Database Query Results : , , TrxR

TrxR, Thioredoxin Reductase: Click to Expand ⟱
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TrxR is an enzyme that reduces Trx, allowing it to perform its reducing functions. It has been shown to have a role in cancer cell metabolism and survival.
TrxR is overexpressed in various types of cancer, including breast, lung, colon, and prostate cancer.

- Part of the thioredoxin system, which regulates reactive oxygen species (ROS).
- TrxR is a major antioxidant systems that maintains the intracellular redox homeostasis.
- Inhibition causes an increase in ROS.
- TrxR is often upregulated in cancer cells to help manage increased oxidative stress, it is seen as a potential therapeutic target. Inhibiting TrxR may result in increased ROS in cancer cells, pushing them toward apoptosis.
- TrxR is a selenoprotein—meaning it incorporates the trace element selenium in the form of the amino acid selenocysteine.

TrxR inhibitors:
-Piperlongumine
-Withania somnifera (Ashwagandha)
-Parthenolide
-EGCG
-Curcumin
-Myricetin
-Gambogic Acid
Scientific Papers found: Click to Expand⟱
1900- AF,    Potential Anticancer Activity of Auranofin
- Review, Var, NA
TrxR↓, Auranofin inhibits the activity of thioredoxin reductase (TrxR
ROS↑, TrxR inhibition leads to an increase in cellular oxidative stress and induces apoptosis
Apoptosis↓,
TumCP↓, TrxR1 knockdown also inhibits cancer cell proliferation and DNA replication
eff↑, cytotoxicity of cisplatin is increased in cells expressing high levels of TrxR1 compared with cells expressing low levels

5459- AF,    Auranofin Induces Lethality Driven by Reactive Oxygen Species in High-Grade Serous Ovarian Cancer Cells
- in-vitro, Ovarian, NA
ROS↑, AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer.
TrxR↓, The primary mechanism of action of auranofin is to act as a pro-oxidative agent, increasing the production of reactive oxygen species (ROS) as a consequence of inhibiting the thioredoxin reductase (TrxR) anti-oxidant system
MMP↓, triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis.
Apoptosis↑,
eff↓, Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC).
Casp3↑, lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage
Casp7↑,
DNAdam↑,
eff↑, Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH.
GSH↓,
angioG↓, Additionally, auranofin has been shown to inhibit angiogenesis
ChemoSen↑, In this study, we identified the mechanisms of cytotoxicity induced by auranofin in HGSOC cells that have different clinical sensitivities to platinum.
cl‑PARP↑, the cleavage of poly-ADP ribose polymerase (PARP), and the polyubiquitination of proteins
eff↑, synergistic lethal interaction between auranofin and a second pro-oxidant agent, the glutathione (GSH) inhibitor, L-buthionine sulfoximine (L-BSO);

5466- AF,    Auranofin Inhibition of Thioredoxin Reductase in a Preclinical Model of Small Cell Lung Cancer
- in-vivo, Lung, NA
TrxR↓, TrxR is viable target in clinical trials using the anti-rheumatic drug, auranofin (AF).
Dose↝, 4 mg/kg once daily resulting in 18 μM gold in the plasma and 50% inhibition of TrxR activity in DMS273 SCLC tumors.
RadioS↑, effective inhibitor of TrxR and suggest that AF could be used as an adjuvant in radio-chemotherapy protocols to enhance therapeutic efficacy.
ChemoSen↑,
ROS↑, We also demonstrated the suppressing TrxR with AF can sensitize breast cancer stem cells to ROS induced differentiation and cytotoxicity.16
Diff↑,
toxicity↓, These results suggest that this dosing regimen is nontoxic to kidneys, liver, and bone marrow as well as demonstrating a trend toward a survival advantage in tumor bearing animals.

5465- AF,    The Thioredoxin Reductase Inhibitor Auranofin Suppresses Pulmonary Metastasis of Osteosarcoma, But Not Local Progression
- in-vitro, OS, NA
TrxR↓, Auranofin (AUR), a thioredoxin reductase (TXNRD) inhibitor, shows anticancer activity against several cancers.
ROS↑, AUR induced apoptosis of OS cells via the oxidative stress-MAPK-Caspase 3 pathway, and suppressed the migration of OS cells.
TumCMig↓,

5464- AF,    Inhibition of Thioredoxin-Reductase by Auranofin as a Pro-Oxidant Anticancer Strategy for Glioblastoma: In Vitro and In Vivo Studies
- vitro+vivo, GBM, NA
TrxR↓, Gold derivatives are irreversible inhibitors of TrxR. Among them, auranofin (AF), a selective TrxR inhibitor, has proven its effectiveness as a drug for the treatment of rheumatoid arthritis
BioAv↓, further clinical application of AF could be challenging due to the low solubility and insufficient delivery to glioblastoma.
ROS↑, The inhibition of TrxR1, which leads to increased ROS levels, is currently recognized as the primary mechanism of AF cytotoxicity [106]. In vitro studies have also shown that AF inhibits other thioredoxin reductases, such as TrxR2 and TrxR3
eff↝, The literature indicates that not all cancer tumors exhibit the same level of TrxR expression, affecting their sensitivity to AF.
TET1?, AF was shown to inhibit TET1 in T-ALL models
BioAv↑, Encapsulating AF into nanoparticles or combining it with other pharmaceutical excipients can minimize its potential adverse effects, preserve its interaction with serum proteins, and result in greater stability.

5463- AF,    Will Auranofin Become a Golden New Treatment Against COVID-19?
- Review, Covid, NA
IL6↓, This gold(I) compound has anti-inflammatory properties because it reduces IL-6 expression via inhibition of the NF-κB-IL-6-STAT3 signaling pathway.
NF-kB↓,
ATF2↓,
TrxR↓, by inhibiting redox enzymes such as thioredoxin reductase, auranofin increases cellular oxidative stress and promotes apoptosis.
ROS↑,
Apoptosis↑,
IL6↓, Recently, it was reported that auranofin reduced by 95% SARS-CoV-2 RNA in infected human cells in vitro and decreased SARS-CoV-2-induced cytokine expression, including IL-6.
Dose↑, After 14 days of treatment with 21 mg/day auranofin, plasma gold concentration reached 1.18 µM to 2.21 µM ‘auranofin equivalent’

5462- AF,    Repurposing Auranofin for Oncology and Beyond: A Brief Overview of Clinical Trials as Mono- and Combination Therapy
- Review, Var, NA
AntiTum↑, Over the last twenty years, AF has also been repurposed as an antitumor, antiviral, and antibacterial drug.
Bacteria↓,
TrxR↓, ability to inhibit thioredoxin reductase (TrxR) and disrupt redox homeostasis, leading to selective cytotoxicity in cancer cells.
ChemoSen↑, synergistic effects observed when AF is combined with chemotherapeutics, targeted therapies, or immune modulators.
Dose↝, Patients received AF orally twice daily on days 1–28. atients received AF orally, 6 mg in the morning and 6 mg in the evening.
ROS↑, AF induces oxidative stress and apoptosis in cancer cells by disrupting redox homeostasis, while sirolimus inhibits mTOR signaling.
Apoptosis↑,
mTOR↓,

5461- AF,    Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells
- in-vitro, BC, MDA-MB-231 - in-vitro, Nor, MCF10
Paraptosis↑, We show here that 4~5 µM AF induces paraptosis, a non-apoptotic cell death mode characterized by dilation of the endoplasmic reticulum (ER) and mitochondria, in breast cancer cells.
ER Stress↑,
TrxR↓, covalent inhibition of thioredoxin reductase (TrxR)
selectivity↑, subtoxic doses of AF and Bz induced paraptosis selectively in breast cancer cells, sparing non-transformed MCF10A cells
toxicity↝, whereas 4~5 μM AF killed both cancer and MCF10A cells
ROS↑, We found that treatment with 5 μM AF very weakly and transiently increased ROS levels at 2~4 h and then again at 24 h
mt-TrxR1↓, AF inhibits cytosolic and mitochondrial TrxR (TrxR1 and TrxR2), two selenoenzymes for the Trx pathway [3]
mt-TrxR2↓,

5460- AF,    Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species
- vitro+vivo, Var, 4T1
RadioS↑, AF at 3–10 μM is a potent radiosensitizer in vitro
ROS↑, . The first one is linked to an oxidative stress, as scavenging of reactive oxygen species (ROS)
eff↓, N-acetyl cysteine counteracted radiosensitization. (NAC)
mt-OCR↓, We also observed a decrease in mitochondrial oxygen consumption with spared oxygen acting as a radiosensitizer under hypoxic conditions.
DNAdam↑, Overall, radiosensitization was accompanied by ROS overproduction, mitochondrial dysfunction, DNA damage and apoptosis
Apoptosis↑,
TrxR↓, targeting thioredoxin reductase (TrxR)
eff↑, a simultaneous disruption of the thioredoxin and glutathione systems by the combination of AF and buthionine sulfoximine was shown to significantly improve tumor radioresponse.

5458- AF,    Auranofin reveals therapeutic anticancer potential by triggering distinct molecular cell death mechanisms and innate immunity in mutant p53 non-small cell lung cancer
- in-vitro, NSCLC, NA
TrxR↓, Auranofin (AF) is an FDA-approved antirheumatic drug with anticancer properties that acts as a thioredoxin reductase 1 (TrxR) inhibitor.
AntiCan↓,
GPx4↓, Although functionally AF appeared a potent inhibitor of GPX4 in all NCI–H1299 cell lines, the induction of lipid peroxidation and consequently ferroptosis was limited to the p53 R273H expressing cells.
DNAdam↑, AF mainly induced large-scale DNA damage and replication stress, leading to the induction of apoptotic cell death rather than ferroptosis.
toxicity↓, AF is an orally available, lipophilic, organogold compound with a well-known safety profile that was approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis (RA).
eff↝, AF represents a potential novel therapeutic strategy to efficiently kill mutant p53 NSCLC tumor cells through distinct immunogenic cell death pathways.

5472- AF,    Auranofin induces apoptosis and necrosis in HeLa cells via oxidative stress and glutathione depletion
- in-vitro, Cerv, HeLa
TrxR↓, Auranofin (Au), an inhibitor of thioredoxin reductase, is a known anti‑cancer drug
AntiCan↑,
TumCG↓, Au inhibited the growth of HeLa cells with an IC50 of ~2 µM at 24 h.
Apoptosis↑, This agent induced apoptosis and necrosis, accompanied by the cleavage of poly (ADP‑ribose) polymerase and loss of mitochondrial membrane potential.
necrosis↑,
cl‑PARP↑,
MMP↓,
ROS↑, With respect to the levels of ROS and GSH, Au increased intracellular O2•- in the HeLa cells and induced GSH depletion.
GSH↓,
eff↓, The antioxidant, N‑acetyl cysteine, not only attenuated apoptosis and necrosis in the Au‑treated HeLa cells, but also decreased the levels of O2•- and GSH depletion in the cells.

5470- AF,    Exploring a Therapeutic Gold Mine: The Antifungal Potential of the Gold-Based Antirheumatic Drug Auranofin
- Review, Var, NA
TrxR↓, mechanism of action of auranofin was correlated with thioredoxin reductase inhibition,
other↝, but other modes of action such as interference with mitochondrial protein import and NADH kinase were also described and discussed
IL6↑, Conversely, auranofin stimulated IL-6 and IL-8 secretion in monocytes,
IL8↑,
NK cell⇅, NK activation was only observed at low doses of auranofin, while high doses inhibited NK activity
COX2↓, suppression of pro-inflammatory factors such as COX-2 (cyclooxygenase-2), NOS (nitric oxide synthase), NF-κB (nuclear factor-κB), and TrxR, as well as on the activation of peroxyredoxin-1 and Nrf2 (nuclear factor erythroid 2-related factor 2) [19].
NOS2↓,
NRF2↑,
Prx↑,
Half-Life↑, plasma half-lives of 15–25 days [24]
Dose↝, To avoid frequently occurring diarrhea, oral doses of 3–6 mg per day, or below, should also be considered when repurposing auranofin for the treatment of other human diseases.
ROS↑, Imbalances in this system lead to the accumulation of cytotoxic ROS.
NF-kB↓, Auranofin can bind to IKK, which ultimately leads to NF-κB inhibition

5468- AF,    The gold complex auranofin: new perspectives for cancer therapy
- Review, Var, NA
TrxR↓, Auranofin mainly targets the anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects the cell from oxidative stress and death in the cytoplasm and the mitochondria.
ROS↑, Inhibiting TrxR dysregulates the intracellular redox state causing increased intracellular reactive oxygen species levels, and stimulates cellular demise
eff↑, TrxR is over-expressed in many cancers as an adaptive mechanism for cancer cell proliferation, rendering it an attractive target for cancer therapy, and auranofin as a potential therapeutic agent for cancer.
Apoptosis↑, promotion of ASK-induced apoptosis, and blockage of cell growth, proliferation, and survival due to reduced AKT activity and NF-kB- and p53-mediated transcription.
TumCG↓,
TumCP↓,
Akt↓,
NF-kB↓,
DNAdam↑, DNA damage
eff↝, auranofin inhibits TrxR1 in a p53-independent manner
eff↓, Pre-treatment with NAC counteracted the cancer cell killing effects of auranofin,
PI3K↓, auranofin induces cytotoxicity in human pancreatic adenocarcinoma and non-small cell lung cancer via the inhibition of the PI3K/AKT/mTOR pathway
Akt↓,
mTOR↓,
Hif1a↓, auranofin inhibits the cancer cell response to hypoxia, demonstrated by a decrease in HIF-1 𝛼 expression and VEGF secretion upon auranofin treatment under hypoxic conditions
VEGF↓,
Casp3↑, auranofin was shown to induce caspase-3-mediated apoptosis in human ovarian carcinoma SKOV-3 cells
CSCs↓,
ATP↓, it was found that auranofin inhibits ABCG2 function by depleting cellular ATP via inhibition of glycolysis [96]
Glycolysis↓,
eff↑, auranofin synergizes with another Trx1 inhibitor, piperlongumine, in killing gastric cancer cells in association with ROS-mediated ER stress response and mitochondrial dysfunction.
eff↑, when the gold complex is combined with either selenite or tellurite [104]
MMP↓, Increased ROS induced by AUR causes decreased membrane potential in the mitochondrial membrane, resulting in a decrease in anti-apoptotic proteins, caspase-dependent cell death, and translocation of apoptosis-inducing factor (AIF)
AIF↑,
toxicity↓, Auranofin is considered safe for human use in treating rheumatoid arthritis; thus, this gold derivative can reach the clinic for other diseases relatively quickly and at a low cost

5467- AF,    Auranofin Inhibition of Thioredoxin Reductase Sensitizes Lung Neuroendocrine Tumor Cells (NETs) and Small Cell Lung Cancer (SCLC) Cells to Sorafenib as well as Inhibiting SCLC Xenograft Growth
- in-vitro, Lung, NA
TrxR↓, AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the lung atypical (neuroendocrine tumor) NET cell line H727.
eff↑, AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, a multi-kinase inhibitor that was shown to decrease intracellular glutathione.
Dose↝, AF was administered intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1 to 5 days in mice with DMS273 xenografts.
OS↑, When this daily AF treatment was extended for 14 days a significant prolongation of median survival from 19 to 23 days (p=0.04, N=30 controls, 28 AF) was observed without causing changes in animal bodyweight, CBCs, bone marrow toxicity, blood urea ni
eff↑, We also demonstrated that suppressing TrxR with AF can sensitize breast cancer stem cells to ROS induced stem cell transitions associated with EMT and cytotoxicity associated with 2-deoxyglucose treatment.

1909- AgNPs,    The Antibacterial Drug Candidate SBC3 is a Potent Inhibitor of Bacterial Thioredoxin Reductase
- in-vivo, Nor, NA
TrxR↓, Our results show that SBC3 is a promising antibiotic drug candidate targeting bacterial TrxR

1908- AgNPs,    Exposure to Silver Nanoparticles Inhibits Selenoprotein Synthesis and the Activity of Thioredoxin Reductase
- in-vitro, Lung, A549
TrxR↓, Exposure likewise inhibited TrxR activity in cultured cells, and Ag ions were potent inhibitors of purified rat TrxR isoform 1 (cytosolic) (TrxR1) enzyme.
TrxR1↓, Exposure to AgNPs leads to the inhibition of selenoprotein synthesis and inhibition of TrxR1
ROS↑, likely mechanism underlying increases in oxidative stress
ER Stress↑, increases endoplasmic reticulum stress,
TumCP↓, reduced cell proliferation during exposure to Ag.
selenoP↓, Exposure to AgNPs inhibits incorporation of selenium into selenoproteins.

1907- AgNPs,  GoldNP,  Cu,    In vitro antitumour activity of water soluble Cu(I), Ag(I) and Au(I) complexes supported by hydrophilic alkyl phosphine ligands
- in-vitro, Lung, A549 - in-vitro, BC, MCF-7 - in-vitro, Melanoma, A375 - in-vitro, Colon, HCT15 - in-vitro, Cerv, HeLa
TrxR↓, In particular, [Au(PTA)4]PF6 was able to decrease by 50% TrxR activity at 4.2 nM
eff↓, C 50 value calculated for [Ag(PTA) 4]PF6 was 10.3 nM.
eff↓, Conversely, [Cu(PTA)4]PF6 was found to be much less effective in inhibiting this cytosolic selenoenzyme, with an IC50 value of 89.5 nM, roughly from 9 to 21 times higher than those calculated for silver and gold derivatives,
other∅, To the best of our knowledge, this is the first example of a phosphino silver complex acting as TrxR inhibitor.

1906- AgNPs,  GoldNP,  Cu,    Current Progresses in Metal-based Anticancer Complexes as Mammalian TrxR Inhibitors
- Review, Var, NA
TrxR↓, 183(Au) was able to decrease TrxR activity by 50% at 4.20 nM
eff↓, IC 50 value calculated for 184(Ag) was 10.30 nM
eff↓, Conversely, 185(Cu) was found to be much less effective in inhibiting TrxR activity, with an IC 50 value of 89.50 nM

1905- AgNPs,    Evaluation of the effect of silver and silver nanoparticles on the function of selenoproteins using an in-vitro model of the fish intestine: The cell line RTgutGC
- in-vivo, Nor, NA
*TrxR↓, TrxR activity was inhibited by AgNO3 (0.4 µM) and cit-AgNP (1, 5 µM).
*ROS∅, Oxidative stress was not observed at any of the doses of AgNO3 or cit-AgNP tested
GPx↑, In this study, we show that dissolved and nano Ag can inhibit selenoenzymes activity (GPx and TrxR) in fish intestinal cells (RTgutGC).

1903- AgNPs,    Novel Silver Complexes Based on Phosphanes and Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands Targeting TrxR: New Promising Chemotherapeutic Tools Relevant to SCLC Managemen
- in-vitro, Lung, U1285
TrxR↓, accumulate into cancer cells and to selectively target Thioredoxin (TrxR),
eff↝, 2 µM was able to decrease TrxR enzyme activity by about 68%, compared with auranofin, which at the same concentration
ROS↑, cellular production of reactive oxygen species (ROS)

1902- AgNPs,    Modulation of the mechanism of action of antibacterial silver N-heterocyclic carbene complexes by variation of the halide ligand
- in-vitro, NA, NA
TrxR↓, antibacterial silver NHC complexes with halide ligands of the general type (NHC)AgX (X = Cl, Br or I) that showed potent inhibition of purified bacterial thioredoxin reductase (TrxR) and glutathione reductase (GR
GSR↓,
GSH↓, glutathione (GSH) depletion

5166- AL,    Antimicrobial properties of allicin from garlic
- in-vitro, Nor, NA
*Bacteria?, Allicin in its pure form was found to exhibit i) antibacterial activity against a wide range of Gram-negative and Gram-positive bacteria, including multidrug-resistant enterotoxicogenic strains of Escherichia coli
*Thiols↓, The main antimicrobial effect of allicin is due to its chemical reaction with thiol groups of various enzymes, e.g. alcohol dehydrogenase, thioredoxin reductase, and RNA polymerase
*TrxR↓,

1361- Ash,  SRF,    Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells
- in-vitro, Liver, HUH7 - in-vivo, Liver, HUH7
TrxR↓, TrxR1
ROS↑,
DNA-PK↑,
ER Stress↑,
Apoptosis↑,
eff↓, Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment

2617- Ba,    Potential of baicalein in the prevention and treatment of cancer: A scientometric analyses based review
- Review, Var, NA
Ca+2↑, MDA-MB-231 ↑Ca2+
MMP2↓, MDA-MB-231 ↓MMP-2/9
MMP9↓,
Vim↓, ↓Vimentin, ↓SNAIL, ↑E-cadherin, ↓Wnt1, ↓β-catenin
Snail↓,
E-cadherin↑,
Wnt↓,
β-catenin/ZEB1↓,
p‑Akt↓, MCF-7 ↓p-Akt, ↓p-mTOR, ↓NF-κB
p‑mTOR↓,
NF-kB↓,
i-ROS↑, MCF-7 ↑Intracellular ROS, ↓Bcl-2, ↑Bax, ↑cytochrome c, ↑caspase-3/9
Bcl-2↓,
BAX↑,
Cyt‑c↑,
Casp3↑,
Casp9↑,
STAT3↓, 4T1, MDA-MB-231 ↓STAT3, ↓ IL-6
IL6↓,
MMP2↓, HeLa ↓MMP-2, ↓MMP-9
MMP9↓,
NOTCH↓, ↓Notch 1
PPARγ↓, ↓PPARγ
p‑NRF2↓, HCT-116 ↓p-Nrf2
HK2↓, ↓HK2, ↓LDH-A, ↓PDK1, ↓glycolysis, PTEN/Akt/HIF-1α regulation
LDHA↓,
PDK1↓,
Glycolysis↓,
PTEN↑, Furthermore, baicalein inhibited hypoxia-induced Akt phosphorylation by promoting PTEN accumulation, thereby attenuating hypoxia-inducible factor-alpha ( HIF-1a) expression in AGS cells.
Akt↓,
Hif1a↓,
MMP↓, SGC-7901 ↓ΔΨm
VEGF↓, ↓VEGF, ↓VEGFR2
VEGFR2↓,
TOP2↓, ↓Topoisomerase II
uPA↓, ↓u-PA, ↓TIMP1, ↓TIMP2
TIMP1↓,
TIMP2↓,
cMyc↓, ↓β-catenin, ↓c-Myc, ↓cyclin D1, ↓Axin-2
TrxR↓, EL4 ↓Thioredoxin reductase, ↑ASK1,
ASK1↑,
Vim↓, ↓vimentin
ZO-1↑, ↑ZO-1
E-cadherin↑, ↑E-cadherin
SOX2↓, PANC-1, BxPC-3, SW1990 ↓Sox-2, ↓Oct-4, ↓SHH, ↓SMO, ↓Gli-2
OCT4↓,
Shh↓,
Smo↓,
Gli1↓,
N-cadherin↓, ↓N-cadherin
XIAP↓, ↓XIAP

2806- CHr,  Se,    Selenium-containing chrysin and quercetin derivatives: attractive scaffolds for cancer therapy
- in-vitro, Var, NA
eff↑, SeChry elicited a noteworthy cytotoxic activity with mean IC50 values 18- and 3-fold lower than those observed for chrysin and cisplatin, respectively
selectivity↑, differential behavior toward malignant and nonmalignant cells was observed for SeChry and SePQue, exhibiting higher selectivity indexes
Dose↝, 5 min. of microwave irradiation at 175 W (150 ºC) of an acetonitrile WR and flavonoid solution on a sealed pyrex microwave vial,
TrxR↓, Both compounds were able to decrease cellular TrxR
GSH↓, The results clearly showed that after treatment with both seleno-flavonoids total glutathione concentration (GSH + GSSG) decreased
MMP↓, MMP reduced by up to four times compared to control cells
ROS↑, Both seleno-derivatives were able to increase the oxidant basal production
H2O2↑, ore dramatic decrease of the MMP and a higher ability to increase the hydrogen peroxide basal production,

1982- CUR,    Inhibition of thioredoxin reductase by curcumin analogs
- in-vitro, NA, NA
eff↑, Curcumin analogs were first investigated for their inhibitory effects on thioredoxin reductase (TrxR). Most of them were more potent TrxR inhibitors than natural curcumin.
TrxR↓,

1981- CUR,    Mitochondrial targeted curcumin exhibits anticancer effects through disruption of mitochondrial redox and modulation of TrxR2 activity
- in-vitro, Lung, NA
eff↑, Mitocurcumin, showed 25-50 fold higher efficacy in killing lung cancer cells as compared to curcumin
ROS↑, Mitocurcumin increased the mitochondrial reactive oxygen species (ROS
mt-GSH↓, decreased the mitochondrial glutathione levels
Bax:Bcl2↑, increased BAX to BCL-2 ratio
Cyt‑c↑, cytochrome C release into the cytosol
MMP↓, loss of mitochondrial membrane potential
Casp3↑, increased caspase-3 activity
Trx2↓, mitocurcumin revealed that it binds to the active site of the mitochondrial thioredoxin reductase (TrxR2) with high affinity
TrxR↓, In corroboration with the above finding, mitocurcumin decreased TrxR activity in cell free as well as the cellular system.
mt-DNAdam↑, mitochondrial DNA damage

1980- CUR,  Rad,    Thioredoxin reductase-1 (TxnRd1) mediates curcumin-induced radiosensitization of squamous carcinoma cells
- in-vitro, Cerv, HeLa - in-vitro, Laryn, FaDu
selectivity↑, previously demonstrated that curcumin radiosensitizes cervical tumor cells without increasing the cytotoxic effects of radiation on normal human fibroblasts
RadioS↑,
TrxR↓, inhibitory activity of curcumin on the anti-oxidant enzyme Thioredoxin Reductase-1 (TxnRd1) is required for curcumin-mediated radiosensitization of squamous carcinoma cells
ROS↑, induced reactive oxygen species
ERK↑, sustained ERK1/2 activation
Dose∅, Curcumin treatment resulted in a dose-dependent decrease in TxnRd activity with an IC50 of approximately 10 µM in both cell lines
cl‑PARP↑, curcumin induced a robust increase in cleaved PARP

1979- CUR,  Rad,    Dimethoxycurcumin, a metabolically stable analogue of curcumin enhances the radiosensitivity of cancer cells: Possible involvement of ROS and thioredoxin reductase
- in-vitro, Lung, A549
eff↑, As compared to its parent molecule curcumin, DIMC showed a very potent radiosensitizing effect as seen by clonogenic survival assay.
ROS↑, significant increase in cellular ROS
GSH/GSSG↓, decrease in GSH to GSSG ratio
TrxR↓, inhibition of thioredoxin reductase enzyme by DIMC
selectivity↑, DIMC can synergistically enhance the cancer cell killing when combined with radiation by targeting thioredoxin system.

1977- CUR,    Synthesis and evaluation of curcumin analogues as potential thioredoxin reductase inhibitors
- in-vitro, BC, MCF-7 - in-vitro, Cerv, HeLa - in-vitro, Lung, A549
TrxR↓, found that most of the analogues can inhibit TrxR in the low micromolar range
Dose↝, TrxR activity in cell lysates declined by approximately 30% after the exposure of HeLa cells to 50 uM of 4g. Similar findings were observed in 4g treated MCF-7 cells
eff↑, showed that analogues 2a, 2e, 2g, and 4g, which turned out to be potent inhibitors of TrxR, exhibited stronger toxicity to A549/R cells than that of the natural curcumin

642- EGCG,    Prooxidant Effects of Epigallocatechin-3-Gallate in Health Benefits and Potential Adverse Effect
ROS↑, under high-dose conditions. Autooxidation of EGCG generates substantial ROS
H2O2↑, One EGCG molecule could produce more than two H2O2 molecules
Apoptosis↑,
Trx↓, High concentration of EGCG inactivated Trx/TrxR via the formation of EGCG-Trx1 and EGCG-TrxR conjugates
TrxR↓, High concentration of EGCG inactivated Trx/TrxR via the formation of EGCG-Trx1 and EGCG-TrxR conjugates
JNK↑,
HO-1↑,
Fenton↑,

1975- EGCG,    Molecular bases of thioredoxin and thioredoxin reductase-mediated prooxidant actions of (-)-epigallocatechin-3-gallate
- in-vitro, Cerv, HeLa
TrxR↓, EGCG-induced inactivation of TrxR and decreased cell survival, revealing TrxR as a new target of EGCG.
Trx↓,
ROS↑, EGCG induced inactivation of Trx/TrxR in parallel with increased ROS levels in HeLa cells.
Dose↑, Statistics indicated that ROS levels were significantly higher within a range of 50-200uM EGCG than that at 25 uM EGCG, but there were no significant differences in ROS levels between 50 uM vs 100 uM,

5148- GamB,    Gambogic acid: A shining natural compound to nanomedicine for cancer therapeutics
- Review, Var, NA
AntiCan↑, In this review, we document distinct biological characteristics of GA as a novel anti-cancer agent.
angioG↓, anti-angiogenesis, and chemo-/radiation sensitizer activities
ChemoSen↑, Moreover, GA has shown chemotherapy/radiation sensitization properties in different types of cancers
RadioS↑,
VEGF↓, Figure 2
MMP2↓,
MMP9↓,
Telomerase↓,
TrxR↓,
ERK↓,
HSP90↓,
ROS↑,
SIRT1↑,
survivin↓,
cFLIP↓,
Casp3↑,
Casp8↑,
Casp9↑,
BAD↓,
BID↓,
Bcl-2↓,
BAX↑,
STAT3↓,
hTERT/TERT↓,
NF-kB↓,
Myc↓,
Hif1a↓,
FOXD3↑,
BioAv↓, Unfortunately, the aqueous solubility of GA (0.013 mg/mL) is very low, thus limiting its clinical application.
BioAv↑, For example, GA can be coupled with alkanolamines to improve aqueous solubility and achieve equivalent anti-proliferation effects
P53↑, This inhibition was co-related with increase of p53 levels and reduced bcl-2 levels
eff↓, Such effect was received for GA due to production of ROS which can be removed by N-acetyl-L-cysteine (NAC, a ROS inhibitor)
OCR↓, GA exhibited a dose-dependent generation of intracellular ROS levels and lowered the oxygen consumption rate and the mitochondrial membrane potential.
MMP↓,
PI3K↓, GA happens to promote antimetastasis properties in melanoma cells by active inhibition of PI3K/Akt and ERK signaling pathways
Akt↓,
BBB↑, This study demonstrated successful uptake of GA through blood-brain barrier (BBB)
TumCG↓, GA-based nanomedicine is efficient in targeting tumors, capable to inhibit tumor growth, metastasis, angiogenesis, and reverse drug resistance
TumMeta↓,
BioAv↑, deliver GA using nanoparticles for enhanced solubility, bioavailability, adsorption and tumor imaging and targeting

1954- GamB,    Gambogic acid induces apoptosis in hepatocellular carcinoma SMMC-7721 cells by targeting cytosolic thioredoxin reductase
- in-vitro, HCC, SMMC-7721 cell
AntiTum↑, Gambogic acid (GA), a natural product that has been used in traditional Chinese medicine for centuries, demonstrates potent anticancer activity in numerous types of human cancer cells and has entered phase II clinical trials
TrxR↓, GA may interact with TrxR1 to elicit oxidative stress
TrxR1↓,
ROS↑,
Apoptosis↑, eventually induce apoptosis in human hepatocellular carcinoma SMMC-7721 cells.
Dose∅, GA effectively inhibited TrxR1 with an IC 50 around 1.2 uM,
Dose?, Under our experimental conditions, GA with concentration less than 5 uM gives only marginal inhibition of Trx

1955- GamB,    Gambogic acid inhibits thioredoxin activity and induces ROS-mediated cell death in castration-resistant prostate cancer
- in-vitro, Pca, PC3 - in-vitro, Pca, LNCaP - in-vitro, Pca, DU145
ROS↑, GA disrupted cellular redox homeostasis, observed as elevated reactive oxygen species (ROS), leading to apoptotic and ferroptotic death.
Apoptosis↑,
Ferroptosis↑,
Trx↓, GA inhibited thioredoxin
eff↑, Auranofin (AUR), a thioredoxin reductase (TrxR) inhibitor was the one compound that demonstrated additive growth inhibition together with GA when both were combined at sub-thresh hold concentrations
TrxR↓, GA may inhibit the thioredoxin (Trx) system, which mainly composes NADPH, TrxR, and Trx.
Dose∅, GA demonstrated sub-micromolar activity (IC50 = 185nM) which was 50 times more potent than the next most active compounds, curcumin and tanshinone (CT)
MMP↓, GA treatment showed increasing loss of membrane polarity at 4 and 6 hours in PCAP-1 cells
eff↑, GA enhanced the cell killing observed for either docetaxel (DOX) or enzalutamide (ENZA)
Casp↑, These results suggest that GA initiates CASP-dependent death of PCAP-1 cells and that both iron-dependent oxidative injury and direct CASP activation contribute
NADPH↓, These results suggest that GA may inhibit the thioredoxin (Trx) system, which mainly composes NADPH, TrxR, and Trx.
TrxR↓,
ChemoSen↑, potential use of GA in combination with standard chemotherapeutic (docetaxel) and anti-androgen endocrine (enzalutamide) therapies for advanced PrCa.
AR↓, inhibit PrCa growth, in part by inhibiting AR signaling

1901- GoldNP,  Rad,    The role of thioredoxin reductase in gold nanoparticle radiosensitization effects
- in-vitro, Lung, A549
MMP↓, GNP incubation led to a time-dependent mitochondria membrane depolarization, oxidative stress and to x-ray and proton radiosensitization.
ROS↑,
RadioS↑,
TrxR↓, We reported a marked inhibition of thioredoxin reductase (TrxR) in cells incubated with GNPs

1904- GoldNP,  AgNPs,    Unveiling the Potential of Innovative Gold(I) and Silver(I) Selenourea Complexes as Anticancer Agents Targeting TrxR and Cellular Redox Homeostasis
- in-vitro, Lung, H157 - in-vitro, BC, MCF-7 - in-vitro, Colon, HCT15 - in-vitro, Melanoma, A375
TrxR↓, selectively inhibit the redox‐regulating enzyme Thioredoxin Reductase (TrxR), being even more effective than auranofin
selectivity↑, Innovative Au(I) and Ag(I) NHC‐based selenourea complexes exhibit a prominent anticancer effect by selectively targeting TrxR in human cancer cells
eff↑, [AuCl{Se(SIMes)}] being the most effective derivative, and able to almost completely abolish TrxR1 activity even at 0.5 nM
eff↝, These results, highlighting the superior activity of gold with respect to silver complexes
ROS↑, treatment of H157 cells with either Au(I) or Ag(I) complexes determined a substantial time‐dependent increase in cellular basal ROS production
MMP↓, collapse of mitochondrial membrane potential (MMP) as well as loss of mitochondrial shape and integrity (swelling), possibly leading to the induction of cell apoptosis.
Apoptosis↑,
eff↑, both Ag(I) and Au(I) selenourea complexes were found to selectively and strongly inhibit mammalian TrxR, being even much more effective than the reference metallodrug auranofin

1997- Myr,  QC,    Inhibition of Mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity
- in-vitro, Lung, A549
TrxR↓, Myricetin and quercetin were found to have strong inhibitory effects on mammalian TrxRs with IC50 values of 0.62 and 0.97 micromol/L, respectively
eff↑, Oxygen-derived superoxide anions enhanced the inhibitory effect whereas anaerobic conditions attenuated inhibition.
TumCCA↑, cell cycle was arrested in S phase by quercetin and an accumulation of cells in sub-G1 was observed in response to myricetin.
eff↓, presence of superoxide dismutase diminished the inhibition dramatically
ROS↑, show that ROS played a critical role in the inhibition of TrxR by flavonoids. ...may occur as a result of their easy oxidization to flavonol semiquinone species.

1998- Myr,  CUR,    Thioredoxin-dependent system. Application of inhibitors
- Review, Var, NA
TrxR↓, myricetin, which like curcumin, can cause irreversible inhibition of TrxR activity
ROS↑, Curcumin-induced alkylation of TrxR can have effects analogous to NADPH oxidase that involve significant increases in ROS production and increased oxidative stress

1946- PL,  PI,    Piperlonguminine and Piperine Analogues as TrxR Inhibitors that Promote ROS and Autophagy and Regulate p38 and Akt/mTOR Signaling
- in-vitro, Liver, NA
eff↑, Among these, compound 9m exerted the most potent antiproliferative activity against drug-resistant Bel-7402/5-FU human liver cancer 5-FU resistant cells (IC50 = 0.8 μM), which was approximately 10-fold lower than piperlongumine (IC50 = 8.4 μM).
toxicity↓, Further, 9m showed considerably lower cytotoxicity against LO2 human normal liver epithelial cells compared to Bel-7402/5-FU.
TrxR↓, Mechanistically, compound 9m inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, reduced mitochondrial transmembrane potential (MTP
ROS↑,
MMP↓,
p38↑, Finally, 9m activated significantly the p38 signaling pathways and suppressed the Akt/mTOR signaling pathways.
Akt↓,
mTOR↓,

1949- PL,    Design, synthesis, and biological evaluation of a novel indoleamine 2,3-dioxigenase 1 (IDO1) and thioredoxin reductase (TrxR) dual inhibitor
- in-vitro, CRC, HCT116 - in-vitro, Cerv, HeLa
TrxR↓, piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR.
selectivity↑, selective killing effect between normal and cancer cells.
ROS↑, ZC0101 had the ability to promote cellular ROS accumulation
IDO1↓, because of 4-phenylimidazole

1951- PL,    Piperlongumine Analogs Promote A549 Cell Apoptosis through Enhancing ROS Generation
- in-vitro, Lung, A549
ROS↑, the ROS accumulation could disrupt the redox balance, induce lipid peroxidation, lead to the loss of MMP (Mitochondrial Membrane Potential), and ultimately result in cell cycle arrest and A549 cell line death.
lipid-P↑,
MMP↓,
TumCCA↑,
TrxR↓, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR
eff↑, For example, curcumin [15] and PL [16], characterized with the Michael acceptor, could irreversibly inhibit thioredoxin reductase (TrxR), and the adduct triggers ROS generation.

1952- PL,  5-FU,    Piperlongumine induces ROS accumulation to reverse resistance of 5-FU in human colorectal cancer via targeting TrxR
- in-vivo, CRC, HCT8
ROS↑, PL acted as a ROS inducer via binding and inhibiting TrxR (IC50 around 10.17 μM).
TrxR↓,
eff↑, enhanced the therapeutic effects of 5-FU through the dephosphorylation of Akt in BALB/c athymic nude mice bearing HCT-8/5-FU tumor xenografts.
p‑Akt↓, promoting inhibition of Akt phosphorylation,

1953- PL,    Designing piperlongumine-directed anticancer agents by an electrophilicity-based prooxidant strategy: A mechanistic investigation
- in-vitro, Lung, A549 - in-vitro, Nor, WI38
ROS↑, Piperlongumine (PL), a natural electrophilic alkaloid bearing two α, β-unsaturated imides, is a promising anticancer molecule by targeting the stress response to reactive oxygen species (ROS).
selectivity↑, 15-fold selectivity toward A549 cells over normal WI-38 cells.
TrxR↓, selenoprotein thioredoxin reductase (TrxR) is one of the targets by which PL-CL promotes the ROS generation.
TumCCA↑, S-phase arrest
GSH?, PL-CL sharply decreased the GSH levels of A549 cells in a dose- and time-dependent fashion (Figure 5A) but barely changed the GSH levels of WI-38 cells
H2O2↑, significant accumulation of ROS (O2.- and H2O2)

2649- PL,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
AntiCan↑, investigated for its anticancer activity in various cancer types, including hematological cancers, colorectal, gastric, lung, breast, prostate, and oral cancers, melanoma, and glioma
ROS↑, Its in vitro anticancer activity can be attributed to induction of ROS through increased glutathione disulfide levels, decreased glutathione levels
GSH↓,
TrxR↓, inhibition of thioredoxin reductase (TrxR), an enzyme which reduces thioredoxin, a redox protein that protects against oxidative stress
Trx↓,
Apoptosis↑, PPL-mediated ROS accumulation further leads to ROS-mediated apoptosis
TumCCA↑, G1 or G2/M cell cycle arrest
ER Stress↑, ER stress
DNAdam↑, oxidative DNA damage
ChemoSen↑, PPL was reported to sensitize head and neck, gastric, and liver cancers to cisplatin [18], oxaliplatin [19], and sorafenib [20], respectively
BioAv↓, Additionally, its poor aqueous solubility and bioavailability limit its therapeutic potential

2942- PL,    Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems
- in-vitro, CRC, CT26 - in-vitro, CRC, DLD1 - in-vivo, CRC, CT26
ROS↑, known to selectively kill tumor cells via perturbation of reactive oxygen species (ROS) homeostasis
GSH↓, PL induced excessive production of ROS due to depletion of glutathione and inhibition of thioredoxin reductase
TrxR↓,
RadioS↑, PL enhanced both the intrinsic and hypoxic radiosensitivity of tumor cells
DNAdam↑, inked to ROS-mediated increase of DNA damage, G2/M cell cycle arrest, and inhibition of cellular respiration
TumCCA↑,
mitResp↓,
GSTs↓, PL proved to perturb GSH system by inhibition of glutathione S-transferase (GST) that catalyzes the conjugation of GSH with its substrate
OS↑, delays tumor growth and improves the survival rate of tumor-bearing mice.

2946- PL,    Piperlongumine, a potent anticancer phytotherapeutic: Perspectives on contemporary status and future possibilities as an anticancer agent
- Review, Var, NA
ROS↑, piperlongumine inhibits cancer growth by resulting in the accumulation of intracellular reactive oxygen species, decreasing glutathione and chromosomal damage, or modulating key regulatory proteins, including PI3K, AKT, mTOR, NF-kβ, STATs, and cycD
GSH↓, reduced glutathione (GSH) levels in mouse colon cancer cells
DNAdam↑,
ChemoSen↑, combined treatment with piperlongumine potentiates the anticancer activity of conventional chemotherapeutics and overcomes resistance to chemo- and radio- therapy
RadioS↑, piperlongumine treatment enhances ROS production via decreasing GSH levels and causing thioredoxin reductase inhibition
BioEnh↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine
selectivity↑, It shows selectivity toward human cancer cells over normal cells and has minimal side effects
BioAv↓, ts low aqueous solubility affects its anti-cancer activity by limiting its bioavailability during oral administration
eff↑, encapsulation of piperlongumine in another biocompatible natural polymer, chitosan, has been found to result in pH-dependent piperlongumine release and to enhance cytotoxicity via efficient intracellular ROS accumulation against human gastric carcin
p‑Akt↓, Fig 2
mTOR↓,
GSK‐3β↓,
β-catenin/ZEB1↓,
HK2↓, iperlongumine treatment decreases cell proliferation, single-cell colony-formation ability, and HK2-mediated glycolysis in NSCLC cells via inhibiting the interaction between HK2 and voltage-dependent anion channel 1 (VDAC1)
Glycolysis↓,
Cyt‑c↑,
Casp9↑,
Casp3↑,
Casp7↑,
cl‑PARP↑,
TrxR↓, piperlongumine (4 or 12 mg/kg/day for 15 days) administration significantly inhibits increase in tumor weight and volume with less TrxR1 activity in SGC-7901 cell
ER Stress↑,
ATF4↝,
CHOP↑, activating the downstream ER-MAPK-C/EBP homologous protein (CHOP) signaling pathway
Prx4↑, piperlongumine kills high-grade glioma cells via oxidative inactivation of PRDX4 mediated ROS induction, thereby inducing intracellular ER stress
NF-kB↓, piperlongumine treatment (2.5–5 mg/ kg body weight) decreases the growth of lung tumors via inhibition of NF-κB
cycD1/CCND1↓, decreases expression of cyclin D1, cyclin- dependent kinase (CDK)-4, CDK-6, p- retinoblastoma (p-Rb)
CDK4↓,
CDK6↓,
p‑RB1↓,
RAS↓, piperlongumine downregulates the expression of Ras protein
cMyc↓, inhibiting the activity of other related proteins, such as Akt/NF-κB, c-Myc, and cyclin D1 in DMH + DSS induced colon tumor cells
TumCCA↑, by arresting colon tumor cells in the G2/M phase of the cell cycle
selectivity↑, hows more selective cytotoxicity against human breast cancer MCF-7 cells than human breast epithelial MCF-10A cells
STAT3↓, thus inducing inhibition of the STAT3 signaling pathway in multiple myeloma cells
NRF2↑, Nrf2) activation has been found to mediate the upregulation of heme oxygenase-1 (HO-1) in piperlongumine treated MCF-7 and MCF-10A cells
HO-1↑,
PTEN↑, stimulates ROS accumulation; p53, p27, and PTEN overexpression
P-gp↓, P-gp, MDR1, MRP1, survivin, p-Akt, NF-κB, and Twist downregulation;
MDR1↓,
MRP1↓,
survivin↓,
Twist↓,
AP-1↓, iperlongumine significantly suppresses the expression of transcription factors, such as AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6, and YY1.
Sp1/3/4↓,
STAT1↓,
STAT6↓,
SOX4↑, increased expression of p21, SOX4, and XBP in B-ALL cells
XBP-1↑,
P21↑,
eff↑, combined use of piperlongumine with cisplatin enhances the sensitivity toward cisplatin by inhibiting Akt phosphorylation
Inflam↓, inflammation (COX-2, IL6); invasion and metastasis, such as ICAM-1, MMP-9, CXCR-4, VEGF;
COX2↓,
IL6↓,
MMP9↓,
TumMeta↓,
TumCI↓,
ICAM-1↓,
CXCR4↓,
VEGF↓,
angioG↓,
Half-Life↝, The analysis of the plasma of piperlongumine treated mice (50 mg/kg) after intraperitoneal administration, 1511.9 ng/ml, 418.2 ng/ml, and 41.9 ng/ml concentrations ofplasma piperlongumine were found at 30 minutes, 3 hours, and 24 hours, respecti
BioAv↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine

2948- PL,    The promising potential of piperlongumine as an emerging therapeutics for cancer
- Review, Var, NA
tumCV↓, inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases,
TumCP↓,
TumCI↓,
angioG↓,
EMT↓,
TumMeta↓,
*hepatoP↑, A study demonstrated the hepatoprotective effects of P. longum via decreasing the rate of lipid peroxidation and increasing glutathione (GSH) levels
*lipid-P↓,
*GSH↑,
cardioP↑, cardioprotective effect
CycB/CCNB1↓, downregulated the mRNA expression of the cell cycle regulatory genes such as cyclin B1, cyclin D1, cyclin-dependent kinases (CDK)-1, CDK4, CDK6, and proliferating cell nuclear antigen (PCNA)
cycD1/CCND1↓,
CDK2↓,
CDK1↓,
CDK4↓,
CDK6↓,
PCNA↓,
Akt↓, suppression of the Akt/mTOR pathway by PL was also associated with the partial inhibition of glycolysis
mTOR↓,
Glycolysis↓,
NF-kB↓, Suppression of the NF-κB signaling pathway and its related genes by PL was reported in different cancers
IKKα↓, inactivation of the inhibitor of NF-κB kinase subunit beta (IKKβ)
JAK1↓, PL efficiently inhibited cell proliferation, invasion, and migration by blocking the JAK1,2/STAT3 signaling pathway
JAK2↓,
STAT3↓,
ERK↓, PL also negatively regulates ERK1/2 signaling pathways, thereby suppressing the level of c-Fos in CRC cells
cFos↓,
Slug↓, PL was found to downregulate slug and upregulate E-cadherin and inhibited epithelial-mesenchymal transition (EMT) in breast cancer cells
E-cadherin↑,
TOP2↓, ↓topoisomerase II, ↑p53, ↑p21, ↓Bcl-2, ↑Bax, ↑Cyt C, ↑caspase-3, ↑caspase-7, ↑caspase-8
P53↑,
P21↑,
Bcl-2↓,
BAX↑,
Casp3↑,
Casp7↑,
Casp8↑,
p‑HER2/EBBR2↓, ↓p-HER1, ↓p-HER2, ↓p-HER3
HO-1↑, ↑Apoptosis, ↑HO-1, ↑Nrf2
NRF2↑,
BIM↑, ↑BIM, ↑cleaved caspase-9 and caspase-3, ↓p-FOXO3A, ↓p-Akt
p‑FOXO3↓,
Sp1/3/4↓, ↑apoptosis, ↑ROS, ↓Sp1, ↓Sp3, ↓Sp4, ↓cMyc, ↓EGFR, ↓survivin, ↓cMET
cMyc↓,
EGFR↓,
survivin↓,
cMET↓,
NQO1↑, G2/M phase arrest, ↑apoptosis, ↑ROS, ↓p-Akt, ↑Bad, ↓Bcl-2, ↑NQO1, ↑HO-1, ↑SOD2, ↑p21, ↑p-ERK, ↑p-JNK,
SOD2↑,
TrxR↓, G2/M cell cycle arrest, ↑apoptosis, ↑ROS, ↓GSH, ↓TrxR
MDM2↓, ↑ROS, ↓MDM-2, ↓cyclin B1, ↓Cdc2, G2/M phase arrest, ↑p-eIF2α, ↑ATF4, KATO III ↑CHOP, ↑apoptosis
p‑eIF2α↑,
ATF4↑,
CHOP↑,
MDA↑, ↑ROS, ↓TrxR1, ↑cleaved caspase-3, ↑CHOP, ↑MDA
Ki-67↓, ↓Ki-67, ↓MMP-9, ↓Twist,
MMP9↓,
Twist↓,
SOX2↓, ↓SOX2, ↓NANOG, ↓Oct-4, ↑E-cadherin, ↑CK18, ↓N-cadherin, ↓vimentin, ↓snail, ↓slug
Nanog↓,
OCT4↓,
N-cadherin↓,
Vim↓,
Snail↓,
TumW↓, ↓Tumor weight, ↓tumor growth
TumCG↓,
HK2↓, ↓HK2
RB1↓, ↓Rb
IL6↓, ↓IL-6, ↓IL-8,
IL8↓,
SOD1↑, ↑SOD1
RadioS↑, ombination with PL, very low intensity of radiation is found to be effective in cancer cells
ChemoSen↑, PL as a chemosensitizer which sensitized the cancer cells towards the commercially available chemotherapeutics
toxicity↓, PL does not have any adverse effect on the normal functioning of the liver and kidney.
Sp1/3/4↓, In vitro SKBR3 ↓Sp1, ↓Sp3, ↓Sp4
GSH↓, In vitro MCF-7 ↓CDK1, G2/M phase arrest ↓CDK4, ↓CDK6, ↓PCNA, ↓p-CDK1, ↑cyclin B1, ↑ROS, ↓GSH, ↓p-IκBα,
SOD↑, In vitro PANC-1, MIA PaCa-2 ↑ROS, ↑SOD1, ↑GSTP1, ↑HO-1

2962- PL,    Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2‑Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents
- in-vitro, Nor, PC12
*GSH↑, compounds 4 and 5 remarkably elevats GSH level and antioxidant enzymes activity (NQO1, Trx, and TrxR).
*NQO1↑,
*Trx↑,
*TrxR↑,
*NRF2↑, revealed that the total Nrf2 expression was slightly upregulated. 4 and 5, have been identified as potent Nrf2 activators with minimal cytotoxicity.
*NRF2⇅, Notably, the cytosolic Nrf2 decreased gradually (Figure 9, middle panel). Coincidently, the amount of Nrf2 in nuclei increased.
*eff↑, Induction of transcription of antioxidant genes via the Nrf2-dependent cytoprotective pathway requires translocation of Nrf2 from cytosol to nucleus.
*BioAv↑, PL could cross the BBB after oral administration
*ROS↓, The elevation of cellular endogenous antioxidant system prevents the accumulation of ROS and thus confers protection against oxidative insults to the cells.

2651- PLB,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
ROS↑, Various studies have shown that plumbagin is a potent inducer of ROS
TrxR↓, The mechanism underlying ROS induction by plumbagin has predominantly been attributed to inhibition of the antioxidant enzymes TrxR
GSR↓, and glutathione reductase
ER Stress↓, mediates its anticancer effect by inducing ER stress-mediated apoptosis
TumCCA↑, S/G2 and G2/M cell cycle arrest
MMP↓, and mitochondrial membrane depolarization in an ROS-dependent manner
NF-kB↓, plumbagin was found to inhibit the NF-κB [57], PI3K/AKT/mTOR [58] and MKP1/2 [59] pathways in non-small cell lung cancer, bladder cancer, and lymphoma,
PI3K↓,
Akt↓,
mTOR↓,
MKP1↓,
MKP2↓,
ChemoSen↑, improve the efficacy of existing chemotherapeutic strategies

1983- PTL,    Targeting thioredoxin reductase by micheliolide contributes to radiosensitizing and inducing apoptosis of HeLa cells
- in-vitro, Cerv, HeLa
eff↑, micheliolide (MCL) is converted readily from parthenolide (PTL), and has better stability and solubility than PTL
TrxR↓, MCL-targeted inhibition of TrxR
ROS↑, promotes oxidative stress-mediated HeLa cell apoptosis
RadioS↑, sensitizes ionizing radiation (IR) treatment

4717- Se,    A systematic review of Selenium as a complementary treatment in cancer patients
- Review, Var, NA
*antiOx↑, Selenium, a trace element with antioxidant properties, has been widely studied for its benefits in cancer treatment.
eff↝, clear statement regarding the effectiveness of Se supplementation is not possible
radioP↑, whereas cancer patients with a Se deficiency could profit from a Se supplementation during radio- or chemotherapy.
chemoP↑,
*selenoP↑, Se is crucial for the biosynthesis of selenoproteins and essential enzymes (glutathione peroxidases (GSH-PPX), thioredoxin reductase, and selenoprotein P
*GPx↑,
TrxR↑,
*ROS↓, Glutathione peroxidase, an enzyme within this group, directly neutralizes reactive oxygen species, which can be detrimental to cells.

4485- Se,    Selenium stimulates the antitumour immunity: Insights to future research
- Review, NA, NA
*antiOx↑, At nutritional low doses, selenium, depending on its form, may act as an antioxidant, protecting against oxidative stress, supporting cell survival and growth, thus, plays a chemo-preventive role
chemoPv↑,
ROS↑, at supra-nutritional higher pharmacological doses, selenium acts as pro-oxidant inducing redox signalling and cell death
Imm↑, selenium stimulates the immune system against cancer
selenoP↑, anti-oxidant through selenoproteins
*IL2↑, consumption of Se-enriched foods (200 μg per serving for 3 days) increases the levels of interleukin IL-2, IL-4, IL-5, IL-13 and IL-22, indicating an activated Th2-type response
*IL4↑,
*TNF-α↓, taking selenised yeast (300 μg.day−1) downregulates the gene expression of tumour necrosis factor (TNF)α and transforming growth factor (TGF)β; thus, consequently inhibit the epithelial-to-mesenchymal transition (EMT) in non-malignant prostate tissue
*TGF-β↓,
*EMT↓,
Risk↓, immune-enhancing effects of Se may reduce the risk of cancer
*GPx↑, chemo-preventive effects of Se are mainly mediated by the anti-oxidant function of selenoenzymes such as GPxs and TXNRDs [68] because Se supplementation increases both GPx1 and GPx4 activity in humans
*TrxR↑,

3663- SFN,    Efficacy of Sulforaphane in Neurodegenerative Diseases
- Review, AD, NA - Review, Park, NA
*antiOx↑, SFN is especially characterized by antioxidant, anti-inflammatory, and anti-apoptotic properties,
*Inflam↓,
*Half-Life↝, SFN in rats reaches the plasma peak in 4 h, with an average half-life of about 2.2 h
*NRF2↑, Nrf2 expression can be regulated by SFN,
*NQO1↑, oxidoreductase 1 (NQO-1), heme oxygenase 1 (HO-1), GSH S-transferase, and thioredoxin reductase, thus counteract the oxidative stress
*HO-1↑, intracellular increase of GSH, as well as HO-1 and NQO-1 activity
*TrxR↑,
*ROS↓,
*TNF-α↓, regulating the levels of inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin (IL) 6, IL-1β, inducible nitric oxide synthetase (iNOS), and cyclooxygenase-2 (COX-2)
*IL1β↓,
*IL6↓,
*iNOS↓,
*COX2↓,
*Aβ↓, SFN inhibited Aβ aggregation, tau hyperphosphorylation, as well as oxidative stress, evaluated through GSH and malondialdehyde (MDA) levels
*GSH↑, reduction of levels of MDA, TNF-α, and IL-1β, as well as by the increase of GSH
*cognitive↑, SFN treatment improved cognitive and locomotor deficits evaluated by Morris water maze and open field test.
*BACE↓, SFN, according to a dose-dependent mechanism, can inhibit BACE-1 and consequently Aβ aggregation
*HSP70/HSPA5↑, SFN increased the levels of co-chaperone of heat shock protein (HSP), C-terminus of HSP 70-interacting protein (CHIP)
*neuroP↑, SFN, through mechanisms that involve Nrf2 activation, can play a protective effect for counteracting the neurodegeneration that occurs in the PD
*ROS↓, SFN treatment has avoided both ROS production and membrane damage.
*BBB↑, SFN protected the integrity of BBB, as shown by tight junction proteins occludin and claudin-5 levels, as well as by the reduction in the expression levels of matrix metallopeptidase 9,
*MMP9↓,

3658- SFN,    Pre-Clinical Neuroprotective Evidences and Plausible Mechanisms of Sulforaphane in Alzheimer’s Disease
- Review, AD, NA
*NRF2↑, Sulforaphane potently induces transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated expression of detoxification, anti-oxidation
*antiOx↑,
*neuroP↑, The study on the neuroprotective effects of sulforaphane began in 2004 with studies showing the protective effects on neurons
*Aβ↓, every other day 10 mg/kg i.p. for 2 months in cortex: (1) reduced the numbers of Aβ plaques/mm2 in cerebral cortex
*BACE↓, reduced BACE1 protein expression
*NQO1↑, increased NQO1 transcript and protein expression
*IL1β↓, decreased IL-1β and TNF-α
*TNF-α↓,
*IL6↓, (1) decreased IL-1β and IL-6 (2) decreased COX-2 and iNOS (3) reduced NF-κB p-p65
*COX2↓,
*iNOS↓,
*NF-kB↓,
*NLRP3↓, reduced NLRP3 inflammasome
*Ca+2↓, decreased intracellular Ca2+ levels
*GSH↑, in brain: (1) increased GSH (2) decreased MDA
*MDA↓,
*ROS↓, (1) decreased ROS and MDA, (2) increased SOD activity
*SOD↑,
*HO-1↑, increased NQO1, HO-1
*TrxR↑, increased HO-1 and TrxR expression
*cognitive↑, ameliorated cognitive deficits
*tau↓, figure 1
*HSP70/HSPA5↑,

1459- SFN,  AF,    Auranofin Enhances Sulforaphane-Mediated Apoptosis in Hepatocellular Carcinoma Hep3B Cells through Inactivation of the PI3K/Akt Signaling Pathway
- in-vitro, Liver, Hep3B - in-vitro, Liver, HepG2
eff↑, sulforaphane significantly enhanced auranofin-induced apoptosis by inhibiting TrxR activity and cell proliferation compared to either single treatment
TumCCA↑, Sub-G1 cells
Apoptosis↑,
MMP↓,
BAX↑,
cl‑PARP↑,
Casp3↑,
Casp8↑,
Casp9↑,
ROS↑, combined treatment induced excessive generation of reactive oxygen species (ROS)
eff↓, treatment with N-acetyl-L-cysteine, a ROS scavenger, reduced combined treatment-induced ROS production and apoptosis.
PI3K↓,
Akt↓,
TrxR↓, treatment with either sulforaphane or auranofin alone at low concentrations weakly inhibit TrxR activity Combined treatment significantly reduced TrxR activity and cell viability
BAX↑,
Bcl-2∅,

3041- SK,    Promising Nanomedicines of Shikonin for Cancer Therapy
- Review, Var, NA
Glycolysis↓, SHK could regulate immunosuppressive tumor microenvironment through inhibiting glycolysis of tumor cells and repolarizing tumor-associated macrophages (TAMs).
TAMS↝,
BioAv↓, HK is a hydrophobic natural molecule with unsatisfactory solubility, rapid intestinal absorption, obvious “first pass” effect, and rapid clearance, leading to low oral bioavailability.
Half-Life↝, SHK displays a half-life of 15.15 ± 1.41 h and Cmax of 0.94 ± 0.11 μg/ml in rats when administered intravenously.
P21↑, Table 1
ERK↓,
ROS↑,
GSH↓,
MMP↓,
TrxR↓,
MMP13↓,
MMP2↓,
MMP9↓,
SIRT2↑,
Hif1a↓,
PKM2↓,
TumCP↓, Inhibit Cell Proliferation
TumMeta↓, Inhibit Cells Metastasis and Invasion
TumCI↓,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 57

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Fenton↑, 1,   Ferroptosis↑, 1,   GPx↑, 1,   GPx4↓, 1,   GSH?, 1,   GSH↓, 9,   mt-GSH↓, 1,   GSH/GSSG↓, 1,   GSR↓, 2,   GSTs↓, 1,   H2O2↑, 3,   HO-1↑, 3,   lipid-P↑, 1,   MDA↑, 1,   NQO1↑, 1,   NRF2↑, 3,   p‑NRF2↓, 1,   Prx↑, 1,   Prx4↑, 1,   ROS↑, 41,   i-ROS↑, 1,   selenoP↓, 1,   selenoP↑, 1,   SOD↑, 1,   SOD1↑, 1,   SOD2↑, 1,   Trx↓, 4,   Trx2↓, 1,   TrxR↓, 51,   TrxR↑, 1,   TrxR1↓, 2,   mt-TrxR1↓, 1,   mt-TrxR2↓, 1,  

Mitochondria & Bioenergetics ⓘ

AIF↑, 1,   ATP↓, 1,   mitResp↓, 1,   MMP↓, 15,   OCR↓, 1,   mt-OCR↓, 1,   XIAP↓, 1,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 3,   Glycolysis↓, 5,   HK2↓, 3,   IDO1↓, 1,   LDHA↓, 1,   NADPH↓, 1,   PDK1↓, 1,   PKM2↓, 1,   PPARγ↓, 1,   SIRT1↑, 1,   SIRT2↑, 1,  

Cell Death ⓘ

Akt↓, 8,   p‑Akt↓, 3,   Apoptosis↓, 1,   Apoptosis↑, 13,   ASK1↑, 1,   ATF2↓, 1,   BAD↓, 1,   BAX↑, 5,   Bax:Bcl2↑, 1,   Bcl-2↓, 3,   Bcl-2∅, 1,   BID↓, 1,   BIM↑, 1,   Casp↑, 1,   Casp3↑, 8,   Casp7↑, 3,   Casp8↑, 3,   Casp9↑, 4,   cFLIP↓, 1,   Cyt‑c↑, 3,   Ferroptosis↑, 1,   hTERT/TERT↓, 1,   JNK↑, 1,   MDM2↓, 1,   MKP1↓, 1,   MKP2↓, 1,   Myc↓, 1,   necrosis↑, 1,   p38↑, 1,   Paraptosis↑, 1,   survivin↓, 3,   Telomerase↓, 1,  

Kinase & Signal Transduction ⓘ

FOXD3↑, 1,   p‑HER2/EBBR2↓, 1,   Sp1/3/4↓, 3,  

Transcription & Epigenetics ⓘ

other↝, 1,   other∅, 1,   tumCV↓, 1,  

Protein Folding & ER Stress ⓘ

CHOP↑, 2,   p‑eIF2α↑, 1,   ER Stress↓, 1,   ER Stress↑, 5,   HSP90↓, 1,   XBP-1↑, 1,  

DNA Damage & Repair ⓘ

DNA-PK↑, 1,   DNAdam↑, 7,   mt-DNAdam↑, 1,   P53↑, 2,   cl‑PARP↑, 5,   PCNA↓, 1,  

Cell Cycle & Senescence ⓘ

CDK1↓, 1,   CDK2↓, 1,   CDK4↓, 2,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 2,   P21↑, 3,   RB1↓, 1,   p‑RB1↓, 1,   TumCCA↑, 8,  

Proliferation, Differentiation & Cell State ⓘ

cFos↓, 1,   cMET↓, 1,   CSCs↓, 1,   Diff↑, 1,   EMT↓, 1,   ERK↓, 3,   ERK↑, 1,   p‑FOXO3↓, 1,   Gli1↓, 1,   GSK‐3β↓, 1,   mTOR↓, 6,   p‑mTOR↓, 1,   Nanog↓, 1,   NOTCH↓, 1,   OCT4↓, 2,   PI3K↓, 4,   PTEN↑, 2,   RAS↓, 1,   Shh↓, 1,   Smo↓, 1,   SOX2↓, 2,   STAT1↓, 1,   STAT3↓, 4,   STAT6↓, 1,   TOP2↓, 2,   TumCG↓, 4,   Wnt↓, 1,  

Migration ⓘ

AP-1↓, 1,   Ca+2↑, 1,   E-cadherin↑, 3,   Ki-67↓, 1,   MMP13↓, 1,   MMP2↓, 4,   MMP9↓, 6,   N-cadherin↓, 2,   Slug↓, 1,   Snail↓, 2,   SOX4↑, 1,   TET1?, 1,   TIMP1↓, 1,   TIMP2↓, 1,   TumCI↓, 3,   TumCMig↓, 1,   TumCP↓, 5,   TumMeta↓, 4,   Twist↓, 2,   uPA↓, 1,   Vim↓, 3,   ZO-1↑, 1,   β-catenin/ZEB1↓, 2,  

Angiogenesis & Vasculature ⓘ

angioG↓, 4,   ATF4↑, 1,   ATF4↝, 1,   EGFR↓, 1,   Hif1a↓, 4,   TAMS↝, 1,   VEGF↓, 4,   VEGFR2↓, 1,  

Barriers & Transport ⓘ

BBB↑, 1,   P-gp↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 2,   CXCR4↓, 1,   ICAM-1↓, 1,   IKKα↓, 1,   IL6↓, 5,   IL6↑, 1,   IL8↓, 1,   IL8↑, 1,   Imm↑, 1,   Inflam↓, 1,   JAK1↓, 1,   JAK2↓, 1,   NF-kB↓, 8,   NK cell⇅, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,   CDK6↓, 2,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 5,   BioAv↑, 4,   BioEnh↑, 1,   ChemoSen↑, 9,   Dose?, 1,   Dose↑, 2,   Dose↝, 6,   Dose∅, 3,   eff↓, 12,   eff↑, 26,   eff↝, 6,   Half-Life↑, 1,   Half-Life↝, 2,   MDR1↓, 1,   MRP1↓, 1,   RadioS↑, 9,   selectivity↑, 9,  

Clinical Biomarkers ⓘ

AR↓, 1,   EGFR↓, 1,   p‑HER2/EBBR2↓, 1,   hTERT/TERT↓, 1,   IL6↓, 5,   IL6↑, 1,   Ki-67↓, 1,   Myc↓, 1,   NOS2↓, 1,  

Functional Outcomes ⓘ

AntiCan↓, 1,   AntiCan↑, 3,   AntiTum↑, 2,   cardioP↑, 1,   chemoP↑, 1,   chemoPv↑, 1,   OS↑, 2,   radioP↑, 1,   Risk↓, 1,   toxicity↓, 5,   toxicity↝, 1,   TumW↓, 1,  

Infection & Microbiome ⓘ

Bacteria↓, 1,  
Total Targets: 225

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 4,   GPx↑, 2,   GSH↑, 4,   HO-1↑, 2,   lipid-P↓, 1,   MDA↓, 1,   NQO1↑, 3,   NRF2↑, 3,   NRF2⇅, 1,   ROS↓, 5,   ROS∅, 1,   selenoP↑, 1,   SOD↑, 1,   Thiols↓, 1,   Trx↑, 1,   TrxR↓, 2,   TrxR↑, 4,  

Cell Death ⓘ

iNOS↓, 2,  

Protein Folding & ER Stress ⓘ

HSP70/HSPA5↑, 2,  

Proliferation, Differentiation & Cell State ⓘ

EMT↓, 1,  

Migration ⓘ

Ca+2↓, 1,   MMP9↓, 1,   TGF-β↓, 1,  

Barriers & Transport ⓘ

BBB↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 2,   IL1β↓, 2,   IL2↑, 1,   IL4↑, 1,   IL6↓, 2,   Inflam↓, 1,   NF-kB↓, 1,   TNF-α↓, 3,  

Synaptic & Neurotransmission ⓘ

tau↓, 1,  

Protein Aggregation ⓘ

Aβ↓, 2,   BACE↓, 2,   NLRP3↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↑, 1,   eff↑, 1,   Half-Life↝, 1,  

Clinical Biomarkers ⓘ

IL6↓, 2,  

Functional Outcomes ⓘ

cognitive↑, 2,   hepatoP↑, 1,   neuroP↑, 2,  

Infection & Microbiome ⓘ

Bacteria?, 1,  
Total Targets: 44

Scientific Paper Hit Count for: TrxR, Thioredoxin Reductase
15 Auranofin
10 Piperlongumine
8 Silver-NanoParticles
6 Curcumin
4 Gold NanoParticles
3 Selenium
3 Radiotherapy/Radiation
3 Gambogic Acid
3 Sulforaphane (mainly Broccoli)
2 Copper and Cu NanoParticles
2 EGCG (Epigallocatechin Gallate)
2 Myricetin
1 Allicin (mainly Garlic)
1 Ashwagandha(Withaferin A)
1 Sorafenib (brand name Nexavar)
1 Baicalein
1 Chrysin
1 Quercetin
1 Piperine
1 5-fluorouracil
1 Plumbagin
1 Parthenolide
1 Shikonin
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#:825  State#:%  Dir#:%
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