Resveratrol / GlutMet Cancer Research Results

RES, Resveratrol: Click to Expand ⟱
Features: polyphenol
Found in red grapes and products made with grapes.
Resveratrol is a polyphenol compound found in various plant species, including grapes, berries, and peanuts.
• Anti-inflammatory effects, Antioxidant effects:
- Antiplatelet aggregation for stroke prevention
- BioAvialability use piperine
- some sources may use Japanese knotweed roots (Reynoutria Japonica - root) as source which might contain Emodin (laxative)
-known as Nrf2 activator, both in cancer and normal cells. Which raises controversity of use in ROS↑ therapies. Interestingly there are reports of NRF2↑ and ROS↑ in cancer cells. This raises the question of if it is a chemosensitizer. However other reports indicate NRF2 droping with Res, indicating it maybe a chemosenstizer.
- RES is also considered to be them most effective natural SIRT1↑ -activating compound (STACs).

However, in the presence of certain metals, such as copper or iron, resveratrol can undergo a process called Fenton reaction, which can lead to the generation of reactive oxygen species (ROS). The pro-oxidant effects of resveratrol are often observed at high concentrations, typically above 50-100 μM, and in the presence of certain metals or other pro-oxidant agents. In contrast, the antioxidant effects of resveratrol are typically observed at lower concentrations, typically below 10-20 μM.

Clinical trials have used doses ranging from 150 mg to 5 grams per day. Lower doses (< 1 g/day) are often well-tolerated, but higher doses might be necessary for therapeutic effects and can be associated with side effects.

-Note half-life 1-3 hrs?.
BioAv poor: min 5uM/L required for chemopreventive effects, but 25mg Oral only yeilds 20nM. co-administration of piperine
Pathways:
- usually induce ROS production in cancer cells, while reducing ROS in normal cells.
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓,
- Lowers AntiOxidant defense in Cancer Cells: NRF2(typically increased), TrxR↓**, SOD↓, GSH↓ Catalase↓ HO1↓(wrong direction), GPx↓
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, TIMP2, IGF-1↓, uPA↓, VEGF↓, ROCK1↓, FAK↓, RhoA↓, NF-κB↓, CXCR4↓, SDF1↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : HDAC↓, EZH2↓, P53↑, HSP↓, Sp proteins↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, FAK↓, ERK↓, EMT↓, TOP1↓, TET1↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, ECAR↓, OXPHOS↓, GRP78↑, Glucose↓, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, FGF↓, PDGF↓, EGFR↓, Integrins↓,
- inhibits Cancer Stem Cells : CSC↓, CK2↓, Hh↓, CD133↓, CD24↓, β-catenin↓, sox2↓, notch2↓, nestin↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK, ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells

Rank Pathway / Axis Cancer Cells Normal Cells Label Primary Interpretation Notes
1 Reactive oxygen species (ROS) ↑ ROS (dose- & context-dependent) ↓ ROS / buffered Conditional Driver Biphasic redox modulation Resveratrol can act as a pro-oxidant in cancer cells while functioning as an antioxidant in normal cells
2 Mitochondrial integrity / intrinsic apoptosis ↓ ΔΨm; ↑ caspase activation ↔ preserved Driver Execution of intrinsic apoptosis Mitochondrial dysfunction and apoptosis follow ROS elevation in cancer cells
3 SIRT1 / AMPK axis ↑ AMPK; context-dependent SIRT1 modulation ↑ SIRT1 / ↑ AMPK Driver Metabolic stress signaling Resveratrol modulates energy-sensing pathways affecting survival and metabolism
4 PI3K → AKT → mTOR axis ↓ AKT / ↓ mTOR ↔ adaptive suppression Secondary Growth and anabolic inhibition Downregulation of growth signaling contributes to cytostasis and apoptosis sensitization
5 NF-κB signaling ↓ NF-κB activation ↓ inflammatory NF-κB tone Secondary Suppression of survival and inflammatory transcription NF-κB inhibition contributes to reduced proliferation and invasion
6 Cell cycle regulation ↑ G1/S or G2/M arrest ↔ largely spared Phenotypic Cytostatic growth control Cell-cycle arrest reflects upstream signaling disruption
7 HIF-1α / VEGF axis ↓ HIF-1α; ↓ VEGF ↔ minimal Secondary Anti-angiogenic pressure Interference with hypoxia-driven adaptation and angiogenesis


GlutMet, Glutamine metabolism: Click to Expand ⟱
Source:
Type:
Glutamine metabolism plays a significant role in cancer biology, as many cancer cells exhibit altered metabolic pathways to support their rapid growth and proliferation.
Glutamine is a non-essential amino acid that serves as a vital nutrient for many cells, including cancer cells. It is involved in various metabolic processes, including protein synthesis, nucleotide synthesis, and energy production.
Warburg Effect: Cancer cells often rely on aerobic glycolysis (the Warburg effect) for energy production, even in the presence of oxygen. Glutamine metabolism can complement this process by providing intermediates for the tricarboxylic acid (TCA) cycle, which is crucial for energy production and biosynthesis.
Inhibitors of glutaminase (an enzyme that converts glutamine to glutamate) and other metabolic pathways are being explored in preclinical and clinical settings.

Key Enzymes in Glutamine Metabolism
Glutaminase (GLS)
Glutamate Dehydrogenase (GLUD)
Glutamine Synthetase (GS)
Asparagine Synthetase (ASNS)
Aminotransferases (e.g., GPT, GOT)

The expression of enzymes involved in glutamine metabolism is often elevated in various cancers and is generally associated with poorer prognosis.


Scientific Papers found: Click to Expand⟱
3099- RES,    Resveratrol and cognitive decline: a clinician perspective
- Review, Nor, NA - NA, AD, NA
*antiOx↑, In preclinical models of cognitive decline, resveratrol displays potent antioxidant activity by scavenging free radicals, reducing quinone reductase 2 activity and upregulating endogenous enzymes.
*ROS↓,
*cognitive↑,
*neuroP↑,
*SIRT1↑, By inducing SIRT1, resveratrol may promote neurite outgrowth and enhance neural plasticity in the hippocampal region
*AMPK↑, Resveratrol also induces neurogenesis and mitochondrial biogenesis by enhancing AMP-activated protein kinase (AMPK), which is known to stimulate neuronal differentiation and mitochondrial biogenesis in neurons.
*GPx↑, figure 1
*HO-1↑,
*GSK‐3β↑,
*COX2↓,
*PGE2↓, Resveratrol also inhibits pro-inflammatory enzyme (i.e., COX-1 and -2) expression, reduces NF-κB activation as well as PGE2, NO, and TNF-α production, and cytokine release
*NF-kB↓,
*NO↓,
*Casp3↓,
*MMP3↓,
*MMP9↓,
*MMP↑, resveratrol attenuated ROS production and mitochondrial membrane-potential disruption; moreover, it restored the normal levels of glutathione (GSH) depleted by Aβ1-42
*GSH↑,
*other↑, resveratrol significantly increased cerebral blood flow (CBF) in the frontal cortex of young healthy humans.
*BioAv↑, receiving 200 mg/day of resveratrol in a formulation with quercetin 320 mg [53], in order to increase its bioavailability,
*memory↑, Resveratrol supplementation induced retention of memory and improved the functional connectivity between the hippocampus and frontal, parietal, and occipital areas, compared with placebo
*GlutMet↑, Also, glucose metabolism was improved and this may account for some of the beneficial effects of resveratrol on neuronal function.
*BioAv↓, The main problems related to the therapeutic or preventive use of resveratrol are linked to its low oral bioavailability and its short half-life in serum
*Half-Life↓,
*toxicity∅, On the other hand, the tolerability and safety profile of resveratrol is very high

3092- RES,    Resveratrol in breast cancer treatment: from cellular effects to molecular mechanisms of action
- Review, BC, MDA-MB-231 - Review, BC, MCF7
TumCP↓, The anticancer mechanisms of RES in regard to breast cancer include the inhibition of cell proliferation, and reduction of cell viability, invasion, and metastasis.
tumCV↓,
TumCI↓,
TumMeta↓,
*antiOx↑, antioxidative, cardioprotective, estrogenic, antiestrogenic, anti-inflammatory, and antitumor properties it has been used against several diseases, including diabetes, neurodegenerative diseases, coronary diseases, pulmonary diseases, arthritis, and
*cardioP↑,
*Inflam↓,
*neuroP↑,
*Keap1↓, RES administration resulted in a downregulation of Keap1 expression, therefore, inducing Nrf2 signaling, and leading to a decrease in oxidative damage
*NRF2↑,
*ROS↓,
p62↓, decrease the severity of rheumatoid arthritis by inducing autophagy via p62 downregulation, decreasing the levels of interleukin-1β (IL-1β) and C-reactive protein as well as mitigating angiopoietin-1 and vascular endothelial growth factor (VEGF) path
IL1β↓,
CRP↓,
VEGF↓,
Bcl-2↓, RES downregulates the levels of Bcl-2, MMP-2, and MMP-9, and induces the phosphorylation of extracellular-signal-regulated kinase (ERK)/p-38 and FOXO4
MMP2↓,
MMP9↓,
FOXO4↓,
POLD1↓, The in vivo experiment involving a xenograft model confirmed the ability of RES to reduce tumor growth via POLD1 downregulation
CK2↓, RES reduces the expression of casein kinase 2 (CK2) and diminishes the viability of MCF-7 cells.
MMP↓, Furthermore, RES impairs mitochondrial membrane potential, enhances ROS generation, and induces apoptosis, impairing BC progression
ROS↑,
Apoptosis↑,
TumCCA↑, RES has the capability of triggering cell cycle arrest at S phase and reducing the number of 4T1 BC cells in G0/G1 phase
Beclin-1↓, RES administration promotes cytotoxicity of DOX against BC cells by downregulating Beclin-1 and subsequently inhibiting autophagy
Ki-67↓, Reducing the Ki-67
ATP↓, RES’s administration is responsible for decreasing ATP production and glucose metabolism in MCF-7 cells.
GlutMet↓,
PFK↓, RES decreased PFK activity, preventing glycolysis and glucose metabolism in BC cells and decreasing cellular growth rate
TGF-β↓, RES (12.5–100 µM) inhibited TGF-β signaling and reduced the expression levels of its downstream targets that include Smad2 and Smad3 and as a result impaired the progression of BC cells.
SMAD2↓,
SMAD3↓,
Vim?, a significant decrease in the levels of vimentin, Snail1 and Slug occurred, while E-cadherin levels increased to suppress EMT and metastasis of BC cells.
Snail↓,
Slug↓,
E-cadherin↑,
EMT↓,
Zeb1↓, a significant decrease in the levels of vimentin, Snail1 and Slug occurred, while E-cadherin levels increased to suppress EMT and metastasis of BC cells.
Fibronectin↓,
IGF-1↓, RES administration (10 and 20 µM) impaired the migration and invasion of BC cells via inhibiting PI3K/Akt and therefore decreasing IGF-1 expression and preventing the upregulation of MMP-2
PI3K↓,
Akt↓,
HO-1↑, The activation of heme oxygenase-1 (HO-1) signaling by RES reduced MMP-9 expression and prevented metastasis of BC cells
eff↑, RES-loaded gold nanoparticles were found to enhance RES’s ability to reduce MMP-9 expression as compared to RES alone
PD-1↓, RES inhibited PD-1 expression to promote CD8+ T cell activity and enhance Th1 immune responses.
CD8+↑,
Th1 response↑,
CSCs↓, RES has the ability to target CSCs in various tumors
RadioS↑, RES in reversing drug resistance and radio resistance.
SIRT1↑, RES administration (12.5–200 µmol/L) promotes sensitivity of BC cells to DOX by increasing Sirtuin 1 (SIRT1) expression
Hif1a↓, downregulating HIF-1α expression, an important factor in enhancing radiosensitivity
mTOR↓, mTOR suppression

119- UA,  CUR,  RES,    Combinatorial treatment with natural compounds in prostate cancer inhibits prostate tumor growth and leads to key modulations of cancer cell metabolism
- in-vitro, Pca, DU145 - in-vitro, Pca, PC3
ROS⇅, ROS↑ only with CUR alone, otherwise ↓
p‑STAT3↓, all the combination treatments decreased phosphorylation of STAT3
Src↓, All the combinations of these natural compounds also decreased phosphorylation of Src
AMPK↑,
GlutMet↑, UA in combination with both CUR or RES greatly enhanced the modulation of a number of metabolic pathways, including the “Alanine, aspartate and glutamate metabolism” and the “tricarboxylic acid (TCA) cycle”
TCA↑,
glut↓, Since the combination of CUR + UA and UA + RES decreased the uptake of glutamine


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:


Redox & Oxidative Stress(tgid=1)

HO-1↑, 1,   ROS↑, 1,   ROS⇅, 1,  

Mitochondria & Bioenergetics(tgid=3)

ATP↓, 1,   MMP↓, 1,  

Core Metabolism/Glycolysis(tgid=4)

AMPK↑, 1,   glut↓, 1,   GlutMet↓, 1,   GlutMet↑, 1,   PFK↓, 1,   POLD1↓, 1,   SIRT1↑, 1,   TCA↑, 1,  

Cell Death(tgid=5)

Akt↓, 1,   Apoptosis↑, 1,   Bcl-2↓, 1,   CK2↓, 1,  

Transcription & Epigenetics(tgid=7)

tumCV↓, 1,  

Autophagy & Lysosomes(tgid=9)

Beclin-1↓, 1,   p62↓, 1,  

Cell Cycle & Senescence(tgid=11)

TumCCA↑, 1,  

Proliferation, Differentiation & Cell State(tgid=12)

CSCs↓, 1,   EMT↓, 1,   FOXO4↓, 1,   IGF-1↓, 1,   mTOR↓, 1,   PI3K↓, 1,   Src↓, 1,   p‑STAT3↓, 1,  

Migration(tgid=13)

E-cadherin↑, 1,   Fibronectin↓, 1,   Ki-67↓, 1,   MMP2↓, 1,   MMP9↓, 1,   Slug↓, 1,   SMAD2↓, 1,   SMAD3↓, 1,   Snail↓, 1,   TGF-β↓, 1,   TumCI↓, 1,   TumCP↓, 1,   TumMeta↓, 1,   Vim?, 1,   Zeb1↓, 1,  

Angiogenesis & Vasculature(tgid=14)

Hif1a↓, 1,   VEGF↓, 1,  

Immune & Inflammatory Signaling(tgid=16)

CRP↓, 1,   IL1β↓, 1,   PD-1↓, 1,   Th1 response↑, 1,  

Drug Metabolism & Resistance(tgid=21)

eff↑, 1,   RadioS↑, 1,  

Clinical Biomarkers(tgid=22)

CRP↓, 1,   Ki-67↓, 1,  

Infection & Microbiome(tgid=24)

CD8+↑, 1,  
Total Targets: 55

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1)

antiOx↑, 2,   GPx↑, 1,   GSH↑, 1,   HO-1↑, 1,   Keap1↓, 1,   NRF2↑, 1,   ROS↓, 2,  

Mitochondria & Bioenergetics(tgid=3)

MMP↑, 1,  

Core Metabolism/Glycolysis(tgid=4)

AMPK↑, 1,   GlutMet↑, 1,   SIRT1↑, 1,  

Cell Death(tgid=5)

Casp3↓, 1,  

Transcription & Epigenetics(tgid=7)

other↑, 1,  

Proliferation, Differentiation & Cell State(tgid=12)

GSK‐3β↑, 1,  

Migration(tgid=13)

MMP3↓, 1,   MMP9↓, 1,  

Angiogenesis & Vasculature(tgid=14)

NO↓, 1,  

Immune & Inflammatory Signaling(tgid=16)

COX2↓, 1,   Inflam↓, 1,   NF-kB↓, 1,   PGE2↓, 1,  

Drug Metabolism & Resistance(tgid=21)

BioAv↓, 1,   BioAv↑, 1,   Half-Life↓, 1,  

Functional Outcomes(tgid=23)

cardioP↑, 1,   cognitive↑, 1,   memory↑, 1,   neuroP↑, 2,   toxicity∅, 1,  
Total Targets: 29

Scientific Paper Hit Count for: GlutMet, Glutamine metabolism
3 Resveratrol
1 Ursolic acid
1 Curcumin
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#:141  Target#:128  State#:%  Dir#:%
wNotes=on sortOrder:rid,rpid

 

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