Grapeseed extract / ROS Cancer Research Results

GSE, Grapeseed extract: Click to Expand ⟱
Features:
Grapeseed extract (GSE) is rich in oligomeric proanthocyanidins (OPCs), catechins, and other polyphenols derived from Vitis vinifera seeds. In cancer research, GSE is most consistently associated with antioxidant and anti-inflammatory signaling modulation, suppression of PI3K/AKT and MAPK pathways, induction of cell-cycle arrest, and promotion of apoptosis in preclinical models. GSE has also been reported to inhibit angiogenesis (via VEGF suppression), reduce metastasis-related markers (e.g., MMPs), and modulate redox balance in tumor cells. Effects are concentration-dependent and vary by tumor type. While GSE is frequently described as antioxidant in normal tissues, pro-oxidant effects have been reported in tumor contexts at higher concentrations. Human oncology data remain limited; most findings derive from in vitro and animal studies.
Made from seeds of grapes and contains antioxidants Vitamin E, linolenic acid and OPCs.

Grapeseed extract — Grapeseed extract (GSE) is a polyphenol-rich botanical extract prepared from seeds of Vitis vinifera, with oligomeric proanthocyanidins/procyanidins as its principal bioactive constituents together with catechin, epicatechin, and related flavan-3-ols. It is classified as a botanical dietary supplement / polyphenolic extract rather than a single molecular drug. Standard abbreviations include GSE, grape seed proanthocyanidin extract (GSPE), and grape seed procyanidin extract. Standardized formulations such as Leucoselect Phytosome complex grape-seed procyanidins with phospholipids to improve oral absorption. Cancer-related effects remain predominantly preclinical, although a small phase I lung-cancer chemoprevention study demonstrated biological activity in human bronchial tissue.

Primary mechanisms (ranked):

  1. Suppression of oncogenic PI3K/AKT signaling, including miR-19a/miR-19b downregulation, PTEN restoration, and reduced AKT phosphorylation in lung-cancer models.
  2. Suppression of proliferative and inflammatory signaling including NF-κB, COX-2, survivin, cyclin D1, and related eicosanoid pathways.
  3. Induction of apoptosis and cell-cycle arrest, including mitochondrial apoptotic signaling and increased CDKN1A/p21 associated with miR-106b suppression.
  4. Suppression of invasion and epithelial-mesenchymal transition through TGF-β/SMAD, MMP, cadherin, and related migration pathways.
  5. Redox modulation: antioxidant activity predominates in normal/nonmalignant tissues, whereas sufficiently high concentrations can produce ROS-dependent mitochondrial stress and apoptosis in some cancer-cell models.
  6. Suppression of angiogenic signaling, including VEGF/VEGFR-related pathways in preclinical models.

Bioavailability / PK relevance: Oral exposure to intact higher-order proanthocyanidin oligomers is limited because polymer size, gastrointestinal stability, metabolism, and microbial degradation restrict systemic absorption. Monomeric flavan-3-ols and smaller metabolites are more readily absorbed. Consequently, biological effects after oral GSE may be mediated substantially by lower-molecular-weight constituents and metabolites rather than by circulating intact oligomeric proanthocyanidins. Phospholipid formulations such as Leucoselect Phytosome were specifically developed to improve exposure.

In-vitro vs systemic exposure relevance: Many direct anticancer experiments expose cancer cells to tens to hundreds of µg/mL of GSE, concentrations that should not be assumed to represent plasma concentrations achievable after conventional oral supplementation. Direct ROS-mediated cytotoxicity and mitochondrial injury are therefore particularly vulnerable to this translation problem. Lower-exposure effects involving inflammatory signaling, circulating metabolites, or tissue microenvironment modulation may be more clinically plausible.

Clinical evidence status: Predominantly preclinical, with small human mechanistic/chemoprevention evidence. A modified phase I study of bioavailability-enhanced Leucoselect Phytosome in eight heavy current/former smokers, six of whom completed treatment, reported good tolerability and approximately 55% reduction in bronchial Ki-67 labeling after three months together with modulation of miR-19a, miR-19b, and miR-106b. Subsequent analysis found reduced pulmonary TNF, CCL3, and granzyme B without significant alteration of CYP3A4 activity. A phase IIa presurgical study in early-stage lung cancer has also been registered, but GSE is not an established or approved cancer treatment and there is no evidence from adequately powered randomized oncology trials demonstrating improved tumor response, progression-free survival, or overall survival.

Grapeseed Extract Cancer-Relevant Mechanisms

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 miR-19 PTEN PI3K AKT axis miR-19a/b ↓; PTEN ↑; p-AKT ↓ ↔ (context-dependent) R, G Growth and survival signaling ↓ One of the better-defined GSE mechanisms in lung-cancer models and supported by biomarker modulation in the small human chemoprevention study.
2 NF-κB COX-2 inflammatory survival signaling NF-κB ↓; COX-2 ↓; PGE2 ↓; survivin ↓ Inflammatory signaling ↓ R, G Inflammation and survival ↓ Observed across colon, skin, and lung-related experimental systems. Human pulmonary studies also show reductions in selected inflammatory mediators.
3 Apoptosis and mitochondrial signaling Apoptosis ↑; Bax/Bcl-2 ratio ↑; caspase activity ↑; mitochondrial dysfunction ↑ (model-dependent) Apoptosis ↔ at lower exposure R, G Tumor-cell death ↑ Frequently observed at cytostatic or cytotoxic GSE concentrations; quantitative clinical relevance is constrained by oral exposure.
4 miR-106b CDKN1A cell-cycle axis miR-106b ↓; CDKN1A/p21 ↑; proliferation ↓ ↔ G Cell-cycle arrest ↑ Mechanistically characterized in lung-neoplastic cells; complements cyclin D1 suppression reported in other tumor models.
5 Cell-cycle proliferation program Cyclin D1 ↓; Ki-67 ↓; proliferation ↓ Minimal suppression at typical noncytotoxic exposure G Cytostasis ↑ Bronchial Ki-67 decreased in the small phase I Leucoselect Phytosome study, providing limited human biomarker support.
6 TGF-β SMAD EMT invasion axis p-SMAD2/3 ↓; N-cadherin ↓; vimentin ↓; E-cadherin ↑; EMT ↓ ↔ G Migration and invasion ↓ Supported particularly in bladder-cancer and other metastatic models.
7 MMP extracellular-matrix remodeling MMP2 ↓; MMP9 ↓; invasion ↓ MMP activity ↓ (context-dependent) G Metastatic potential ↓ Likely partly downstream of NF-κB, TGF-β, and MAPK modulation.
8 VEGF angiogenic signaling VEGF ↓; VEGFR signaling ↓; angiogenesis ↓ Angiogenesis ↓ (context-dependent) G Tumor vascularization ↓ Primarily preclinical evidence; systemic concentrations required for direct antiangiogenic activity remain uncertain.
9 ROS mitochondrial stress ROS ↑; mitochondrial membrane dysfunction ↑; oxidative DNA damage ↑ (high concentration only) ROS ↓; oxidative damage ↓ P, R Selective redox stress Biphasic behavior is important: GSE is generally antioxidant systemically but can become pro-oxidant in cancer cells under sufficiently high experimental exposure.
10 NRF2 antioxidant defense ↔ or ↑ (context-dependent) NRF2 ↑; antioxidant defenses ↑ R, G Oxidative-stress protection Secondary rather than a defining anticancer mechanism. Activation may protect normal tissue but theoretically could also support antioxidant defenses in some tumors.
11 Pulmonary inflammatory microenvironment Migration/invasion ↓ when exposed to post-treatment BAL fluid TNF ↓; CCL3 ↓; granzyme B ↓ G Pro-tumor inflammatory environment ↓ Observed in a very small human Leucoselect Phytosome cohort and therefore biologically interesting but not evidence of therapeutic efficacy.
12 Clinical Translation Constraint Direct cytotoxic exposure difficult to reproduce systemically Generally well tolerated in short human studies — Translation limited Complex extract composition, poor absorption of larger proanthocyanidins, metabolite-dependent exposure, formulation differences, small human studies, and absence of definitive oncology RCT outcomes substantially limit clinical inference.

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⟱
7330- GSE,    Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention
- Review, Var, NA
*BioAv↑, *ROS↓, AntiCan↑, selectivity↑, RenoP↑, *hepatoP↑, *DNAdam↓, *Stroke↓, *Bcl-2↑, cMyc↓,
7331- GSE,    Protection against drug- and chemical-induced multiorgan toxicity by a novel IH636 grape seed proanthocyanidin extract
- in-vivo, Nor, NA
*ROS↓, TumCD↑, *RenoP↑,
7332- GSE,    The impact of grape seed extract treatment on blood pressure changes: A meta-analysis of 16 randomized controlled trials
- Review, Nor, NA
*BP↓, *eff↑, *ROS↓, *DNAdam↓, *cardioP↑, *eff↝,

Showing Research Papers: 1 to 3 of 3

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 3

Pathway results for Effect on Cancer / Diseased Cells:


Core Metabolism/Glycolysis(tgid=4) ⓘ

cMyc↓, 1,  

Cell Death(tgid=5) ⓘ

TumCD↑, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

selectivity↑, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiCan↑, 1,   RenoP↑, 1,  
Total Targets: 5

Pathway results for Effect on Normal Cells:


NA, unassigned(tgid=0) ⓘ

Stroke↓, 1,  

Redox & Oxidative Stress(tgid=1) ⓘ

ROS↓, 3,  

Cell Death(tgid=5) ⓘ

Bcl-2↑, 1,  

DNA Damage & Repair(tgid=10) ⓘ

DNAdam↓, 2,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↑, 1,   eff↑, 1,   eff↝, 1,  

Clinical Biomarkers(tgid=22) ⓘ

BP↓, 1,  

Functional Outcomes(tgid=23) ⓘ

cardioP↑, 1,   hepatoP↑, 1,   RenoP↑, 1,  
Total Targets: 11

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

 

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