Lemongrass Extract/Citral / ROS Cancer Research Results

LGE, Lemongrass Extract/Citral: Click to Expand ⟱
Features:
lemongrass extract/ Cymbopogon citratus / lemongrass essential oil

Promising in vitro and limited animal anticancer evidence, especially via ROS-mediated apoptosis and mitochondrial/cell-cycle effects. Citral likely is main active ingredient.

Lemongrass Extract/Citral — Lemongrass preparations are derived principally from the leaves of Cymbopogon citratus and may be prepared as aqueous or ethanolic extracts or as volatile essential oil. Citral (CIT) is an acyclic monoterpene aldehyde and is usually the dominant constituent of lemongrass essential oil; chemically, citral is a mixture of the geometric isomers geranial (citral A) and neral (citral B). The database abbreviation LGE is appropriate for lemongrass extract, while CIT is preferable when the isolated compound is specifically studied. Essential-oil preparations can contain roughly 60–80% citral, but composition varies substantially with cultivar, plant tissue, extraction method, and geographic origin. Whole aqueous or ethanolic lemongrass extracts are not pharmacologically equivalent to purified citral because they contain additional terpenes and nonvolatile phytochemicals.

Primary mechanisms (ranked):

  1. ROS accumulation and oxidative stress in cancer cells, producing DNA damage and triggering mitochondrial apoptosis.
  2. Mitochondrial apoptotic signaling through ↓ mitochondrial membrane potential, ↑ Bax, ↓ Bcl-2/Bcl-xL, and ↑ caspase-3 activation; p53-dependent signaling is important in several models.
  3. ALDH1A3 inhibition, potentially suppressing cancer stem-cell phenotype, clonogenicity, retinoic-acid-linked transcription, and chemotherapy resistance.
  4. Microtubule disruption through inhibition of tubulin polymerization together with MARK4 inhibition, producing antiproliferative and cell-cycle effects.
  5. Suppression of proliferative and survival signaling including AKT, ERK1/2, and NF-κB in selected cancer models.
  6. Cell-cycle arrest, commonly G0/G1 or G1/S depending on model and preparation.
  7. Endoplasmic-reticulum stress and stress-associated autophagy in some p53-deficient cancer cells.
  8. Chemosensitization, including enhanced effects of doxorubicin, docetaxel, FOLFOX-associated drugs, paclitaxel, and other cytotoxics in preclinical models; transporter effects including MDR1/MRP1/BCRP suppression have been reported.

Bioavailability / PK relevance: Citral is lipophilic, volatile, chemically unstable, and rapidly metabolized. Animal disposition studies indicate extensive gastrointestinal absorption but rapid conversion to oxidized, reduced, and conjugated metabolites, with little persistence of unchanged citral in circulation and predominantly urinary elimination of metabolites. Thus, good absorption does not imply high systemic exposure to intact citral. Encapsulation with polymers, cyclodextrins, lipid systems, or nanoparticles has been investigated to improve stability and effective exposure. Human pharmacokinetic data defining circulating intact citral after therapeutic oral dosing remain limited.

In-vitro vs systemic exposure relevance: Many anticancer experiments use citral concentrations in the tens to hundreds of micromolar range, commonly about 20–200 µM, or relatively concentrated lemongrass extracts. These exposures cannot presently be assumed to be attainable as sustained concentrations of intact citral in human plasma after tea, food, or conventional oral supplementation because parent citral undergoes very rapid metabolism. Whole-extract studies also cannot be quantitatively translated into equivalent systemic citral exposure. Consequently, the strongest mechanistic findings should be considered preclinical and concentration-dependent.

Clinical evidence status: Preclinical. Anticancer activity is supported by numerous cancer-cell studies and several animal xenograft experiments using citral or lemongrass extracts. Chemosensitization is also preclinical. Human studies of lemongrass tea and topical essential oil provide limited tolerability and non-oncology clinical information, but there is no established human anticancer efficacy and no approved oncology indication for citral or lemongrass extract. Citral is permitted as a food flavoring agent and is listed by the FDA under food-use regulations; this regulatory status does not establish therapeutic anticancer efficacy. Safety is concentration- and formulation-dependent: concentrated citral and essential oils can be cytotoxic or genotoxic in cultured normal cells, while some cancer models demonstrate relative tumor-cell selectivity.

Mechanistic Effects of Lemongrass Extract and Citral

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 ROS and oxidative stress ↑ ROS, ↓ GSH ↔ or ↑ ROS (dose-dependent) R Oxidative damage and apoptosis One of the best-supported anticancer mechanisms of citral and lemongrass preparations. ROS elevation precedes mitochondrial dysfunction in several cancer models; antioxidant effects can occur in non-cancer systems, making modulation context-dependent.
2 Mitochondrial apoptosis ↓ membrane potential, ↑ Bax, ↓ Bcl-2, ↓ Bcl-xL, ↑ caspase-3 ↔ or weaker effect (model-dependent) R/G Intrinsic apoptosis Demonstrated in colorectal, leukemia, breast, ovarian, and other cancer models. ROS frequently acts upstream of mitochondrial depolarization.
3 ALDH1A3 and cancer stem cells ↓ ALDH1A3 activity Not established R/G ↓ clonogenicity and stem-cell-associated tumor growth Citral directly inhibits ALDH1A3-associated activity and reduced growth of ALDH1A3-driven breast tumor models. Potential relevance to cancer stem cells and drug resistance.
4 Tubulin and microtubules ↓ tubulin polymerization, ↑ microtubule depolymerization ↓ (high concentration or exposure-dependent) P/R Microtubule disruption and proliferation inhibition Citral can directly disrupt microtubules and inhibit polymerization. This is not inherently cancer-selective and is therefore an efficacy and toxicity mechanism.
5 MARK4 ↓ MARK4 Not established R Antiproliferative signaling and microtubule regulation Biochemical binding and kinase inhibition studies support MARK4 as a direct citral target associated with its microtubule-related activity.
6 p53 apoptotic signaling ↑ p53 phosphorylation and activity Not established R/G ↑ Bax, PUMA, NOXA and apoptosis ROS-dependent p53 activation contributes strongly to apoptosis in p53-competent cells. p53-deficient cells may instead depend more heavily on ER-stress mechanisms.
7 AKT and PI3K survival signaling ↓ AKT, ↓ PI3K signaling Not established R/G Reduced survival and proliferation Reported particularly in melanoma and other cancer-cell systems; importance varies by cancer type.
8 ERK signaling ↓ ERK1/2 Not established R/G Reduced proliferative signaling Observed alongside AKT suppression and oxidative stress in melanoma models.
9 NF-κB survival signaling ↓ NF-κB Context-dependent R/G Reduced prosurvival and inflammatory signaling NF-κB suppression has been reported in melanoma and leukemia models and may contribute to apoptosis.
10 Cell cycle ↑ G0/G1 or G1/S arrest ↔ or less affected (model-dependent) G ↓ proliferation Phase of arrest varies with cell type, citral concentration, and whether purified citral or whole lemongrass extract is used.
11 Endoplasmic reticulum stress ↑ CHOP, ↑ ATF4, ↑ phospho-eIF2α, ↑ GADD45 Not established R/G Stress-associated growth inhibition and apoptosis Especially relevant in p53-deficient models where ER stress may compensate for reduced p53-mediated apoptotic signaling.
12 Autophagy ↑ (context-dependent) Not established G Stress response contributing to cytotoxicity Autophagy-associated proteins including ATG5 have been altered after citral treatment; whether autophagy is lethal or adaptive is model-dependent.
13 Chemosensitization ↑ Potential toxicity sparing in selected models G Enhanced chemotherapy response Lemongrass extract or citral has enhanced responses to FOLFOX-associated drugs, paclitaxel, docetaxel, doxorubicin, and other agents in preclinical studies. Clinical confirmation is absent.
14 Drug efflux and multidrug resistance ↓ MDR1, ↓ MRP1, ↓ BCRP, ↑ intracellular doxorubicin Not established G Reduced multidrug resistance Lemongrass oil and citral increased doxorubicin accumulation in resistant cancer-cell models. Whole oil and purified citral are not necessarily equivalent.
15 Drug metabolism signaling ↓ PXR, ↓ CYP3A4, ↓ GST (model-dependent) Drug-metabolizing enzymes can also be altered G Potential alteration of chemotherapy disposition Potentially contributes to chemosensitization but also raises a possible drug-interaction concern. Rat studies demonstrate modulation of hepatic xenobiotic-metabolizing enzymes at high citral or lemongrass-oil doses.
16 Clinical Translation Constraint Preclinical activity Limited selectivity at sufficiently high exposure G Low parent-drug exposure and uncertain therapeutic window Citral is rapidly metabolized, volatile, and chemically unstable. Many effective in-vitro concentrations likely exceed sustained systemic concentrations of intact citral achievable through ordinary oral intake. Nanoparticle and other delivery systems improve experimental exposure but are not established cancer treatments.

TSF: P: 0–30 min    R: 30 min–3 hr    G: >3 hr
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⟱
6322- DRE,  LGE,    Dandelion Root and Lemongrass Extracts Induce Apoptosis, Enhance Chemotherapeutic Efficacy, and Reduce Tumour Xenograft Growth In Vivo in Prostate Cancer
- vitro+vivo, Pca, DU145
AntiCan↑, ChemoSen↑, Dose↝, *ROS↓, Apoptosis↑, selectivity↑, *toxicity↓, *chemoP↑, eff↓, ROS↑,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

ROS↑, 1,  

Cell Death(tgid=5) ⓘ

Apoptosis↑, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

ChemoSen↑, 1,   Dose↝, 1,   eff↓, 1,   selectivity↑, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiCan↑, 1,  
Total Targets: 7

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

ROS↓, 1,  

Functional Outcomes(tgid=23) ⓘ

chemoP↑, 1,   toxicity↓, 1,  
Total Targets: 3

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#:398  Target#:275  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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