ROS Cancer Research Results

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
Selective <span class="wphighlight">ROS</span> stressor, Prevents compensatory upregulation of NRF2, ie GSH↓



ROS">Shikonin
+++ ↓/± [D][T] ROS-dominant
<span class="wphighlight">ROS</span> + glycolysis + GPX4 inhibition



ROS">Vitamin K3 (menadione)
+++ ↓ [D] ROS-dominant
Quinone redox cycler; toxicity limits use



ROS">Copper (ionic / nano)
+++ ↓ [Fe][F] ROS-dominant
Fenton-type redox chemistry



ROS">Sodium Selenite
+++ ↓ [D] ROS-dominant
Pro-oxidant, depletes GSH



ROS">Juglone
+++ ↓ [D] ROS-dominant
Strong quinone <span class="wphighlight">ROS</span> chemistry



ROS">Auranofin
+++ ↓ [D] ROS-dominant
TrxR inhibition → redox collapse



ROS">Photodynamic Therapy (PDT)
+++ 0 [L][O₂] ROS-dominant
Singlet oxygen is core cytotoxic mechanism



ROS">Radiotherapy / Radiation
+++ 0 [O₂] ROS-dominant
DNA damage largely via <span class="wphighlight">ROS</span>



ROS">Doxorubicin
+++ ↓ [D] ROS-dominant
Chemo; redox cycling + mitochondrial <span class="wphighlight">ROS</span>



ROS">Cisplatin
++ ↓ [D][T] ROS-dominant
<span class="wphighlight">ROS</span> contributes to DNA/protein damage



ROS">Salinomycin
++ ↓ [D][T] ROS-dominant
<span class="wphighlight">ROS</span>-mediated CSC toxicity



ROS">Artemisinin / DHA
++ ↓ [Fe][T] ROS-dominant
Iron-activated radical generation



ROS">Sulfasalazine
++ ↓ [C][T] ROS-dominant
Ferroptosis; xCT inhibition → lipid <span class="wphighlight">ROS</span>



ROS">FMD / fasting
++ ↓ [M][C][O₂] ROS-dominant
Metabolic stress → mitochondrial <span class="wphighlight">ROS</span>



ROS">Vitamin C (pharmacologic)
++ ↓ [Fe][D] ROS-dominant
Extracellular H₂O₂ at high dose



ROS">Silver nanoparticles
++ ± [F][D] ROS-dominant
<span class="wphighlight">ROS</span> common; selectivity unreliable



ROS">Gambogic acid
++ ↓ [D][T] ROS-dominant
<span class="wphighlight">ROS</span>-mediated apoptosis



ROS">Parthenolide
++ ↓ [D][T] ROS-dominant
<span class="wphighlight">ROS</span> + NF-κB suppression



ROS">Plumbagin
++ ↓ [D] ROS-dominant
Quinone <span class="wphighlight">ROS</span> driver



ROS">Allicin
++ ↓ [D] ROS-dominant
Thiol-reactive oxidative stress



ROS">Ashwagandha (Withaferin A)
++ ↓ [D][T] ROS-dominant
<span class="wphighlight">ROS</span>-mediated apoptosis



ROS">Berberine
++ ↓ [D][M] ROS-dominant
Mitochondrial <span class="wphighlight">ROS</span> induction



ROS">PEITC
++ ↓ [D][C] ROS-dominant
GSH depletion + <span class="wphighlight">ROS</span>



ROS">Methionine restriction
+ ↓ [M][C][T] ROS-secondary
Redox vulnerability increased; <span class="wphighlight">ROS</span> indirect



ROS">DCA
+ ± [M][T] ROS-secondary
<span class="wphighlight">ROS</span> via forced OXPHOS



ROS">Capsaicin
+ ± [D][T] ROS-secondary
Ca²⁺ stress → <span class="wphighlight">ROS</span>



ROS">Galloflavin
+ 0 [D] ROS-secondary
<span class="wphighlight">ROS</span> not primary driver



ROS">Piperine
+ ± [D][F] ROS-secondary
Weak <span class="wphighlight">ROS</span> induction



ROS">Propyl gallate
+ ↓ [D] ROS-secondary
Pro-oxidant at high dose



ROS">Scoulerine
+ ? [D][T] ROS-secondary
Sparse <span class="wphighlight">ROS</span> data



ROS">Thymoquinone
± ± [D][T] Dual redox
Antioxidant ↔ pro-oxidant switch



ROS">Emodin
± ± [D][T] Dual redox
Not cancer-exclusive



ROS">Alpha-lipoic acid (ALA)
± ↑ [D][M] NRF2-dominant
Antioxidant at low dose



ROS">Curcumin
± ↑/↓ [D][F] NRF2-dominant
Hormetic redox behavior



ROS">EGCG
± ↑/↓ [D][O₂] NRF2-dominant
Auto-oxidation artifacts common



ROS">Quercetin
± ↑/↓ [D][Fe] NRF2-dominant
GSH-dependent cycling



ROS">Resveratrol
± ↑ [D][M] NRF2-dominant
<span class="wphighlight">ROS</span> only at high dose



ROS">Sulforaphane
± ↑↑ [D] NRF2-dominant
Strong NRF2 activator



ROS">Lycopene
0 ↑ — Antioxidant
Consistently antioxidant



ROS">Rosmarinic acid
0 ↑ — Antioxidant
Primarily antioxidant



ROS">Citrate
0 0 — Neutral
Metabolic; not a <span class="wphighlight">ROS</span> agent

Scientific Papers found: Click to Expand⟱

1253-

aLinA,

The Antitumor Effects of α-Linolenic Acid

Review,

NA,

PPARγ↑,
COX2↓,
E6↓,
E7↓,
P53↑,
p‑ERK↓,
p38↓,
lipid-P↑,
ROS⇅, ALA could inhibit cancer by stimulating ROS production to induce apoptosis (other places implies reduced) appropriate dose of ALA can also reduce OS by regulating SOD, CAT, GPx, GSH, and NADPH oxidase
MPT↑, directly activate mitochondrial permeability transition
MMP↓,
Cyt‑c↑, cytochrome c (cyt c) release
Casp↑,
iNOS↓,
NO↓,
Casp3↑,
Bcl-2↓,
Hif1a↓,
FASN↓,
CRP↓,
IL6↓,
IL1β↓,
IFN-γ↓,
TNF-α↓,
Twist↓,
VEGF↓,
MMP2↓,
MMP9↓,

4759-

antiOx,

Chemo,

Potential Contributions of Antioxidants to Cancer Therapy: Immunomodulation and Radiosensitization

Review,

Var,

TumCD↑, curcumin has been shown to modulate immunoediting processes including resurrecting immune surveillance mechanisms to help eradicate cancer cells
TumCG↓, studies by Lee-Chang et al34 have shown that administration of resveratrol, a dietary polyphenol compound possessing antioxidant properties at low doses that are nontoxic to immune cells, inhibits lung metastasis of breast cancer tumor.
ROS⇅, Of importance, resveratrol can exert both antioxidant and pro-oxidant properties depending on its concentration and cell types used
eff↑, Wang et al36 have demonstrated that a combination of fish oil and selenium that possesses anti-inflammatory and antioxidant activities exerted synergistic effects in suppressing lung tumor growth mediated via decreasing the population of splenic Treg
RadioS↑, Several nutritional cancer chemopreventive compounds having antioxidant properties have been documented to potentiate radiation therapy–induced cytotoxic effects on cancer cells while reducing its toxicity on normal surrounding tissues.77-86
TumCG↓, soy isoflavone component genistein on prostate cancer demonstrated that both soy and genistein inhibited the growth of in vitro human PC-3 prostate cancer cells and in vivo orthotopic PC-3 tumors
OS↑, While a statistically significant improved survival rate either at 1 year or 5 years was associated with melatonin supplementation
toxicity∅, 9 RCTs reported no differences in the toxicities by antioxidants supplementation
toxicity↑, and 1 RCT with vitamin A reported increased toxicity.

4804-

ASTX,

Astaxanthin in cancer therapy and prevention (Review)

Review,

Var,

Review,

AD,

*antiOx↑, gained significant attention for its potent antioxidant, anti-inflammatory and anti-proliferative properties.
*Inflam↓,
ChemoSen⇅, In some instances, it reduces the cytotoxicity of cisplatin, particularly with cisplatin on the SKBR3 breast cancer cell line, indicating a potential protective effect. In certain cases, AXT enhances the cytotoxic effect of the chemotherapy drugs
chemoP↑, The present review detailed both in vitro and in vivo studies highlighting the effectiveness of AXT in sensitizing cancer cells to chemotherapy, thereby enhancing therapeutic outcomes and potentially reducing treatment-related side effects.
BioAv↑, incorporation of AXT in nanoparticle-based delivery systems has further improved its bioavailability
TumCP↑, AXT exhibits hormetic effects on U251-MG, T98G and CRT-MG cell lines, where low doses stimulate cell proliferation
ROS⇅, while higher doses induce apoptosis by triggering a dose-dependent oxidative stress response, significantly increasing reactive oxygen species (ROS) levels and promoting apoptosis
Apoptosis↑,
PI3K↑, AXT activates the PI3K/Akt/GSK3β pathway, leading to the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, in SH-SY5Y cells under oxygen and glucose deprivation conditions
Akt↑,
GSK‐3β↑,
NRF2↑,
AntiCan↑, antioxidant, AXT has the potential to act as both an anticancer drug and a neuroprotectant.
*neuroP↑, AXT protects against oxidative stress, which causes mitochondrial dysfunction and apoptosis, thereby reducing the detrimental effects associated with neurodegenerative diseases such as Alzheimer's, Parkinson's
eff↑, The synergistic cytotoxic effect of AXT with melatonin showed enhanced efficacy in the T47D cell line compared with the MDA-MB-231 line
AntiTum↑, AXT effectively reduced tumor size and the number of cancer cells in mice, supporting its potential anti-tumor activity.

1532-

Ba,

Baicalein as Promising Anticancer Agent: A Comprehensive Analysis on Molecular Mechanisms and Therapeutic Perspectives

Review,

NA,

ROS↑, Baicalein initially incited the formation of ROS, which subsequently aimed at endoplasmic reticulum stress and stimulated the Ca2+/-reliant mitochondrial death pathway.
ER Stress↑,
Ca+2↑,
MMPs↓,
Cyt‑c↑, cytochrome C release
Casp3↑,
ROS↑, Baicalein on apoptosis in human bladder cancer 5637 cells was investigated, and it was found that it induces ROS generation
DR5↑, Baicalein activates DR5 up-regulation
ROS↑, MCF-7 cells by inducing mitochondrial apoptotic cell death. It does this by producing ROS, such as hydroxyl radicals, and reducing Cu (II) to Cu (I) in the Baicalein–Cu (II) system
BAX↑,
Bcl-2↓,
MMP↓,
Casp3↑,
Casp9↑,
P53↑,
p16↑,
P21↑,
p27↑,
HDAC10↑, modulating the up-regulation of miR-3178 and Histone deacetylase 10 (HDAC10), which accelerates apoptotic cell death
MDM2↓, MDM2-mediated breakdown
Apoptosis↑,
PI3K↓, baicalein-influenced apoptosis is controlled via suppression of the PI3K/AKT axis
Akt↓,
p‑Akt↓, by reducing the concentrations of p-Akt, p-mTOR, NF-κB, and p-IκB while increasing IκB expression
p‑mTOR↓,
NF-kB↓,
p‑IκB↓,
IκB↑,
BAX↑,
Bcl-2↓,
ROS⇅, Based on its metabolic activities and intensity, Baicalein can act as an antioxidant and pro-oxidant.
BNIP3↑, Baicalein also increases the production of BNIP3 which is a protein stimulated by ROS and promotes apoptosis
p38↑,
12LOX↓, inhibition of 12-LOX (Platelet-type 12-Lipoxygenase)
Mcl-1↓,
Wnt?, decreasing Wnt activity
GLI2↓, Baicalein significantly reduced the presence of Gli-2, a crucial transcription factor in the SHH pathway
AR↓, downregulating the androgen receptor (AR)
eff↑, PTX/BAI NE could increase intracellular ROS levels, reduce cellular glutathione (GSH) levels, and trigger caspase-3 dynamism in MCF-7/Tax cells. Moreover, it exhibited higher efficacy in inhibiting tumors in vivo

2474-

Ba,

Anticancer properties of baicalein: a review

Review,

Var,

in-vitro,

Nor,

BV2

ROS⇅, Like other flavonoids, baicalein can be either anti-oxidant or pro-oxidant, depending on its metabolism and concentration.
ROS↑, It is reported that baicalein generated ROS, subsequently caused endoplasmic reticulum (ER) stress, activated Ca2+-dependent mitochondrial death pathway, finally triggered apoptosis
ER Stress↑,
Ca+2↑,
Apoptosis↑,
eff↑, Due to this, ROS production is a mechanism shared by all non-surgical therapeutic approaches for cancer, including chemotherapy, radiotherapy and photodynamic therapy
DR5↑, baicalein-induced ROS generation up-regulated DR5 expression and then activated the extrinsic apoptotic pathway in human prostate cancer cells
12LOX↓, Baicalein is known as a 12-LOX inhibitor.
Cyt‑c↑, It markedly induced the release of Cytochrome c from mitochondria into the cytosol and activated Caspase-9, Caspase-7, and Caspase-3, concomitant with cleavage of the Caspase-3 substrate poly(ADP-ribose) polymerase
Casp7↑,
Casp9↑,
Casp3↑,
cl‑PARP↑,
TumCCA↑, Baicalein induces G1/S arrest due to increased Cyclin E expression, a major factor in the regulation of the G1/S checkpoint of the cell cycle, accompanied by reduced levels of Cdk 4 and Cyclin D1 in human lung squamous carcinoma (CH27) cells
cycE/CCNE↑,
CDK4↓,
cycD1/CCND1↓,
VEGF↓, In ovarian cancer cells, baicalein effectively lowered the protein level of VEGF, c-Myc, HIF-α, and NFκB
cMyc↓,
Hif1a↓,
NF-kB↓,
BioEnh↑, curcumin and high-dose (−)-epicatechin were demonstrated to subsequently increase the absorption of baicalein
BioEnh↑, Baicalein can increase the oral bioavailability of tamoxifen by inhibiting cytochrome P450 (CYP) 3A4-mediated metabolism of tamoxifen in the small intestine and/or liver,
P450↓,
*Hif1a↓, In BV2 microglia, baicalein suppressed expression of hypoxia-induced HIF-1α and hypoxia responsive genes, including inducible nitric oxide synthase (iNOS), COX-2, and VEGF, by inhibiting ROS and PI3K/Akt pathway (Hwang et al. 2008).
*iNOS↓,
*COX2↓,
*VEGF↓,
*ROS↓,
*PI3K↓,
*Akt↓,

1566-

betaCar,

Lyco,

Antioxidant and pro-oxidant effects of lycopene in comparison with beta-carotene on oxidant-induced damage in Hs68 cells

in-vitro,

Nor,

HS68

*ROS↑, beta-carotene is known to have pro-oxidant activity in vitro
*ROS⇅, The present study in Hs68 cells demonstrates that lycopene can be either an antioxidant or a pro-oxidant depending on the oxidants used, and that lycopene and beta-carotene behave similarly under the in vitro oxidative conditions.
*Dose?, Both the antioxidant and pro-oxidant effects of lycopene tended to be dose-dependent

5685-

BML,

The Therapeutic Effects of Bromelain against Colorectal Cancer: A Systematic Review

Review,

CRC,

TumCG↓, impeding tumor growth and metastasis
TumMeta↓,
ROS⇅, reducing mucins production/secretion and increasing/reducing reactive oxygen species (ROS) production.
Bcl-2↓, bromelain induces apoptosis via reduced expression of Bcl-2
Casp3↑, activation caspase system (caspase-3, 7, 8, and 9), and extranuclear p53.
Casp7↑,
Casp8↑,
Casp9↑,
P53↑,

1652-

CA,

Caffeic Acid and Diseases—Mechanisms of Action

Review,

Var,

Dose∅, Black chokeberries seem to be the most potent source of caffeic acid (645 mg/100 g of dry weight)
ROS⇅, Therefore, we will mention the antioxidant (and prooxidant) effects of caffeic acid only briefly
NF-kB↓, In HepG2 cells, caffeic acid (100 µM) inhibited the activity of NF-κB/IL-6/STAT3 signaling, which decreased the expression of VEGF
STAT3↓,
VEGF↓,
MMP9↓, inhibited another downstream product of NF-κB: matrix metalloproteinase 9 (MM-9), which promotes tumor invasiveness and metastases
HSP70/HSPA5↑, caffeic acid (20 μM) also decreased the expression of mortalin(mitochondrial 70 kDa heat shock protein),
AST↝, normalized levels of alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bile acid, total cholesterol, HDL and LD
ALAT↝,
ALP↝,
Hif1a↓,
IL6↓,
IGF-1R↓,
P21↑,
iNOS↓,
ERK↓,
Snail↓,
BID↑,
BAX↑,
Casp3↑,
Casp7↑,
Casp9↑,
cycD1/CCND1↓,
Vim↓,
β-catenin/ZEB1↓,
COX2↓,
ROS↑, the chelating ability of caffeic acid is also responsible for its occasional pro-oxidant ability. After chelating Cu2+, the Cu2+ can be reduced to Cu+. combination of caffeic acid and endogenous copper ions can result in oxidative damage

1646-

CA,

Caffeic acid: a brief overview of its presence, metabolism, and bioactivity

Review,

Nor,

*BioAv↓, egins in the stomach where a very small amount of it is passively absorbed. Followed by the action of microbial esterases in the colon, the caffeic acid is cleaved in free form and absorbed by the intestinal mucosa (most 95%)
ROS⇅, antioxidant and pro-oxidant properties
selectivity↑, exhibits pro-oxidative properties in cancer cells that are associated with oxidative DNA (deoxyribonucleic acid) damage
other∅, caffeic acid phenethyl ester, the main representative component of propolis
VEGF↓,
MMP2↓,
MMP9↓,

5928-

Catechins,

Bioavailability of Tea Catechins and Its Improvement

Review,

Nor,

*BioAv↝, The inconsistency between catechins’ superior in vitro biological activity and low absorption in in vivo studies can also be attributed to its low stability,
*BioAv↓, Even if administered intravenously, catechins were partially degraded before reaching the target tissues
*ROS⇅, Tea polyphenols are antioxidants, but they can also generate reactive oxygen species (ROS).
*NRF2↑, may also activates nuclear factor erythroid 2-related factor 2 (Nrf2) to activate antioxidant and detoxifying enzymes
*BioAv↑, Many studies showed promising EGCG-loaded nano-carriers with sustained release and improved bioavailability even at much lower doses than conventional preparations.
*Half-Life↓, Although the half-life period of EGCG (5.0–5.5 h) is about two times longer than that of EGC or EC (2.5–3.4 h), it is still too short to exert clinical effect.
*BioAv↑, Catechins + Ascorbic acid (and sucrose or xylitol): Improving catechins bioavailability by enhancing bioaccessibility and intestinal uptake.
*BioAv↑, Piperine Increasing EGCG bioavailability by inhibiting glucuronidation and gastrointestinal transit.
BioAv↑, Caffeine Enhancing the absorption of EGCG in humans.

641-

EGCG,

Se,

Antioxidant effects of green tea

ROS↑, Concentration is a factor that could determine whether green tea polyphenols act as antioxidants or pro-oxidants. EGC and EGCG, both generate hydrogen peroxide at concentrations greater than 10 μM
H2O2↑, Adding milk to green tea decreases formation of hydrogen peroxide,
ROS⇅, Selenium could enhance anticancer activity of green tea [29], possibly by enhancing antioxidant activity [30, 31], or even its pro-oxidant activity [32].

1645-

HCAs,

Chapter 8 - Hydroxycinnamic Acids: Natural Sources, Biosynthesis, Possible Biological Activities, and Roles in Islamic Medicine

Review,

Nor,

Dose∅, HCAs such as caffeic, ferulic, and coumaric acids in fruits can be as high as 2 g/kg fresh weight [13], with caffeic acid (free or esterified) accounting for the overwhelming majority (75%–100%).
ROS⇅, Consumption of foods rich in caffeic acid has also been shown to protect against carcinogenesis due to its antioxidant and pro-oxidant properties.
Dose∅, Coffee beans are an important source of HCAs such as caffeic and chlorogenic acids; a single cup of coffee contains between 70 and 350 mg of these compounds

1643-

HCAs,

Mechanisms involved in the anticancer effects of sinapic acid

Review,

Var,

*BioAv↓, Studies have shown that SA is poorly soluble in water, but soluble in carbitol and freely soluble in DMSO
*toxicity↓, SA is found to be generally non-toxic
Dose∅, oral administration of SA up to 80 mg/kg body weight reduced the number of aberrant crypt foci up to 34.55%
ROS⇅, Other than its potent antioxidant function, SA also possesses pro-oxidant effect that has been identified to affect the redox state of tumor cells
ROS↑, SA at higher concentrations acts as a potent pro-oxidant agent, resulting in increased generation of free radicals. (50 and 75 μM) increased ROS accumulation
Igs↑, SA administration markedly improved the levels of IgG and IgA in
TumCCA↑, SA induced G2/M phase cell cycle arrest
TumAuto↑, autophagy inducing effect of SA has been reported by Zhao et al. (2021) in HepG2 and SMMC-7721 cells
eff↑, Beclin, Atg 5 increased and expression of p62 decreased in SA along with cisplatin treated HepG2 and SMMC-7721 cells
angioG↓, SA has been demonstrated to inhibit angiogenesis, cell invasion and metastasis in cancer cells
TumCI↓,
TumMeta↓,
EMT↓, SA (10 mM) treated cells showed decreased protein expression of EMT related proteins such as vimentin, MMP-9, MMP-2, and Snail and increased expression of E-cadherin in PANC-1 and SW1990 cell lines.
Vim↓,
MMP9↓,
MMP2↓,
Snail↓,
E-cadherin↑,
p‑Akt↓, SA treatment downregulated phosphorylated AKT and Gsk-3β in PANC-1 and SW1990 prostate cancer cell lines.
GSK‐3β↓,
TumCP↓, SA can inhibit cell proliferation in prostate cancer
ChemoSen↑, SA acts in collaboration with other chemotherapeutic agents to improve treatment sensitivity

2079-

HNK,

Honokiol Microemulsion Causes Stage-Dependent Toxicity Via Dual Roles in Oxidation-Reduction and Apoptosis through FoxO Signaling Pathway

in-vitro,

Nor,

PC12

*toxicity↝, Our previous studies have already demonstrated that a high dose of the honokiol microemulsion (0.6 μg/mL) induces developmental toxicity in rats and zebrafish by inducing oxidative stress.
*ROS↓, In zebrafish, low doses of honokiol microemulsion (0.15, 0.21 μg/mL) significantly decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the mRNA expression of bcl-2.
*ROS↑, In contrast, high dose (0.6 μg/mL) increased the levels of ROS and MDA, decreased activities and mRNA expression of superoxide dismutase (SOD) and catalase (CAT), and increased mRNA expression of bax, c-jnk, p53 and bim.
*Dose⇅, In rat pheochromocytoma cells (PC12 cells), low doses of the honokiol microemulsion (1, 5, 10 µM) exerted a protective effect against H2O2-induced oxidative damage while high doses (≥20 µM) induced oxidative stress, which further confirms the dual ef
*BioAv↑, highly lipophilic property of honokiol allows it to readily cross the blood-brain barrier and blood-cerebrospinal fluid barrier with high bioavailability.
*BioAv↓, However, this property also limits its clinical usage due to low oral bioavailability and difficulty in intravenous administration.
*ROS⇅, levels of ROS and MDA were significantly decreased at a concentration of 0.21 μg/mL and increased at a concentration of 0.6 μg/mL in both 24 and 96 hpf embryos
*SOD↓, The activity of SOD showed only a slight reduction at 20 µM but was significantly reduced at 40 and 80 μM
*toxicity↑, According to the human rat equivalent dosage conversion, the potential toxic dose in humans may be 320 µg/kg/d

3260-

Lyco,

Lycopene in human health

Review,

NA,

*BioAv↝, Lycopene bioavailability is lower in raw sources than in thermal processed food sources.
*BioAv↓, As a result of the low bioavailability of lycopene, its circulating levels are more suitable as prognostic data for health outcomes than its dietary intake values
*ROS⇅, A beneficial or prejudicial cellular response by lycopene will depend on its antioxidant or prooxidant properties respectively, depending on the cellular and extracellular environment
*BioAv↝, Thus, there is less bioavailability of lycopene in fresh tomatoes than in processed tomato products (such as pasteurized tomato juice, soup, sauce and ketchup)

1713-

Lyco,

Lycopene: A Potent Antioxidant with Multiple Health Benefits

Review,

Nor,

*antiOx↑, As one of the most potent antioxidants, its capacity to neutralise singlet oxygen is double that of ?-carotene, ten times greater than that of ?-tocopherol, and one hundred and twenty-five times more effective than glutathione
*ROS⇅, lycopene acts as an antioxidant in systems that produce singlet oxygen but behaves as a pro-oxidant in systems that create peroxide
*Dose↝, In low doses, it acts as an antioxidant, but at high doses, it acts as a pro-oxidant
*eff↑, In situation where there is an imbalance between antioxidant defences and ROS production, such as during inflammation or exposure to environmental toxins [91], lycopene may switch from its antioxidant role to a pro-oxidant role
*LDL↓, Wistar rats given a high-fat diet and 50mg/kg body weight of lycopene daily for 3mths had significant reductions in plasma total cholesterol, triglycerides, and lLDL levels but increased HDL cholesterol
*RenoP↑, shown to protect the kidney against chemically induced damage
*Inflam↓, evidence is plentiful demonstrating the anti-inflammatory effects of lycopene both in vitro and in vivo
neuroP↑, mice with Alzheimer's disease induced by ? amyloid, lycopene reduced oxidative stress, decreased neuronal loss, improved synaptic plasticity, and inhibited neuroinflammation
Rho↓, lycopene treatment was demonstrated to have the potential to mitigate vascular arteriosclerosis in allograft transplantation by inhibiting Rho-associated kinases

1719-

Lyco,

Lycopene for the prevention and treatment of prostate disease.

Review,

Var,

ROS⇅, Lycopene, a member of the carotenoid family, found commonly in red pigmented fruit and vegetables has been established as having strong antioxidant and pro-oxidant properties.

1718-

Lyco,

The role of carotenoids in the prevention of human pathologies

Review,

Var,

ROS⇅, Thus, in thymocytes, β-Carotene is an antioxidant at low oxygen pressure but a pro-oxidant at high oxygen concentrations
ROS↑, lycopene may have also prooxidant activities depending on the type of oxidants used.

1717-

Lyco,

Potential Role of Carotenoids as Antioxidants in Human Health and Disease

Review,

Var,

antiOx↑, unique antioxidative properties.
ROS⇅, The molecular mechanisms underlying these reactions are still not fully understood, especially in the context of the anti- and pro-oxidant activity of carotenoids
ROS↑, antioxidant potential (e.g., lutein) or even leads to pro-oxidant behavior (i.e., zeaxanthin)

4790-

Lyco,

Role of Lycopene in the Control of ROS-Mediated Cell Growth: Implications in Cancer Prevention

Review,

Var,

*antiOx↑, t has also been suggested that lycopene might act as an antioxidant by repairing vitamin E and vitamin C radicals
*ROS⇅, It is hypothesized that lycopene can behave as an antioxidant at low concentrations and as a prooxidant at high concentrations.
TumCP↓, n vitro study, the treatment of androgen-independent prostate cancer cells (PC-3) with various concentrations of lycopene (20, 40 and 60 μM) showed a significant decrease in cell proliferation
AP-1↓, It has been reported that lycopene is able to inhibit AP-1 signalling in mammary cancer cells
eff↓, prostate cancer cell lines, lycopene alone (at physiological concentrations of 1 μM) was without much effect, but in combination with -tocopherol at 50 μM, it exhibited a synergistic effect

2540-

M-Blu,

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

Review,

Var,

Review,

AD,

*OCR↑, MB was found to increase oxygen consumption of normal tissues having aerobic glycolysis and of tumors
*Glycolysis↓, Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro.
*GlucoseCon↑, Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment.
neuroP↑, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Alzheimer’s, Parkinson’s, and Huntington’s disease.
Warburg↓, In glioblastoma cells, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation, arrests glioma cell cycle at s-phase, and inhibits glioma cell proliferation.
mt-OXPHOS↑,
TumCCA↑,
TumCP↓,
ROS⇅, MB has very unique redox property that exists in equilibrium between oxidized state in dark blue (MB) and colorless reduced state (leucomethylene blue), making it both prooxidant and antioxidant under different conditions.
*cognitive↑, Methylene blue feeding improved water-maze and bridge walking performance in 5 X FAD mice. MB enhances memory function in normal rodents potentially through neurometabolic mechanisms
*mTOR↓, MB has been demonstrated to induce autophagy and attenuate tauopathy through inhibition of mTOR signaling both in vitro and in vivo
*mt-antiOx↑, Secondly, the distinct redox property enables MB as a regenerable anti-oxidant in mitochondria that distinct from the traditional free radical scavenges
*memory↑, , MB has been found to improve various experimental memory tasks in rodents
*BBB↑, MB can cross BBB and reach brain at concentrations 10 times higher than that in the circulation
*eff↝, In fibroblast cells, MB has been shown to stimulate 2-deoxyglucose uptake (Louters et al., 2006; Roelofs et al., 2006). Using MRI and PET, we demonstrated that acute treatment of MB significantly enhance glucose uptake
*ECAR↓, MB increased oxygen consumption rate and decreased extracellular acidification rate in both neuronal cells and astrocytes
eff↑, MB has also been used as a tracer for cancer diagnosis and as a photosensitizer for cancer treatment
lactateProd↓, MB increase oxygen consumption rate, decrease lactic acid production and extracellular acidification rate, reduce NADPH, and inhibit proliferation
NADPH↓,
OXPHOS↑, increases oxidative phosphorylation, decreases glycolytic flux and metabolic intermediates, hence, exhausts the building brick for cancer cell proliferation.
AMPK↑, MB is capable of activating AMPK signal pathway
selectivity↑, with low toxicity, and the high affinity to both neuronal and cancer tissues

4568-

MF,

Extremely low-frequency pulses of faint magnetic field induce mitophagy to rejuvenate mitochondria

Study,

NA,

*ETC↓, We report that ELF-WMF efficiently suppresses the mitochondrial mass to 70% by inhibiting the mitochondrial ETC complex II, which subsequently induces mitophagy and rejuvenates mitochondria.
*OCR↑, We found that Opti-ELF-WMF increased both the OCR and mitochondrial membrane potential by approximately 40%
*MMP↑,
*ROS⇅, Opti-ELF-WMF most strongly decreased the level of mitochondrial superoxide at 1 h, mitochondrial mass at 3 h, and mitochondrial membrane potential at 6 h, and most strongly increased them at 12 h
*MMP⇅,

4571-

MF,

Magnetic Fields and Reactive Oxygen Species

Review,

NA,

*ROS⇅, Although in most cases, MFs increased ROS levels in human, mouse, rat cells, and tissues, there are also studies showing that ROS levels were decreased or not affected by MFs.
*ETC↓, The electron transport chain (ETC) in the cell respiration process at mitochondrial membrane is the main source of ROS production. During ATP synthesis, electrons may escape from the ETC
Dose↝, Electromagnetic fields (EMFs)-induced ROS level changes were time-dependent.
Dose↝, 50 Hz 2 mT ELF-EMF increased ROS after 2/6 h exposure, but returned to normal level after 12/24 h

2039-

PB,

TXNIP mediates the differential responses of A549 cells to sodium butyrate and sodium 4‐phenylbutyrate treatment

in-vitro,

Lung,

A549

in-vitro,

Nor,

HEK293

TXNIP↑, TXNIP was strongly induced by NaBu (30‐ to 40‐fold mRNA) but was only slightly induced by 4PBA (two to fivefold) in A549 cells.
Casp3↑, Additionally, A549 cells that were treated with these showed changes in glucose consumption, caspase 3/7 activation and histone modifications, as well as enhanced mitochondrial superoxide production
Casp7↑,
mt-ROS↑, as well as enhanced mitochondrial superoxide production. 4PBA induced a mitochondrial superoxide‐associated cell death, while NaBu did so mainly through a TXNIP‐mediated pathway
GlucoseCon↓, both NaBu and 4PBA can decrease the glucose consumption compared to the vehicle control
TumCP↓, both inhibitors can prevent A549 cell proliferation and induce cell death
TumCD↑,
IGF-2↑, NaBu and 4PBA induce insulin‐like growth factor 2 (somatomedin A) (IGF2) 31‐fold and 48‐fold (Fig. S1 and S2), respectively.
HDAC↓, As inhibitors of HDACs, NaBu and 4PBA are capable of changing histone modifications
ROS⇅, suggests that 4PBA‐induced ROS generation might be a cell type or concentration dependent

1685-

PBG,

Antitumor Activity of Chinese Propolis in Human Breast Cancer MCF-7 and MDA-MB-231 Cells

in-vitro,

BC,

MCF-7

25, 50, 100, and 200 μg/mL

ANXA7↑, Exposure to EECP significantly increased ANXA7 expression and ROS level
ROS↑,
NF-kB↓, NF-κB p65 level and mitochondrial membrane potential were depressed by EECP dramatically.
MMP↓,
selectivity↑, Interestingly, EECP had little or small cytotoxicity on normal human umbilical vein endothelial cells (HUVECs)
Dose⇅, propolis plays a dual role on ROS depending on concentrations: at high concentration, it exerts a prooxidant effect; at low concentration, it can also act as an antioxidant by scavenging free radicals.
ROS⇅,

1666-

PBG,

Molecular and Cellular Mechanisms of Propolis and Its Polyphenolic Compounds against Cancer

Review,

Var,

ChemoSen↑, Ingredients from propolis also ”sensitize“ cancer cells to chemotherapeutic agents
TumCCA↑, cell-cycle arrest and attenuation of cancer cells proliferation
TumCP↓,
Apoptosis↑,
antiOx↓, behave as antioxidants against peroxyl and hydroxyl radicals,
ROS↑, whereas prooxidant activity is observed in the presence of Cu2+.
COX2↑, Propolis, as well as flavonoids derived from propolis, such as galangin, is a potent COX-2 inhibitor
ER(estro)↓, Some flavonoids from propolis, such as galangin, genistein, baicalein, hesperetin, naringenin, and quercetin, suppressed the proliferation of an estrogen receptor (ER)
cycA1/CCNA1↓, by suppressing expressions of cyclin A, cyclin B, and Cdk2 and by stopping proliferation at the G2 phase, by increasing levels of p21 and p27 proteins, and through the inhibition of telomerase reverse transcriptase (hTERT),
CycB/CCNB1↓,
CDK2↓,
P21↑,
p27↑,
hTERT/TERT↓, leukemia cells, propolis successfully reduced hTERT mRNA expression
HDAC↓, by suppressing expressions of cyclin A, cyclin B, and Cdk2 and by stopping proliferation at the G2 phase, by increasing levels of p21 and p27 proteins, and through the inhibition of telomerase reverse transcriptase (hTERT),
ROS⇅, Mexican propolis, demonstrated both pro- and anti-inflammatory effects, depending on the dose applied
Dose?, Mexican propolis, demonstrated both pro- and anti-inflammatory effects, depending on the dose applied
ROS↓, By scavenging free radicals, chelating metal ions (mainly iron and copper), and stimulating endogenous antioxidant defenses, propolis and its flavonoids directly attenuate the generation of ROS
ROS↑, Romanian propolis [99], exhibits prooxidant properties at high concentrations, by mobilizing endogenous copper ions and DNA-associated copper in cells.
DNAdam↑, propolis, i.e., its polyphenolic components, may induce DNA damage in the presence of transition metal ions.
ChemoSen↑, Algerian propolis + doxorubicin decreased cell viability, prevented cell proliferation and cell cycle progression, induced apoptosis by activating caspase-3 and -9 activities, and increased the accumulation of chemotherapeutic drugs in MDA-MB-231 cel
LOX1↓, propolis components inhibited the LOX pathway
lipid-P↓, Croatian propolis improved psoriatic-like skin lesions induced by irritant agents n-hexyl salicylate or di-n-propyl disulfide by decreasing the extent of lipid peroxidation
NO↑, Taken together, propolis may increase the phagocytic index, NO production, and production of IgG antibodies
Igs↑,
NK cell↑, propolis treatment for 3 days increases the cytotoxic activity of NK cells against murine lymphoma.
MMPs↓, extracts of propolis containing artepillin C and CAPE decreased the formation of new vessels and expression of MMPs and VEGF in various cancer cells
VEGF↓,
Hif1a↓, Brazilian green propolis inhibit the expression of the hypoxia-inducible factor-1 (HIF-1) protein and HIF-1 downstream targets such as glucose transporter 1, hexokinase 2, and VEGF-A
GLUT1↓,
HK2↓,
selectivity↑, Portuguese propolis was selectively toxic against malignant cells.
RadioS↑, propolis increased the lifespan of mice that received the radiotherapy with gamma rays
GlucoseCon↓, Portuguese propolis disturbed the glycolytic metabolism of human colorectal cancer cells, as evidenced by a decrease in glucose consumption and lactate production
lactateProd↓,
eff↓, Furthermore, different pesticides or heavy metals can be found in propolis, which can cause unwanted side effects.
*BioAv↓, Due to the low bioavailability and clinical efficacy of propolis and its flavonoids, their biomedical applications remain limited.

3251-

PBG,

The Antioxidant and Anti-Inflammatory Effects of Flavonoids from Propolis via Nrf2 and NF-κB Pathways

Review,

AD,

Review,

Diabetic,

Review,

Var,

in-vitro,

Nor,

H9c2

To induce oxidative stress, H9c2 cells were exposed to multiple H2O2 concentrations (0, 50, 100, 150, 200, and 250 μM) for 1 h

*antiOx↑, In this study, the antioxidant and anti-inflammatory effects of the main flavonoids of propolis (chrysin, pinocembrin, galangin, and pinobanksin) and propolis extract were researched.
*Inflam↓,
*ROS↓, ROS levels were decreased; SOD and CAT activities were increased; and the expression of HO-1 protein was increased by chrysin.
*SOD↑,
*Catalase↑,
*HO-1↑,
*NO↓, The results demonstrated that NO (Nitric Oxide), NOS (Nitric Oxide Synthase), and the activation of the NF-κB signaling pathway were inhibited in a dose-dependent manner
*NOS2↓,
*NF-kB↓,
*NRF2↑, it is possible that phytochemicals activate the Nrf2 pathway and inhibited the NF-κB (Nuclear factor kappa B) pathway.
*hepatoP↑, propolis has antioxidant, anti-inflammatory, anti-cancer, anti-bacterial, and hepatoprotective properties.
*MDA↓, chrysin reduced the cytotoxicity, MDA levels, and lysosomal and mitochondrial damage induced by AlP in a dose-dependent manner and increased the GSH activity induced by AlP i
*mtDam↓,
*GSH↑,
*p65↓, Similarly, galangin at 15, 30, and 60 mg/kg inhibited the expression of NF-κB p65, NOS, TNF-α, and IL-1β in a dose-dependent manner
*TNF-α↓,
*IL1β↓,
*NRF2↑, Nrf2 translocation from the cytoplasm to the nucleus was up-regulated (chrysin range of 5 μM–10 μM, pinocembrin range of 5 μM–40 μM, and propolis-extract range of 5 μg/mL–40 μg/mL)
*NRF2↓, and then down-regulated (chrysin range of 15 μM–25 μM, pinocembrin range of 40 μM–60 μM, and propolis-extract range of 40 μg/mL–100 μg/mL) following treatments with chrysin, pinocembrin, and propolis extract
*ROS⇅, Secondly, chrysin, pinocembrin, galangin, pinobanksin, and propolis extract exhibited antioxidant and pro-oxidant effects in a dose-dependent manner.
*BioAv↓, bioavailability values of galangin and chrysin in propolis extracts were determined in a study, and they were at 7.8% and 7.5%, respectively
*BioAv↑, Moreover, propolis extract has a higher bioavailability than single-flavonoid standards

1772-

PG,

Propyl gallate decreases the proliferation of Calu-6 and A549 lung cancer cells via affecting reactive oxygen species and glutathione levels

in-vitro,

Lung,

Calu-6

PG (100–1,600 μM)

in-vitro,

Lung,

A549

ROS⇅, PG either increased or decreased ROS levels, including O2˙− and ˙OH, depending on the incubation doses and times of 1 or 24 h.
TumCP↓, PG dose-dependently decreased the proliferation of Calu-6 and A549 lung cancer cells, which was related to changes in ROS levels and the depletion of GSH.
GSH↓,

66-

QC,

Emerging impact of quercetin in the treatment of prostate cancer

Review,

Pca,

CycB/CCNB1↓, quercetin has a role in the reduction of cyclin B1 and CDK1 levels,
CDK1↓,
EMT↓, quercetin suppresses epithelial to mesenchymal transition (EMT) and cell proliferation through modulation of Sonic Hedgehog signaling pathway
PI3K↓, Inhibitory effects of quercetin on other pathways such as PI3K, MAPK and WNT pathways have also been validated in cervical cancer
MAPK↓,
Wnt/(β-catenin)↓, wnt
PSA↓,
VEGF↓,
PARP↑,
Casp3↑,
Casp9↑,
DR5↑,
ROS⇅,
Shh↓,
P53↑, figure 1
P21↑, quercetin regulates p21 expression
EGFR↓,
TumCCA↑, quercetin has cell-specific anti-proliferative impacts via stimulation of cell cycle arrest at the G1 stage.
ROS↑, quercetin has been shown to suppress carcinogenesis through various mechanisms including affecting cell proliferation, production of reactive oxygen species and expression of miR-21
miR-21↓,
TumCP↓,
selectivity↑, In breast cancer cells, quercetin inhibits cell proliferation without exerting any cytotoxic impact on normal breast epithelium
PDGF↓, figure 1
EGF↓,
TNF-α↓,
VEGFR2↓,
mTOR↓,
cMyc↓,
MMPs↓,
GRP78/BiP↑,
CHOP↑,

38-

QC,

Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways

in-vitro,

Pca,

DU145

 (PI3K/Akt down regulate)

in-vitro,

Pca,

PC3

 (PI3K/Akt up regulate)

ROS⇅, LNCaP and PC-3 cells that have an oxidative cellular environment showed ROS quenching after quercetin treatment while DU-145 showed rise in ROS levels despite having a highly reductive environment.
GSH↓,
PI3K/Akt⇅, DU-145↓, PC3↑

87-

QC,

Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways

in-vitro,

Pca,

LNCaP

 5, 10, 20, 40, 80, 160 uM

 <span class="wphighlight">ROS</span>↓

in-vitro,

Pca,

DU145

 <span class="wphighlight">ROS</span>↑

in-vitro,

Pca,

PC3

 <span class="wphighlight">ROS</span>↓

ROS⇅,
BAX↑, quercetin treatment increased BAX levels
PUMA⇅,
β-catenin/ZEB1↓,
Shc↓,
TAp63α↑, DU-145
MAPK↑, DU-145 DU-145
p‑p42↑,
p‑p44↑,
BIM↑, . In androgen-independent PCa cells with mutated p53 (DU-145), quercetin treatment increases cellular BAX levels whereas PUMA and BIM increased

895-

QC,

Theoretical Study of the Antioxidant Activity of Quercetin Oxidation Products

Analysis,

Var,

ROS⇅,

897-

QC,

Anti- and prooxidant effects of chronic quercetin administration in rats

in-vivo,

Nor,

Rats

*MDA↓, in rat livers (decrease was more pronounced in vitamin E-deprived rats)
*GSH⇅, in liver
*ROS⇅, results suggest that quercetin may act not only as an antioxidant, but also as a prooxidant in rats.

903-

QC,

Potential toxicity of quercetin: The repression of mitochondrial copy number via decreased POLG expression and excessive TFAM expression in irradiated murine bone marrow

in-vivo,

NA,

mice

ROS⇅, antioxidant and prooxidant effects largely relates to its dose

4787-

QC,

Quercetin: A Phytochemical with Pro-Apoptotic Effects in Colon Cancer Cells

Review,

CRC,

Inflam↓, quercetin, has been shown to have anti-inflammatory and anti-carcinogenic effects
AntiCan↑,
Apoptosis↑, nduce apoptosis via the mitochondrial apoptotic pathway by causing changes in the mitochondrial membrane potential.
MMP↓,
P53↑, quercetin also induces apoptosis through the activation of p53, increasing the expression of pro-apoptotic molecules such as Bax, caspase-3, caspase-9, and inhibition of anti-apoptotic proteins such as Bcl-2
BAX↑,
Casp3↑,
Casp9↑,
Bcl-2↓,
NF-kB↓, Quercetin might exert anti-inflammatory properties by suppressing NF-kB translocation and the expression of pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), IL-1b
IL6↓,
IL1β↓,
*antiOx↑, Quercetin is a powerful antioxidant and lipid peroxidation inhibitor, thanks to its catechol and hydroxyl group configuration, its capacity to scavenge free radicals and to bind metal ions.
*lipid-P↓,
*ROS↓,
MAPK↓, Quercetin has the potential to exert an anti-cancer effect by inhibiting important signaling pathways in carcinogenesis such as MAPK, JAK-STAT, and PI3K-Akt.
JAK↓,
STAT↓,
PI3K↓,
Akt↓,
chemoP↑, Quercetin is a lipophilic compound which can cross the cell membrane and activate multiple intracellular signaling pathways in chemoprevention
ROS⇅, dual function as a pro-oxidant or anti-oxidant. Oxidative stress caused by ROS species causes DNA damage and mutation development.
DNAdam↑,
ChemoSen↝, Therefore, it is thought that quercetin can be applied as a supplement in cancer treatment in combination with existing chemotherapies.

3344-

QC,

Quercetin induced ROS production triggers mitochondrial cell death of human embryonic stem cells

in-vitro,

Nor,

hESC

mt-ROS↑, mitochondrial reactive oxygen species (ROS), strongly induced by QC in human embryonic stem cells (hESCs) but not in human dermal fibroblasts (hDFs), were responsible for QC-mediated hESC’s cell death.
selectivity↑,
P53↑, . Increased p53 protein stability and subsequent mitochondrial localization by QC treatment triggered mitochondrial cell death only in hESCs.
ROS⇅, QC acts either as a pro-oxidant to be cytotoxic to cancer cells with active proliferation [8, 10] or as an anti-oxidant [9], depending on the cell models,

3350-

QC,

Quercetin and the mitochondria: A mechanistic view

Review,

NA,

*antiOx↑, antioxidant and anti-inflammatory properties
*Inflam↓,
*NRF2↑, Quercetin is able to activate the master regulator nuclear factor erythroid 2-related factor 2 (Nrf2)
ROS⇅, That is, as a free radical-scavenging antioxidant, quercetin protects cells against DNA damage induced by reactiveoxygen species (ROS), but the oxidized quercetin intermediates (see above) can then react with glutathione (GSH) thereby lowering GSH
*NRF2↑, 10uM (24 h) Mouse primary hepatocytes Activation of Nrf2; ↑HO-1 levels; ↑expression of PPARÎ± and PGC-1Î±
*HO-1↑,
*PPARα↑,
*PGC-1α↑,
*SIRT1↑, Rat hippocampus ↑ SIRT1, PGC-1Î±, NRF-1, and TFAM levels; ATP levels;
*ATP↑,
ATP↓, L1210 and P388 leukemia cells (Suolinna et al., 1975). At least in part, the authors attributed the pro-apoptotic effect of quercetin in these cell lines to its capacity to inhibit ATP synthase, causing a decrease in ATP content.
ERK↓, downregulation of ERK1/2 by quercetin (50-100 uM for 24 or 48 h, combined or not with resveratrol
cl‑PARP↑, NCaP cells ↑PARP cleavage ↑ Caspase-9, caspase-8, and caspase-3 activities
Casp9↑,
Casp8↑,
BAX↑, MDA-MB-231 cells ↑Bax levels, ↓MMP, ↑cytochrome c release, ↑caspase-9 and caspase-3 activities
MMP↓,
Cyt‑c↑,
Casp3↑,
HSP27↓, T98G cells: ↓Hsp27 and Hsp72 contents, ↓Ras and Raf level
HSP72↓,
RAS↓,
Raf↓,

104-

RES,

QC,

Resveratrol and Quercetin in Combination Have Anticancer Activity in Colon Cancer Cells and Repress Oncogenic microRNA-27a

in-vitro,

Colon,

HT-29

 18.7 ug/mL

Casp3↑, RQ also induced caspase-3-cleavage (2-fold) and increased PARP cleavage.
PARP↑,
survivin↓, RQ also decreased expression of survivin protein
miR-27a-3p↓, RQ decreased microRNA-27a (miR-27a) and induced zinc finger protein ZBTB10
Sp1/3/4↓, RQ treatment decreased the expression of Sp1, Sp3, and Sp4 mRNA and this was accompanied by decreased protein expression
ZBTB10↑,
ROS⇅, RQ slightly induced the generation of ROS at low concentrations (0–10 μg/mL) whereas at concentrations higher than 20 μg/mL generation of ROS was signiﬁcantly reduced
TAC↑, RQ decreased the generation of reactive oxygen species (ROS) by up to 2.25-fold and increased the antioxidant capacity by up to 3-fold in HT-29 cells (3.8-60 μg/mL)
tumCV↓, HT-29 cell viability (Fig. 2A) was significantly decreased by RQ in a dose- and time-dependent manner

3030-

RosA,

Anticancer Activity of Rosmarinus officinalis L.: Mechanisms of Action and Therapeutic Potentials

Review,

Var,

ROS⇅, could defend against their oxidative damage of DNA, proteins, and lipids [15], although, as subsequently observed, the derivatives of rosemary are, in some conditions, capable of inducing a cytotoxic effect precisely through the release of ROS
*NRF2↑, scavenging action, RE has also been stated to control intracellular antioxidant systems, by stimulating the activation of nuclear transcription factor (Nrf)2 target genes
*GSH↑, augmenting the glutathione level, with an increase in its reduced form (GSH) compared with that of its oxidized form (GSSG)
HDAC2↓, Similar to the effects of SAHA, RA reduced cell growth and blocked cancer spheroid formation, caused the apoptosis of tumor cells, and blocked the expression of HDAC2

2555-

SFN,

Chemopreventive functions of sulforaphane: A potent inducer of antioxidant enzymes and apoptosis

Review,

Var,

chemoPv↑, induction of Metallothioneins MT by sulforaphane as a strategy for achieving chemoprevention and chemoprotection.
HDAC↓, sulforaphane supplementation resulted in slower tumor growth and significant histone deacetylase (HDAC) inhibition in the xenografts,
TumCCA↑, HDAC inhibition represents a novel chemoprevention mechanism by which sulforaphane can promote cell cycle arrest and apoptosis.
Apoptosis↑,
Mets↑, induction of Metallothioneins MT by sulforaphane
*NRF2↑, We have shown that sulforaphane can activate Nrf2 ...suggesting that increased expression of Nrf2 protein may play a key role in sulforaphane-induced MT gene activation.
ROS⇅, exposure to high concentrations of sulforaphane might generate an oxidant signal to stimulate caspase 3 pathway activation and DNA fragmentation, leading to cell death.

2553-

SFN,

Mechanistic review of sulforaphane as a chemoprotective agent in bladder cancer

Review,

Bladder,

antiOx↓, SFN is a bioactive compound with both antioxidant and anti-inflammatory properties.
Inflam↓,
ChemoSen↑, SFN also improves the efficacy of certain traditional chemotherapeutic regimens
ROS⇅, A lesser established mechanism proposed by Li, et al. is that SFN induces mild increases ROS, leading to transcription factor EB (TFEB) activation. TFEB plays a role in activating antioxidant response elements and...ultimately reducing overall oxidat
*NRF2↑, SFN treatment increased Nrf2 and, therefore, glutathione levels
*GSH↑,
Catalase↑, Cancer cells treated with SFN showed higher catalase levels, heme oxygenase 1, and NAD(P)
HO-1↑,
NAD↑,
chemoP↑, Taken together, these studies provide strong evidence for the chemoprotective nature of SFN in various human epithelial cancers, including those of the bladder.

2127-

TQ,

Therapeutic Potential of Thymoquinone in Glioblastoma Treatment: Targeting Major Gliomagenesis Signaling Pathways

Review,

GBM,

chemoP↑, TQ can specifically sensitize tumor cells towards conventional cancer treatments and minimize therapy-associated toxic effects in normal cells
ChemoSen↑,
BioAv↑, TQ adds another advantage in overcoming blood-brain barrier
PTEN↑, TQ upregulates PTEN signaling [72, 73], interferes with PI3K/Akt signaling and promotes G(1) arrest, downregulates PI3K/Akt
PI3K↓,
Akt↓,
TumCCA↓,
NF-kB↓, and NF-κB and their regulated gene products, such as p-AKT, p65, XIAP, Bcl-2, COX-2, and VEGF, and attenuates mTOR activity
p‑Akt↓,
p65↓,
XIAP↓,
Bcl-2↓,
COX2↓,
VEGF↓,
mTOR↓,
RAS↓, Studies in colorectal cancer have demonstrated that TQ inhibits the Ras/Raf/MEK/ERK signaling
Raf↓,
MEK↓,
ERK↓,
MMP2↓, Multiple studies have reported that TQ downregulates FAC and reduces the secretion of MMP-2 and MMP-9 and thereby reduces GBM cells migration, adhesion, and invasion
MMP9↓,
TumCMig↓,
TumCI↓,
Casp↑, caspase activation and PARP cleavage
cl‑PARP↑,
ROS⇅, TQ is hypothesized to act as an antoxidant at lower concentrations and a prooxidant at higher concentrations depending on its environment [89]
ROS↑, In tumor cells specifically, TQ generates ROS production that leads to reduced expression of prosurvival genes, loss of mitochondrial potential,
MMP↓,
eff↑, elevated level of ROS generation and simultaneous DNA damage when treated with a combination of TQ and artemisinin
Telomerase↓, inhibition of telomerase by TQ through the formation of G-quadruplex DNA stabilizer, subsequently leads to rapid DNA damage which can eventually induce apoptosis in cancer cells specifically
DNAdam↑,
Apoptosis↑,
STAT3↓, TQ has shown to suppress STAT3 in myeloma, gastric, and colon cancer [86, 171, 172]
RadioS↑, TQ might enhance radiation therapeutic benefit by enhancing the cytotoxic efficacy of radiation through modulation of cell cycle and apoptosis [31]

2135-

TQ,

Thymoquinone induces heme oxygenase-1 expression in HaCaT cells via Nrf2/ARE activation: Akt and AMPKα as upstream targets

in-vitro,

Nor,

HaCaT

TQ (1, 5,
10, 20 lM) for 6 h

skin cells

*HO-1↑, TQ induced the expression of HO-1 in HaCaT/ Cells treated with TQ (1, 5, 10, 20 lM) for 6 h induced the expression of HO-1 protein. maximal induction observed until 12 h and then returned to basal level time thereafter
*NRF2↑, Treatment with TQ increased the localization of nuclear factor (NF)-erythroid2-(E2)-related factor-2 (Nrf2) in the nucleus and elevated the antioxidant response element (ARE)-reporter gene activity.
*e-ERK↑, TQ induced the phosphorylation of extracellular signal-regulated kinase (ERK), Akt and cyclic AMP-activated protein kinase-α (AMPKα).
*e-Akt↑,
*AMPKα↑,
*ROS⇅, Treatment of HaCaT cells with TQ resulted in a concentration-dependent increase in the intracellular accumulation of ROS (most occurs at 20uM concentration -see figure 5A) (later it drops the ROS)
*eff↓, pretreatment with N-acetyl cysteine (NAC) abrogated TQ-induced ROS accumulation, Akt and AMPKα activation, Nrf2 nuclear localization, the ARE-luciferase activity, and HO-1 expression in HaCaT cells
*tumCV∅, does not change much 1-20uM of TQ (normal cells) see figure 1A

2084-

TQ,

Thymoquinone, as an anticancer molecule: from basic research to clinical investigation

Review,

Var,

*ROS↓, An interesting study reported that thymoquinone is actually a potent apoptosis inducer in cancer cells, but it exerts antiapoptotic effect through attenuating oxidative stress in other types of cell injury
*chemoPv↑, antioxidant activity of thymoquinone is responsible for its chemopreventive activities
ROS↑, other studies reported thymoquinone induce apoptosis in cancer cells by exerting oxidative damage
ROS⇅, Another hypothesis states that thymoquinone acts as an antioxidant at lower concentrations and a prooxidant at higher concentrations
MUC4↓, Torres et al. [17] revealed that thymoquinone down-regulates glycoprotein mucin 4 (MUC4)
selectivity↑, thymoquinone was found to inhibit DNA synthesis, proliferation, and viability of cancerous cells, such as LNCaP, C4-B, DU145, and PC-3, but not noncancerous BPH-1 prostate epithelial cells [20].
AR↓, Down-regulation of androgen receptor (AR) and cell proliferation regulator E2F-1 was indicated as the mechanism behind thymoquinone’s action in prostate cancer
cycD1/CCND1↓, expression of STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor (VEGF), was inhibited by thymoquinone, which ultimately increased apoptosis and killed cancer cells
Bcl-2↓,
Bcl-xL↓,
survivin↓,
Mcl-1↓,
VEGF↓,
cl‑PARP↑, induction of the cleavage of poly-(ADP-ribose) polymerase (PARP
ROS↑, In ALL cell line CEM-ss, thymoquinone treatment generated reactive oxygen species (ROS) and HSP70
HSP70/HSPA5↑,
P53↑, thymoquinone can induce apoptosis in MCF-7 breast cancer cells via the up-regulation of p53 expression
miR-34a↑, Thymoquinone significantly increased the expression of miR-34a via p53, and down-regulated Rac1 expression
Rac1↓,
TumCCA↑, In hepatic carcinoma, thymoquinone induced cell cycle arrest and apoptosis by repressing the Notch signaling pathway
NOTCH↓,
NF-kB↓, Evidence revealed that thymoquinone suppresses tumor necrosis factor (TNF-α)-induced NF-kappa B (NF-κB) activation
IκB↓, consequently inhibits the activation of I kappa B alpha (I-κBα) kinase, I-κBα phosphorylation, I-κBα degradation, p65 phosphorylation
p‑p65↓,
IAP1↓, down-regulated the expression of NF-κB -regulated antiapoptotic gene products, like IAP1, IAP2, XIAP Bcl-2, Bcl-xL;
IAP2↑,
XIAP↓,
TNF-α↓, It also inhibited monocyte chemo-attractant protein-1 (MCP-1), TNF-α, interleukin (IL)-1β and COX-2, ultimately reducing the NF-κB activation in pancreatic ductal adenocarcinoma cells
COX2↓,
Inflam↓, indicating its role as an inhibitor of proinflammatory pathways
α-tubulin↓, Without affecting the tubulin levels in normal human fibroblast, thymoquinone induces degradation of α and β tubulin proteins in human astrocytoma U87 cells and in T lymphoblastic leukaemia Jurkat cells, and thus exerts anticancer activity
Twist↓, thymoquinone treatment inhibits TWIST1 promoter activity and decreases its expression in breast cancer cell lines; leading to the inhibition of epithelial-mesenchymal transition (EMT)
EMT↓,
mTOR↓, thymoquinone also attenuated mTOR activity, and inhibited PI3K/Akt signaling in bladder cancer
PI3K↓,
Akt↓,
BioAv↓, Thymoquinone is chemically hydrophobic, which causes its poor solubility, and thus bioavailability. bioavailability of thymoquinone was reported ~58% with a lag time of ~23 min
ChemoSen↑, Some studies revealed that thymoquinone in combination with other chemotherapeutic drugs can show better anticancer activities
BioAv↑, Thymoquinone-loaded liposomes (TQ-LP) and thymoquinone loaded in liposomes modified with Triton X-100 (XLP) with diameters of about 100 nm were found to maintain stability, improve bioavailability and maintain thymoquinone’s anticancer activity
PTEN↑, Thymoquinone also induces apoptosis by up-regulating PTEN
chemoPv↑, A recent study showed that thymoquinone can potentiate the chemopreventive effect of vitamin D during the initiation phase of colon cancer in rat model
RadioS↑, thymoquinone also mediates radiosensitization and cancer chemo-radiotherapy
*Half-Life↝, Thymoquinone-loaded nanostructured lipid carrier (TQ-NLC) has been developed to improve its bioavailability (elimination half-life ~5 hours)
*BioAv↝, calculated absolute bioavailability of thymoquinone was reported ~58% with a lag time of ~23 min by Alkharfy et al.

2100-

TQ,

Dual properties of Nigella Sative: Anti-oxidant and Pro-oxidant

Review,

NA,

ROS⇅, Pubmed data indicated that NS has both anti-oxidant and pro-oxidant properties in different cell types
*antiOx↑, NS acts as an anti-oxidant by scavenging ROS [4]. It can ameliorate ischemic reperfusion injury conditions and attenuated ROS in heart [5] intestine [6] and kidney [7]
*SOD↑, improved the activities of various enzymes like superoxide dismutase [SOD] and myeloperoxidase (MPO)
*MPO↑,
*neuroP↑, NS oil has been found to be neuroprotective against oxidative stress in epileptogenesis, pilocarpine-induced seizures [25] and opioid tolerance
*chemoP↑, Anticancer drugs leave toxic effect due to over-production of ROS. NS oil or TQ can potentially up-regulate anti-oxidant mechanisms caused by anticancer drug
*radioP↑, NS seed extracts can protect normal tissue from oxidative damage during radiotherapy of cancer patients [35,36]
NF-kB↓, TQ has been shown to exhibit down regulation of NF-κB expression in lung cancer cells
IAP1↓, Anti-apoptotic (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc) and angiogenic genes (matrix metalloproteinase-9 orMMP-9) and vascular endothelial growth factor (VEGF) were down-regulated
IAP2↓,
XIAP↓,
Bcl-xL↓,
survivin↓,
COX2↓,
MMP9↓,
VEGF↓,
ROS↑, TQ causes release of ROS in ABC cells which in turn inhibits NF-κB activity
P21↑, TQ up regulated the expression of p21 and down regulated the histone deacetylase (HDAC) activity and induced histone hyperacetylation causing induction of apoptosis and inhibition of proliferation in pancreatic cancer cell
HDAC↓,
GSH↓, TQ was found to decrease glutathione (GSH) levels in prostate cancer cells resulting in up-regulated expression of GADD45 alpha (growth arrest and DNA damage inducible gene) and AIF
GADD45A↑,
AIF↑,
STAT3↓, TQ suppressed the STAT 3; the signal transducer and activator of transcription which is involved in the abnormal transformation of a number of human malignancies [53].

3397-

TQ,

Thymoquinone: A Promising Therapeutic Agent for the Treatment of Colorectal Cancer

Review,

CRC,

6-112uM (table 1)

ChemoSen↑, TQ can be used synergistically with chemotherapeutic agents to enhance their anticancer effects and to influence the expression of signaling pathways and other genes important in cancer development.
*Half-Life↝, These parameters remained associated with an elimination half-life (t1/2) of 63.43 ± 10.69 and 274.61 ± 8.48 min for intravenous and oral administration, respectively
*BioAv↝, TQ is characterized by slow absorption, rapid metabolism, rapid elimination and low physicochemical stability, which limits its pharmaceutical applications
*antiOx↑, Biologically active compounds from Nigella sativa have been shown to have antioxidant, antimicrobial, anti-inflammatory, antidiabetic, hepatoprotective, antiproliferative, proapoptotic, antiepileptic and immunomodulatory activities,
*Inflam↓,
*hepatoP↑,
TumCP↓, TQ exerts tumorigenic effects in a variety of ways, including modulation of the epigenetic machinery and effects on proliferation, the cell cycle, apoptosis, angiogenesis, carcinogenesis and metastasis
TumCCA↑,
Apoptosis↑,
angioG↑,
selectivity↑, TQ has low toxicity to normal cells, as confirmed by several studies, including studies on normal mouse kidney cells, normal human lung fibroblasts and normal human intestinal cells.
JNK↑, activation of c-Jun N-terminal kinases (JNK) and p38, as well as the phosphorylation of nuclear factor-?B (NF-?B) and the reduction of extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) activi
p38↑,
p‑NF-kB↑,
ERK↓,
PI3K↓,
PTEN↑, showing higher expression of p21/p27/PTEN/BAX/Cyto-C/Casp-3
Akt↓, TQ has also been shown to downregulate the PI3K/PTEN/Akt/mTOR and WNT/?-catenin pathways, which are critical for tumorigenesis
mTOR↓,
EMT↓, downregulating the epithelial to mesenchymal transition (EMT) transcription factors twist-related protein 1 (TWIST1) and E-cadherin
Twist↓,
E-cadherin↓,
ROS⇅, TQ has been shown to act as an antioxidant at low concentrations. Higher concentrations, however, induce apoptosis of cancer cells through the induction of oxidative stress
*Catalase↑, Thymoquinone upregulates the expression of genes encoding specific enzymes, such as catalase, superoxide dismutase, glutathione reductase, glutathione S-transferase and glutathione peroxidase, whose role is to protect against reactive oxygen species
*SOD↑,
*GSTA1↑,
*GPx↑,
*PGE2↓, TQ has the ability to downregulate NF-?B, interleukin-1?, tumor necrosis factor alpha, cyclooxygenase-2 (COX-2,) matrix metalloproteinase 13 (MMP-13), prostaglandin E2 (PGE2), the interferon regulatory factor, which are associated with inflammation a
*IL1β↓,
*COX2↓,
*MMP13↓,
MMPs↓, Figure 2
TumMeta↓,
VEGF↓,
STAT3↓, TQ affects the induction of apoptosis in cancer cells by blocking the signal transducer and activator of transcription 3 (STAT3) signaling
BAX↑, upregulation of Bax and inhibition of Bcl-2 and B-cell lymphoma-extra large (Bcl-xl) expression, as well as activated caspase-9, -7 and -3, and induced cleavage of poly (ADP-ribose) polymerase (PARP).
Bcl-2↑,
Casp9↑,
Casp7↑,
Casp3↑,
cl‑PARP↑,
survivin↓, TQ also attenuated the expression of STAT3 target gene products, such as survivin, c-Myc and cyclin-D1, -D2, and enhanced the expression of cell cycle inhibitory proteins p27 and p21
cMyc↓,
cycD1/CCND1↓,
p27↑,
P21↑,
GSK‐3β↓, TQ reduces the levels of p-PI3K, p-Akt, p-glycogen synthase kinase 3 (p-GSK3?) and ?-catenin, thereby inhibiting downstream COX-2 expression, which in turn leads to a reduction in PGE2
β-catenin/ZEB1↓,
chemoP↑, results support the potential use of thymoquinone in colorectal cancer chemoprevention, as TQ is effective in protecting and treating the DMH-initiated early phase of colorectal cancer.

3427-

TQ,

Chemopreventive and Anticancer Effects of Thymoquinone: Cellular and Molecular Targets

ROS⇅, It appears that the cellular and/or physiological context(s) determines whether TQ acts as a pro-oxidant or an anti-ox- idant in vivo
Fas↑, Figure 2, cell death
DR5↑,
TRAIL↑,
Casp3↑,
Casp8↑,
Casp9↑,
P53↑,
mTOR↓,
Bcl-2↓,
BID↓,
CXCR4↓,
JNK↑,
p38↑,
MAPK↑,
LC3II↑,
ATG7↑,
Beclin-1↑,
AMPK↑,
PPARγ↑, cell survival
eIF2α↓,
P70S6K↓,
VEGF↓,
ERK↓,
NF-kB↓,
XIAP↓,
survivin↓,
p65↓,
DLC1↑, epigenetic
FOXO↑,
TET2↑,
CYP1B1↑,
UHRF1↓,
DNMT1↓,
HDAC1↓,
IL2↑, inflammation
IL1↓,
IL6↓,
IL10↓,
IL12↓,
TNF-α↓,
iNOS↓,
COX2↓,
5LO↓,
AP-1↓,
PI3K↓, invastion
Akt↓,
cMET↓,
VEGFR2↓,
CXCL1↓,
ITGA5↓,
Wnt↓,
β-catenin/ZEB1↓,
GSK‐3β↓,
Myc↓,
cycD1/CCND1↓,
N-cadherin↓,
Snail↓,
Slug↓,
Vim↓,
Twist↓,
Zeb1↓,
MMP2↓,
MMP7↓,
MMP9↓,
JAK2↓, cell proliferiation
STAT3↓,
NOTCH↓,
cycA1/CCNA1↓,
CDK2↓,
CDK4↓,
CDK6↓,
CDC2↓,
CDC25↓,
Mcl-1↓,
E2Fs↓,
p16↑,
p27↑,
P21↑,
ChemoSen↑, Such chemo-potentiating effects of TQ in different cancer cells have been observed with 5-fluorouracil in gastric cancer and colorectal cancer models

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

4468-

VitC,

SSE,

Selenium modulates cancer cell response to pharmacologic ascorbate

in-vivo,

GBM,

U87MG

in-vitro,

CRC,

HCT116

eff↓, In vivo, dietary selenium deficiency resulted in significant enhancement of ascorbate activity against glioblastoma xenografts
TumCD↑, pharmacologic ascorbate raises the serum ascorbate concentration into the millimolar range, a concentration at which ascorbate has been shown to kill cancer cells in vitro
ChemoSen↑, Pharmacologic ascorbate has been shown to synergize with multiple chemotherapeutic agents in animal models and is well-tolerated in human patients [1,4], motivating ongoing clinical trials.
ROS⇅, Indeed, the role of ascorbate as either a pro- or anti-oxidant has been suggested to depend on concentration, with low doses mitigating ROS and high doses generating them
DNAdam↑, H2O2 generation by ascorbate has been associated with DNA damage and subsequent PARP activation, which can deplete NAD and thereby inhibit glycolysis
PARP↑,
NAD↓,
Glycolysis↓,
Fenton↑, Ascorbate cytotoxicity depends on the intracellular labile iron pool (Fig 1a) [3,9]. One explanation for this phenomenon is that ascorbate-generated H2O2 causes toxicity through Fenton chemistry
lipid-P↑, extensive lipid peroxidation
eff↓, More generally, they establish dietary selenium depletion as a potential means of sensitizing tumors to free radical stress.
H2O2↑, High concentrations (mM) of ascorbate have been shown to generate H2O2 in vitro
other↝, Selenium supplementation has been shown to protect cells against iron-dependent cell death by supporting increased expression of selenoproteins, including GPX4, which defend against oxidative stress

Showing Research Papers: 1 to 49 of 49

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 49

Pathway results for Effect on Cancer / Diseased Cells:

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx↑, 8, mt-antiOx↑, 1, Catalase↑, 2, GPx↑, 1, GSH↑, 3, GSH⇅, 1, GSTA1↑, 1, HO-1↑, 3, lipid-P↓, 1, MDA↓, 2, MPO↑, 1, NRF2↓, 1, NRF2↑, 9, ROS↓, 5, ROS↑, 2, ROS⇅, 11, SOD↓, 1, SOD↑, 3,

Mitochondria & Bioenergetics ⓘ

ATP↑, 1, ETC↓, 2, MMP↑, 1, MMP⇅, 1, mtDam↓, 1, OCR↑, 2, PGC-1α↑, 1,

Core Metabolism/Glycolysis ⓘ

ECAR↓, 1, GlucoseCon↑, 1, Glycolysis↓, 1, LDL↓, 1, PPARα↑, 1, SIRT1↑, 1,

Cell Death ⓘ

Akt↓, 1, e-Akt↑, 1, iNOS↓, 1,

Kinase & Signal Transduction ⓘ

AMPKα↑, 1,

Transcription & Epigenetics ⓘ

tumCV∅, 1,

Proliferation, Differentiation & Cell State ⓘ

e-ERK↑, 1, mTOR↓, 1, PI3K↓, 1,

Migration ⓘ

MMP13↓, 1,

Angiogenesis & Vasculature ⓘ

Hif1a↓, 1, NO↓, 1, VEGF↓, 1,

Barriers & Transport ⓘ

BBB↑, 1,

Immune & Inflammatory Signaling ⓘ

COX2↓, 2, IL1β↓, 2, Inflam↓, 5, NF-kB↓, 1, p65↓, 1, PGE2↓, 1, TNF-α↓, 1,

Drug Metabolism & Resistance ⓘ

BioAv↓, 7, BioAv↑, 5, BioAv↝, 5, Dose?, 1, Dose⇅, 1, Dose↝, 1, eff↓, 1, eff↑, 1, eff↝, 1, Half-Life↓, 1, Half-Life↝, 2,

Clinical Biomarkers ⓘ

NOS2↓, 1,

Functional Outcomes ⓘ

chemoP↑, 1, chemoPv↑, 1, cognitive↑, 1, hepatoP↑, 2, memory↑, 1, neuroP↑, 2, radioP↑, 1, RenoP↑, 1, toxicity↓, 1, toxicity↑, 1, toxicity↝, 1,
Total Targets: 74

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species

10 Quercetin
7 Lycopene
6 Thymoquinone
3 Propolis -bee glue
2 Baicalein
2 Caffeic acid
2 Hydroxycinnamic-acid
2 Magnetic Fields
2 Resveratrol
2 Sulforaphane (mainly Broccoli)
1 alpha Linolenic acid
1 Anti-oxidants
1 Chemotherapy
1 Astaxanthin
1 beta-carotene(VitA)
1 Bromelain
1 Catechins
1 EGCG (Epigallocatechin Gallate)
1 Selenium
1 Honokiol
1 Methylene blue
1 Phenylbutyrate
1 Propyl gallate
1 Rosmarinic acid
1 Ursolic acid
1 Curcumin
1 Vitamin C (Ascorbic Acid)
1 Selenite (Sodium)

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#:%  Target#:275  State#:%  Dir#:3
  wNotes=on  sortOrder:rid,rpid

ROS Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Transcription & Epigenetics ⓘ

Protein Folding & ER Stress ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Hormonal & Nuclear Receptors ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Transcription & Epigenetics ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

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