TrxR Cancer Research Results

TrxR, Thioredoxin Reductase: Click to Expand ⟱

Source:

Type:

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⟱

5459-

AF,

Auranofin Induces Lethality Driven by Reactive Oxygen Species in High-Grade Serous Ovarian Cancer Cells

in-vitro,

Ovarian,

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,

AF was administered intraperitoneal, daily or twice daily for 1 to 5 days in mice bearing DMS273 xenografts.

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,

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,

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,

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,

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,

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,

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,

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,

DMS53 human small cell lung cancer cells

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.

1900-

AF,

Potential Anticancer Activity of Auranofin

Review,

Var,

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

1909-

AgNPs,

The Antibacterial Drug Candidate SBC3 is a Potent Inhibitor of Bacterial Thioredoxin Reductase

in-vivo,

Nor,

Bacteria

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,

MCF7

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,

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,

fish

*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

2uM, 24hr

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,

0.03–0.12 μM

bacterial

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,

*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,

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/KDR/Flk1↓,
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

7180-

CHA,

Chaetocin: A review of its anticancer potentials and mechanisms

Review,

Var,

TumCG↓, . Several studies have demonstrated that chaetocin suppresses the growth and proliferation of various tumour cells by regulating multiple signalling pathways related
TumCP↓,
Apoptosis↑, inducing cancer cell apoptosis (intrinsic and extrinsic), enhancing autophagy, inducing cell cycle arrest, and inhibiting tumour angiogenesis, invasion, and migration.
TumCCA↑,
angioG↓,
TumCI↓,
TumCMig↓,
SUV39H↓, chaetocin inhibits the activities of histone lysine methyltransferase SUV39H1
TrxR↓, formed covalent adducts with numerous proteins, including the thioredoxin-thioredoxin reductase (Trx-TrxR) system, hypoxia inducible factor-1 alpha (HIF-1α), heat shock protein 90 (Hsp90)
Hif1a↓,
HSP90↓,
ox-Trx1↑, ↑ oxidized TRX-1 & ROS activation; ↓ PI3K/AKT pathway & p-AKT; ↑ caspase-3, caspase-8 & caspase-9 activation; ↑ cleaved PARP proteins; ↓ BCL-2, BCL-XL, MCL-1, XIAP
ROS↑,
PI3K↓,
Akt↓,
Casp3↑,
Casp8↑,
Casp9↑,
cl‑PARP↑,
Bcl-2↓,
Bcl-xL↓,
Mcl-1↓,
XIAP↓,
DR5↑, ↑ DR5 & CHOP, ATF3;
CHOP/DDIT3↑,
ATF3↑,
angioG↓, chaetocin also indirectly targets tumour cells by inducing antiangiogenic effects in the tumour microvasculature.
VEGF↑, robust decrease in secreted VEGF in the culture media of treated cells and subsequent downregulation of the target genes of VEGFA, LDHA, ENO1 and HZF-1,
LDHA↓,
ENO1↓,

7184-

CHA,

Chaetocin antileukemia activity against chronic myelogenous leukemia cells is potentiated by bone marrow stromal factors and overcomes innate imatinib resistance

in-vitro,

CML,

ROS↑, Here, we report that chaetocin, a mycotoxin that exhibits anticancer properties and imposes oxidative stress by inhibiting thioredoxin reductase-1
TrxR↓,
eff↓, Pretreatment of CML-LSKs with the antioxidant N-acetylcysteine (NAC) blocked chaetocin cytotoxicity
eff↑, Our findings indicate that chaetocin activity against CML-LSKs is significantly enhanced in the presence of BMSFs and suggest that chaetocin may be effective as a codrug to complement TKIs in CML treatment

7185-

CHA,

Chaetocin-induced ROS-mediated apoptosis involves ATM–YAP1 axis and JNK-dependent inhibition of glucose metabolism

vitro+vivo,

GBM,

A172

xenograft glioma mouse model

in-vitro,

GBM,

T98G

in-vitro,

GBM,

U87MG

HMTs↓, Chaetocin, a histone methyltransferase inhibitor, is known to induce ROS generation.
ROS↑,
p‑ATM↑, Chaetocin-treated tumors exhibited heightened ROS, pATM, YAP1 and pJNK levels
YAP/TEAD↑, An increase in YAP1 level and decrease in YAP1 phosphorylation was observed upon Chaetocin treatment
p‑JNK↑,
TumPF↓, Chaetocin inhibits glioma cell proliferation
SUV39H↓, Chaetocin, an inhibitor of lysine-specific histone methyltransferase SUV39H1
TrxR↓, Chaetocin reduces thioredoxin reductase activity in a dose-dependent manner.
Casp3↑, Treatment with Chaetocin resulted in ∼3–5-fold increase in caspase-3 activity
Trx1↓, Chaetocin decreases the expression of TRX-1 in glioma cells
H3↓, Chaetocin-mediated inhibition of histone H3 methylation is ROS dependent
lactateProd↓, Chaetocin decreases lactate levels, ATP production and glucose uptake in a ROS- and JNK-dependent manner
ATP↓,
GlucoseCon↓,
TumCG↓, Chaetocin inhibits growth of tumor xenograft in nude mice
Dose↝, 10 animals each and were administered either with vehicle or Chaetocin (0.5 mg/kg body weight), intraperitoneally on alternate days for 25 days.

7167-

CHA,

Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism

vitro+vivo,

GBM,

A172

heterotypic xenograft glioma mouse model

in-vitro,

GBM,

T98G

in-vitro,

GBM,

U87MG

HMTs↓, Chaetocin, a histone methyltransferase inhibitor, is known to induce ROS generation.
ROS↑,
YAP/TEAD↑, Increased intracellular ROS induced (i) Yes-associated protein 1 (YAP1) expression independent of the canonical Hippo pathway as well as (ii) ATM and JNK activation.
ATM↑,
JNK↑,
Apoptosis↑, Increased interaction of YAP1 with p73 and p300 induced apoptosis in an ATM-dependent manner.
GlucoseCon↓, decreased ATP production was accompanied by a ROS/JNK-dependent decrease in cellular glucose uptake by glioma cells in the presence of Chaetocin
lactateProd↓, A significant decrease in lactate production (Figure 5d) and ATP generation (Figure 5e) was observed in Chaetocin-treated cells as compared with the untreated control.
ATP↓,
TumCP↓, Chaetocin inhibits glioma cell proliferation
TrxR↓, Chaetocin treatment reduced thioredoxin reductase activity in a dose-dependent manner with ∼40% decrease in activity observed at 1 μM concentration
Trx1↓, Chaetocin decreases the expression of TRX-1 in glioma cells
H3K9↓, The decrease in H3K9me3 levels observed upon Chaetocin treatment was reverted in the presence of ROS inhibitor NAc
p‑ATM↑, Chaetocin induced an increase in pATM and γH2AX expression in a ROS-dependent manner
γH2AX↑,
ALDOB↑, ALDOB, ENO3, FBP1, FBP2 G6PC, GCK GSK3B, GYS2, HK3, PCK1, PGK2, PGM3, PHKG1, PKLR, PRPS1L1 and PYGM) were elevated by more than 2 fold upon Chaetocin treatment
ENO3↑,
FBP1↑,
GSK‐3β↑,
HK3↑,
PCK1↑,
PGK2↑,
PGM1↑,
PGM3↑,
PHKG1↑,
PKLR↑, PKLR, up-regulated by 20.9
HK2↓, HK2, downregulated by 4.5 fold
PCNA↓, Decrease in both PCNA-positive cells and its protein level in Chaetocin-treated tumors indicated inhibition of cell proliferation

7164-

CHA,

Chaetocin induces apoptosis in human melanoma cells through the generation of reactive oxygen species and the intrinsic mitochondrial pathway, and exerts its anti-tumor activity in vivo

vitro+vivo,

Melanoma,

A375

12.55± 2.31 μM(A375)

TumCP↓, chaetocin treatment significantly suppressed cell proliferation and induced apoptosis in the Sk-Mel-28 and A375 cells in a dose- and time-dependent manner.
Apoptosis↑,
ROS↑, chaetocin treatment resulted in an increased level of cellular reactive oxygen species (ROS)
eff↓, pre-incubation of cells with N-acetylcysteine (NAC) significantly abrogated chaetocin-induced apoptosis in the melanoma cells.
MMP↓, A significant reduction of mitochondrial membrane potential and the release of cytochrome c were observed after chaetocin treatment.
Cyt‑c↑,
BAX↑, chaetocin treatment significantly up-regulated the protein levels of Bax, cleaved caspase-9/-3, simultaneously down-regulated the protein levels of Bcl-2, procaspase-9/-3, and activated caspase-9/-3 activity in the melanoma cells.
cl‑Casp3↑,
cl‑Casp9↑,
Bcl-2↓,
TumCG↓, in vivo data demonstrated that chaetocin treatment significantly inhibited the growth of melanoma tumor xenografts in nude mice, which was closely associated with apoptosis induction, a reduced level of PCNA
PCNA↓,
tumCV↓, Chaetocin inhibits cell viability of melanoma cells
NRF2↑, 5 and 10 μM of chaetocin for 4 h significantly upregulated the protein expression levels of Nrf2, SOD2and catalase compared to the control
SOD2↑,
Catalase↑,
NRF2↓, However, with the extension of chaetocin treatment to 12 h, the expression levels of Nrf2, SOD2 and catalase were markedly downregulated in the cells.
SOD2↓,
Catalase↓,
TrxR↓, Chaetocin is a natural product produced by Chaetomium species fungi, and was found to have a potent in vitro and in vivo anti-myeloma activity attributed to induction of ROS imposed by inhibition of thioredoxin reductase

2806-

CHr,

Se,

Selenium-containing chrysin and quercetin derivatives: attractive scaffolds for cancer therapy

in-vitro,

Var,

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,

6225-

CUR,

Natural products for enhancing the sensitivity or decreasing the adverse effects of anticancer drugs through regulating the redox balance

Review,

Var,

ox-Trx1↑, Curcumin increases Trx1 oxidation and subsequent apoptosis in prostate cancer cells [95].
TrxR1↓, (curcuminoid B63) has been shown to induce ROS-mediated paraptosis-like cell death by targeting TrxR1 in gastric cancer cells
TrxR↓, curcumin-induced inhibition of TrxR may depend on its Michael acceptor function.
ROS↑, leads to dramatic pro-oxidant effects, the induction of NOX activity, and the production of ROS
GSH/GSSG↓, significant decrease in the GSH/GSSG ratio was observed in lung cancer cells after treatment with curcumin
eff↓, NAC partially or completely reversed these effects, suggesting that ROS generation may be the underlying cause of curcumin-induced cell death.
Fenton↑, curcumin reduces Cu(II) to Cu(I) and leads to the formation of H2O2, which further reacts with Cu(I) through the Fenton reaction to produce •OH.
H2O2↑,
*NRF2↑, curcumin pretreatment significantly increases Nrf2 in the nucleus and decreases the expression of Keap1, as well as reverses the doxorubicin-induced reduction of HO-1 and NQO1, which provides a rational mechanism against doxorubicin-induced neurotoxi
*Keap1↓,
*HO-1↑,
*NQO1↑,
ChemoSen↑, The cisplatin and curcumin coloaded liposome system extends the drug duration and promotes drug accumulation in tumours.

6224-

CUR,

Thioredoxin reductase: An emerging pharmacologic target for radiosensitization of cancer

Review,

Var,

RadioS↑, dimethoxycurcumin (DiMC) interacts with side chains E & F of TrxR and inhibits its activity in cell-free system. DiMC significantly increased the radiosensitivity of A549 cells via suppression of TrxR activity.
TrxR↓,

6221-

CUR,

Oxidative Stress and Cancer: Harnessing the Therapeutic Potential of Curcumin and Analogues Against Cancer

Review,

Var,

NF-kB↓, NF-Kβ suppression from Cur interaction led to the identification of Cur’s immunomodulatory effects
Imm↑, on various cytokines and immune related proteins such as IL-6, TNF-α, and PD-L1 and is suggested as a potential adjuvant treatment for immunotherapy
*TAC↑, In clinical trials, Cur is shown to increase total antioxidant capacity (TAC) and decrease malondialdehyde.53
*MDA↓,
ROS↑, increases overall ROS accumulation in SiHa cervical cancer cells resulting in increased autophagy and G2/M phase cell cycle arrest.54
TumAuto↑,
TumCCA↑,
Keap1↑, activate KEAP1/NRF2/ARE pathways and serve as an effective therapeutic especially in combination with 5-FU
ChemoSen↑,
ER Stress↑, administration of 1g resulted in ROS production, G1 cell cycle phase arrest, and increased ER-stress which was reversed upon addition of NAC, an ROS scavenging agent
eff↓, reversed upon addition of NAC
TrxR↓, Non-small cell lung cancer cell lines showed marked increases in apoptosis and ferroptosis driven by the analogs ability to generate ROS through TrxR inhibition.
STAT3↓, analog WZ26 increased ROS and cell death in cholangiocarcinoma via STAT3 inhibition
*BioAv↓, Studies with doses as high as 12 g/day still resulted in small amounts of traceable plasma Cur, mostly due to low absorption in the small intestine and rapid elimination in the body via the gall bladder.

6218-

CUR,

Exploring the Thioredoxin System as a Therapeutic Target in Cancer: Mechanisms and Implications

Review,

Var,

NF-kB↓, curcumin inhibits, among others, NF-κB and TrxR [177].
TrxR↓,
ROS↑, Several studies show that curcumin leads to an accumulation of ROS in tumor cells, inhibiting metastasis formation and inducing cell death and/or sensitizing the cells to radiation
TumMeta↓,
TumCD↑,
RadioS↑,
BioAv↝, Curcumin exhibits limitations for potential clinical applications due to its poor water solubility. Therefore, analogues have been developed, such as WZ26, which inhibits TrxR and restricts the proliferation and survival of tumor cells
BioAv↑, Phase I trial with theracurmin, a curcumin derivative that demonstrates higher bioavailability than curcumin, it was shown that a combination with irinotecan is safe and well-tolerated in patients with advanced solid tumors

1982-

CUR,

Inhibition of thioredoxin reductase by curcumin analogs

in-vitro,

NA,

IC50 values from the nano to
the low micromolar range.

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,

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

10 µM

in-vitro,

Laryn,

FaDu

10 µM

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,

MCF7

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

6238-

CUSP9,

A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: CUSP9v3

Trial,

GBM,

Ten adults with histologically confirmed GBM and recurrent or progressive disease were included.

toxicity↓, CUSP9v3 is safe in patients with recurrent GBM.
TrxR↓, The anti-rheumatoid arthritis drug auranofin inhibits thioredoxin reductase, resulting in increased intracellular reactive oxygen species
ROS↓,
TumCI↓, The anti-hypertensive captopril reduces invasion, migration and adhesion of GBM cell activity through soluble matrix metalloproteinase (MMP)-2 and MMP-9 inhibition.12
TumCMig↓,
TumCA↓,
MMP2↓,
MMP9↓,
COX2↓, celecoxib has long been shown to have anticancer properties related to cyclooxygenase-2 inhibition and has demonstrated encouraging results in combination with low-dose temozolomide
ALDH↓, alcohol deterrent disulfiram is consistently cytotoxic to a wide range of cancer cells and is effective against GBM stem cells through aldehyde dehydrogenase inhibition.15
TumAuto↑, itraconazole likely exerts its anticancer activity due to its multiple pharmacological effects16 with specific data in GBM pointing towards an effect on autophagy
P-gp↓, the antidepressant sertraline was included for its ability to inhibit P-glycoprotein at the blood-brain barrier21
eff↑, Best overall response was stable disease (SD) in 6 patients and progressive disease (PD) in 4 patients

6237-

CUSP9,

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

NA,

GBM,

PI3K↓, ARTESUNATE phosphoinositide 3-kinase, Akt, increases ROS, NF-κB activation, TNF-alpha, IL-6, TLR2,
Akt↓,
ROS↑,
NF-kB↓,
TNF-α↓,
TLR2↓,
other↓, APREPITANT 10 hrs NK-1 receptors
TrxR↓, AURANOFIN 10 days thioredoxin, increases ROS, STAT3
STAT3↓,
MMPs↓, CAPTOPRIL 2 hrs ACE, AT1 receptors, MMPs
COX1↓, CELECOXIB 9 hrs COX-1 and -2, carbonic anhydrase -2 and -9
COX2↓,
CA↓,
ALDH↓, DISULFIRAM ALDH, increases ROS
P-gp↓, ITRACONAZOLE P-gp efflux transporters, BCRP, Hedgehog, 5-lipoxygenase
HH↓,
5LO↓,
mTOR↓, RITONAVIR P-gp efflux transporters [weak], Akt, mTOR, cyclin D3, proteasome,
CycD3↓,
Proteasome↓,
other↓, SERTRALINE Akt, mTOR, TCTP
MMP2↓, Captopril inhibited the activity of soluble MMP-2 and MMP-9
MMP9↓,
ALDH↓, Disulfiram potent inhibitor of all isoforms of aldehyde dehydrogenase, ALDH, disulfiram stops ethanol metabolism at the acetaldehyde stage
Copper↓, Since disulfiram chelates Cu++ in the stomach even without adding exogenous Cu

7450-

CYN,

Cynaropicrin Induces Cell Cycle Arrest and Apoptosis by Inhibiting PKM2 to Cause DNA Damage and Mitochondrial Fission in A549 Cells

in-vitro,

Lung,

A549

in-vitro,

Nor,

BEAS-2B

PKM2↓, CYN not only inhibited the purified PKM2 activity but also decreased the cellular PKM2 expression in A549 cells.
P53↑, The inhibition of PKM2 leads to the upregulation of p53 and the downregulation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP), and subsequently causes the cell cycle arrest.
PARP↓, The results revealed that CYN promoted the downregulation of the DNA repair enzyme PARP and upregulation of p53 in A549 cells in a dose-dependent manner
TumCCA↑,
selectivity↑, CYN Preferential Killing of A549 and H1299 over BEAS-2B Cells.
DNAdam↑, CYN Induced the DNA Damage and then Cell Cycle Arrest by Targeting PKM2.
NRF2↓, This observation, i.e. the decreased Nrf2 level in the immunocomplex, could be due to the decrease of PKM2 expression caused by CYN
NQO1↓, decreased interaction of PKM2 with Nrf2 resulted in downregulated NQO1/TrxR/Trx expression
TrxR↓,
Trx↓,
ROS↑, Hence, ROS level in A549 cells was likely to increase, triggering oxidative stress, once the expression of NQO1/TrxR/Trx was inhibited.
MMP↓, CYN Induced the Decrease of MMP and Mitochondrial Fission by Targeting PKM2.
Cyt‑c↑, resulting in the release of cytochrome c from mitochondria to the cytoplasm, and cytochrome c could activate caspase-3 and induce apoptosis.
Casp3↑,
Apoptosis↑,

7446-

CYN,

Promotion of HeLa cells apoptosis by cynaropicrin involving inhibition of thioredoxin reductase and induction of oxidative stress

in-vitro,

Cerv,

HeLa

ROS↑, Most of these functions are concomitant with the production of reactive oxygen species (ROS).
Apoptosis↑, CYN induces apoptosis of Hela cells.
TrxR↓, CYN impinges on the thioredoxin system via inhibition of TrxR, which leads to Trx oxidation and ROS accumulation in HeLa cells.

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,

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

1.2 uM

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

185nM

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

7087-

GAR,

Garcinol as an Epigenetic Modulator: Mechanisms of Anti-Cancer Activity and Therapeutic Potential

Review,

Var,

HATs↓, Its activities include inhibition of histone acetyltransferases (HATs)
p300↓, By inhibiting HAT enzymes such as p300/CBP and PCAF, garcinol affects the acetylation status of multiple transcription factors and histones,
CBP↓,
NF-kB↓, including NF-κB, STAT3, PI3K/AKT, MAPK, and Wnt/β-catenin, resulting in the suppression of inflammation, angiogenesis, proliferation, and metastasis.
STAT3↓, inhibition of NF-kB, STAT 3, P13/Akt, COX-2, MAPK pathways
PI3K↓,
Akt↓,
MAPK↓,
Wnt↓,
β-catenin/ZEB1↓,
Inflam↓,
angioG↓,
TumCP↓,
TumMeta↓,
TumCCA↑, figure 3
EMT↓, inhibition of epithelial-to-mesenchymal transition (EMT), and cancer stem cell targeting.
CSCs↓,
P53↑, garcinol activates tumor-suppressor proteins such as p53 and inhibits thioredoxin reductase, resulting in elevated intracellular reactive oxygen species (ROS).
TrxR↓,
ROS↑,
JNK↑, The accumulation of ROS subsequently stimulates JNK activation and DNA damage signaling, reinforcing p53 function and promoting apoptosis rather than mere growth inhibition
DNAdam↑,
mt-Apoptosis↑, showing activation of mitochondrial apoptosis through the ROS/JNK/ATF-2/Bcl-2 axis
ER Stress↑, In rhabdomyosarcoma cells, garcinol was also shown to trigger endoplasmic reticulum (ER) stress, elevating the expression of stress-responsive genes such as DDIT3, DDIT4, TRIB3, and SESN2, which facilitate apoptosis under prolonged stress [
CHOP/DDIT3↑,
DDIT4↑,
TRIB3↑,
SESN2↑,
miR-218↑, garcinol upregulates let-c family miRNAs and miR-218 in breast cancer and NSCLC cells by the suppression of EMT and stemness
eff↑, When combined with HDAC inhibitors such as SAHA (Suberoylanilide Hydroxamic Acid), also known by its clinical name Vorinostat, garcinol provides complementary effects on maintaining histone acetylation balance,
ChemoSen↑, when used alongside chemotherapeutic agents such as doxorubicin or cisplatin, garcinol sensitizes resistant tumor cells by restoring apoptotic gene expression and overcoming drug resistance mechanisms
BioAv↓, garcinol suffers from poor aqueous solubility, rapid metabolism, and limited bioavailability,
Half-Life↓,
BioAv↑, These nanoformulations have demonstrated enhanced cellular uptake, prolonged plasma half-life, and superior cytotoxicity in breast, colon, and lung cancer models compared with free garcinol

1901-

GoldNP,

Rad,

The role of thioredoxin reductase in gold nanoparticle radiosensitization effects

in-vitro,

Lung,

A549

10nm, 50 ug Au/ml

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

Showing Research Papers: 1 to 50 of 71
Page 1 of 2 Next

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 71

Pathway results for Effect on Cancer / Diseased Cells:

Infection & Microbiome(tgid=24) ⓘ

Bacteria↓, 1,
Total Targets: 223

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress(tgid=1) ⓘ

HO-1↑, 1, Keap1↓, 1, MDA↓, 1, NQO1↑, 1, NRF2↑, 1, ROS∅, 1, TAC↑, 1, Thiols↓, 1, TrxR↓, 2,

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↓, 1,

Infection & Microbiome(tgid=24) ⓘ

Bacteria?, 1,
Total Targets: 11

Scientific Paper Hit Count for: TrxR, Thioredoxin Reductase

15 Auranofin
10 Curcumin
10 Piperlongumine
8 Silver-NanoParticles
5 chaetocin
4 Gold NanoParticles
3 Selenium
3 Radiotherapy/Radiation
3 Gambogic Acid
3 Sulforaphane (mainly Broccoli)
2 Copper and Cu NanoParticles
2 CUSP9
2 Cynaropicrin
2 EGCG (Epigallocatechin Gallate)
2 Myricetin
1 Allicin (mainly Garlic)
1 Ashwagandha(Withaferin A)
1 Sorafenib (brand name Nexavar)
1 Baicalein
1 Chrysin
1 Garcinol
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#:%
  wNotes=on  sortOrder:rid,rpid

TrxR Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

NA, unassigned(tgid=0) ⓘ

Redox & Oxidative Stress(tgid=1) ⓘ

Mitochondria & Bioenergetics(tgid=3) ⓘ

Core Metabolism/Glycolysis(tgid=4) ⓘ

Cell Death(tgid=5) ⓘ

Kinase & Signal Transduction(tgid=6) ⓘ

Transcription & Epigenetics(tgid=7) ⓘ

Protein Folding & ER Stress(tgid=8) ⓘ

Autophagy & Lysosomes(tgid=9) ⓘ

DNA Damage & Repair(tgid=10) ⓘ

Cell Cycle & Senescence(tgid=11) ⓘ

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

Migration(tgid=13) ⓘ

Angiogenesis & Vasculature(tgid=14) ⓘ

Barriers & Transport(tgid=15) ⓘ

Immune & Inflammatory Signaling(tgid=16) ⓘ

Hormonal & Nuclear Receptors(tgid=20) ⓘ

Drug Metabolism & Resistance(tgid=21) ⓘ

Clinical Biomarkers(tgid=22) ⓘ

Functional Outcomes(tgid=23) ⓘ

Infection & Microbiome(tgid=24) ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress(tgid=1) ⓘ

Drug Metabolism & Resistance(tgid=21) ⓘ

Infection & Microbiome(tgid=24) ⓘ

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