF2-associated cytoprotection reported in non-cancer and injury models; direction is strongly context-dependent.

Bioavailability / PK relevance: Geraniol is lipophilic and can be absorbed after oral administration, but it is rapidly distributed and extensively converted to geranic acid, dihydrogeranic acid, glucuronide conjugates, and other metabolites. Rat studies indicate a short blood half-life and large formulation-dependent differences in oral bioavailability. Recent mouse studies likewise show rapid metabolism, so free-geraniol exposure is transient. Emulsions, lipid carriers, nanoformulations, and encapsulation may increase exposure, but these delivery systems do not establish clinical anticancer efficacy. Citronella-oil composition and exposure vary substantially with species, chemotype, cultivation, storage, and formulation.

In-vitro vs systemic exposure relevance: Many anticancer experiments use geraniol concentrations in the tens to hundreds of micromolar range, and some use still higher levels. These sustained concentrations may exceed free systemic concentrations achievable through ordinary dietary or flavouring exposure because geraniol is rapidly metabolized and cleared. Direct comparison is difficult because human plasma PK data for therapeutic dosing are limited. Cytotoxic findings from undiluted or concentrated citronella oil should not be attributed solely to geraniol because citronellal, citronellol, methyl isoeugenol, limonene, and minor constituents may contribute independently or interact.

Clinical evidence status: Preclinical. Evidence consists primarily of cancer-cell studies, chemically induced animal-tumour models, and xenograft studies. Geraniol has shown enhancement of 5-fluorouracil in colorectal-cancer models, but there are no established randomized controlled trials demonstrating that isolated oral or systemic geraniol treats cancer. A clinical study of a multi-ingredient topical essential-oil formulation for HPV-related disease cannot establish geraniol-specific efficacy. Neither geraniol nor citronella oil is an approved anticancer treatment or validated oncology adjunct.

Safety / regulatory relevance: Geraniol is widely used as a flavouring and fragrance ingredient, while citronella oil is also used as a flavouring and insect-repellent ingredient. Food-use safety evaluations do not establish safety at pharmacological anticancer doses. Geraniol is a recognized fragrance allergen and can cause allergic contact dermatitis, particularly after oxidation. Concentrated citronella oil can irritate skin, eyes, mucosa, and the gastrointestinal tract and should not be treated as interchangeable with food-grade geraniol. Citronella oil also contains composition-dependent constituents, including methyl isoeugenol in some preparations, that require separate toxicological consideration.

Geraniol Cancer Mechanisms

Rank Pathway / Axis Cancer Cells Normal Cells Primary Effect Notes / Interpretation
1 Mitochondrial apoptosis ↑ BAX/BCL-2 ratio; ↑ cytochrome-c release; ↑ caspase-9 and caspase-3; ↓ mitochondrial membrane potential ↔ or ↓ apoptotic injury in some oxidative-stress models (context-dependent) Apoptosis and reduced tumour-cell survival One of the most consistently reported endpoints, but effective concentrations and upstream triggers vary by cell line.
2 PI3K AKT mTOR signalling ↓ PI3K; ↓ phosphorylated AKT; ↓ mTOR and downstream survival signalling ↔ or ↑ AKT-mediated survival in selected injury models (context-dependent) Reduced proliferation, survival, protein synthesis, and treatment resistance Observed in oral, nasopharyngeal, prostate, and other experimental cancer systems; direct molecular binding has not been established consistently.
3 Mevalonate and lipid metabolism ↓ HMG-CoA reductase activity; ↓ mevalonate-pathway flux; altered fatty-acid and phospholipid metabolism ↓ cholesterol synthesis (dose-dependent) Reduced membrane synthesis, proliferation, and potentially protein prenylation Mechanistically important in hepatocarcinoma and chemically induced colorectal-tumour models. Rescue by mevalonate has not been demonstrated uniformly across models.
4 NF-κB inflammatory survival signalling ↓ NF-κB activation; ↓ inflammatory and anti-apoptotic signalling ↓ NF-κB-driven inflammation in several non-cancer models Reduced survival, inflammation, invasion, and apoptosis resistance NF-κB modulation may be downstream of AKT inhibition or redox changes rather than a single direct target.
5 JAK STAT3 signalling ↓ STAT3 activation; ↓ survival and proliferation signals Insufficient evidence Apoptosis and suppression of tumour-promoting transcription Reported in selected thyroid and other cancer-cell models; breadth across tumour types remains uncertain.
6 MAPK stress and proliferation signalling ↓ or altered ERK, JNK, and p38 signalling (model-dependent) ↔ or protective modulation (context-dependent) Cell-cycle arrest, stress signalling, and apoptosis The direction differs by cell type, concentration, and treatment duration; the MAPK family should not be represented as uniformly inhibited.
7 Cell cycle and DNA synthesis ↓ DNA synthesis; ↓ cyclin-associated progression; ↑ cell-cycle arrest Insufficient evidence at comparable exposure Reduced proliferation Cell-cycle phase varies among studies and may reflect secondary effects of metabolic stress or apoptosis.
8 Migration invasion and EMT ↓ migration; ↓ invasion; ↓ mesenchymal phenotype (model-dependent) Insufficient evidence Reduced metastatic behaviour Predominantly in-vitro evidence; clinically relevant anti-metastatic activity has not been demonstrated.
9 Mitochondrial ROS increase ↑ ROS and oxidative stress in some cytotoxic models (dose-dependent) (high concentration only) ↓ oxidative injury in multiple inflammatory or toxic-injury models (context-dependent) Oxidative mitochondrial damage and apoptosis Geraniol is not uniformly pro-oxidant. Redox direction depends on tissue, baseline stress, concentration, and treatment duration.
10 NRF2 antioxidant response ↔ or uncertain; possible cytoprotection in some contexts ↑ NRF2-associated antioxidant enzymes in selected injury models Secondary antioxidant and tissue-protective response NRF2 is not a well-established central anticancer mechanism for geraniol. Persistent NRF2 activation could theoretically protect some tumour cells.
11 5-Fluorouracil chemosensitization ↑ response to 5-fluorouracil; ↓ tumour growth in colorectal xenograft models Insufficient selectivity data Enhanced chemotherapy activity Promising preclinical interaction, but human efficacy, optimal scheduling, toxicity, and pharmacokinetic interactions are unknown.
12 Clinical Translation Constraint Rapid metabolism; transient free-geraniol exposure; many studies use high concentrations Fragrance sensitization and irritation; systemic high-dose safety incompletely characterized Limits direct translation of experimental cytotoxicity Formulation strongly affects bioavailability. Citronella oil is a heterogeneous mixture and cannot be dosed or interpreted as purified geraniol.


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)

"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⟱
6569- Ger,    Geraniol inhibits cell growth and promotes caspase-dependent apoptosis in nasopharyngeal cancer C666-1 cells via inhibiting PI3K/Akt/mTOR signaling pathway
- in-vitro, NPC, C666-1
tumCV↓, MMP↓, Apoptosis↑, TBARS↑, GSH↓, SOD↓, BAX↑, Casp3↑, Casp9↑, PI3K↓, Akt↓, mTOR↓, DNAdam↑, ROS↑,
6570- Ger,    Apoptosis-Mediated Anticancer Activity of Geraniol Inhibits NF-κB, MAPK, and JAK-STAT-3 Signaling Pathways in Human Thyroid Cancer Cells
- in-vitro, Thyroid, TPC-1
*Inflam↓, AntiCan↑, *neuroP↑, tumCV↓, TumCP↓, ROS↑, Apoptosis?, MMP↓, Bcl-2↓, cycD1/CCND1↓, cMyc↓, COX2↓, TNF-α↓, NF-kB↓, IL6↓, survivin↓, BAX↑, Casp3↑, JAK2↓, STAT3↓, ERK↓,

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 ⓘ

GSH↓, 1,   ROS↑, 2,   SOD↓, 1,   TBARS↑, 1,  

Mitochondria & Bioenergetics ⓘ

MMP↓, 2,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 1,  

Cell Death ⓘ

Akt↓, 1,   Apoptosis?, 1,   Apoptosis↑, 1,   BAX↑, 2,   Bcl-2↓, 1,   Casp3↑, 2,   Casp9↑, 1,   survivin↓, 1,  

Transcription & Epigenetics ⓘ

tumCV↓, 2,  

DNA Damage & Repair ⓘ

DNAdam↑, 1,  

Cell Cycle & Senescence ⓘ

cycD1/CCND1↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

ERK↓, 1,   mTOR↓, 1,   PI3K↓, 1,   STAT3↓, 1,  

Migration ⓘ

TumCP↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   IL6↓, 1,   JAK2↓, 1,   NF-kB↓, 1,   TNF-α↓, 1,  

Clinical Biomarkers ⓘ

IL6↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,  
Total Targets: 29

Pathway results for Effect on Normal Cells:


Immune & Inflammatory Signaling ⓘ

Inflam↓, 1,  

Functional Outcomes ⓘ

neuroP↑, 1,  
Total Targets: 2

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#:414  Target#:275  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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