PERK Cancer Research Results

PERK, protein kinase-like ER kinase: Click to Expand ⟱

Source:

Type:

PERK is a type of kinase that is activated in response to endoplasmic reticulum (ER) stress, which occurs when the ER is overwhelmed with unfolded or misfolded proteins. Once activated, PERK phosphorylates and activates the eukaryotic translation initiation factor 2 alpha (eIF2α), leading to the attenuation of global protein synthesis and the induction of specific genes involved in the UPR.
PERK is overexpressed in various types of cancer, including breast, lung, and colon cancer, and that its expression is often associated with poor prognosis.
PERK has been shown to have both tumor-suppressive and tumor-promoting roles, depending on the context.
-PERK, as the sensor of ER stress.

Scientific Papers found: Click to Expand⟱

4561-

AgNPs,

VitC,

Cellular Effects Nanosilver on Cancer and Non-cancer Cells: Potential Environmental and Human Health Impacts

in-vitro,

CRC,

HCT116

in-vitro,

Nor,

HEK293

NRF2↑, Nanosilver increased Nrf2 protein expression and disrupted the cell cycle at the G1 and G2/M phases.
TumCCA↑, AgNPs interact with DNA to stop the cell cycle and lead to apoptosis
ROS↑, Nanosilver induced significant mitochondrial oxidative stress in HCT116, whereas it did not in the non-cancer HIEC-6 and nanosilver/sodium ascorbate co-treatment was preferentially lethal to HCT116 cells,
selectivity↑,
*AntiViral↑, AgNPs are effective antiviral agents against various viruses such as human immunodeficiency virus, hepatitis B virus, and monkey pox virus through interaction with surface glycoproteins on the virus
*toxicity↝, Citrate and PVP-coated AgNPs have been found to be less toxic than non-coated AgNPs
ETC↓, AgNPs affects mitochondrial function through the disruption of the electron transport chain2,24,26,33,39–41
MMP↓, Studies have shown that exposure to AgNPs resulted in a decrease of mitochondrial membrane potential (MMP) in various in vitro and in vivo experiments
DNAdam↑, AgNPs has also been shown to interact with and induce damage to DNA, DNA strand breaks, DNA damage
Apoptosis↑, apoptosis induced by AgNPs were through membrane lipid peroxidation, ROS, and oxidative stress
lipid-P↑,
other↝, Several studies have showed AgNPs interact with various proteins such as haemoglobin, serum albumin, metallothioneins, copper transporters, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), malate dehydrogenase (MDH), and bacterial proteins.
UPR↑, Studies have shown exposure to AgNPs induces activation of the UPR
*GRP78/BiP↑, AgNPs induced increased levels of GRP78, phosphorylated PERK, phosphorylated eIF2-α, and phosphorylated IRE1α, spliced XBP1, cleaved ATF-6, CHOP, JNK and caspase 12
*p‑PERK↑,
*cl‑eIF2α↑,
*CHOP↑,
*JNK↑,
Hif1a↓, One study showed AgNPs inhibits HIF-1 accumulation and suppresses expression of HIF-1 target genes in breast cancer cells (MCF-7) and also found the protein levels of HIF-1α and HIF-1β decreased
AntiCan↑, Many studies have shown that ascorbic acid, on its own, has anti-cancer effects
*toxicity↓, However, when the rats were treated with both ascorbic acid and AgNPs, a decrease in toxic effects was observed in non-cancer parotid glands in rats
eff↑, Studies have shown both AgNPs and ascorbic acid have greater effects and toxicity in cancer cells relative to non-cancer cells

5145-

AgNPs,

Silver nanoparticles induce irremediable endoplasmic reticulum stress leading to unfolded protein response dependent apoptosis in breast cancer cells

in-vitro,

BC,

MCF-7

in-vitro,

BC,

T47D

Bacteria↓, Nowadays, silver nanoparticles (AgNP) are widely used in the medical field mainly for their antibacterial properties
Apoptosis↑, AgNP of 2 (AgNP2) and 15 nm (AgNP15) induce apoptosis in human MCF-7 and T-47D breast cancer cells.
ER Stress↑, Treatment with AgNP2 and AgNP15 led to accumulation and aggregation of misfolded proteins causing an endoplasmic reticulum (ER) stress and activating the unfolded protein response (UPR).
UPR↑,
PERK↑, The three main ER sensors, PERK, IRE-1α and ATF-6, were rapidly activated in response to AgNP2 and AgNP15
IRE1↑,
ATF6↑,
ATF4↑, AgNP2 and AgNP15 induced upregulation of the transcription factors ATF-4 and GADD153/CHOP
CHOP↑,
Casp9↑, Moreover, the initiating caspase-9 and the effector caspase-7 were activated in response to these NPs.
Casp7↑,
Mcl-1↓, In contrast, a downregulation of Mcl-1 and xIAP protein expression as well as a processing of PARP were observed.
XIAP↓,
PARP↝,
selectivity↑, Of note, the non-cancerous MCF-10A cells were more resistant to both AgNP2 and AgNP15 when compared to MCF-7 and T-47D cell lines.

319-

AgNPs,

Endoplasmic reticulum stress signaling is involved in silver nanoparticles-induced apoptosis

Apoptosis↑,
Ca+2↑, mitochondrial Ca(2+) overloading
ER Stress↑,
PERK↑, ER stress marker
IRE1↑, ER stress marker
cl‑ATF6↑, ATF6, ER stress marker

354-

AgNPs,

Silver nanoparticles induce SH-SY5Y cell apoptosis via endoplasmic reticulum- and mitochondrial pathways that lengthen endoplasmic reticulum-mitochondria contact sites and alter inositol-3-phosphate receptor function

in-vitro,

neuroblastoma,

SH-SY5Y

  Ca2+ overload and disrupted homeostasis in the mitochondria triggered apoptotic cell death.

TumCD↑, dose dependent manner
ER Stress↑,
GRP78/BiP↑,
p‑PERK↑, p-PERK
CHOP↑,
Ca+2↑, enhanced mitochondrial Ca2+ uptake
XBP-1↑,
p‑IRE1↑,

3384-

ART/DHA,

Dihydroartemisinin triggers ferroptosis in primary liver cancer cells by promoting and unfolded protein response‑induced upregulation of CHAC1 expression

in-vitro,

Liver,

Hep3B

29.4±1.7 µM

in-vitro,

Liver,

HUH7

32.1±4.5 µM

in-vitro,

Liver,

HepG2

40.2±2.1 µM

Ferroptosis↑, DHA displayed classic features of ferroptosis, such as increased lipid reactive oxygen species
ROS↑,
GSH↓, decreased activity or expression of glutathione (GSH), glutathione peroxidase 4, solute carrier family (SLC) 7 member 11 and SLC family 3 member 2.
UPR↑, DHA activated all three branches of the UPR
GPx4↓, GSH depletion leads to the suppression of glutathione peroxidase (GPX)4, a key glutathione peroxidase known to catalyze the reduction of lipid ROS
PERK↑, DHA was found to activate PERK/eIF2α/ATF4
eIF2α↑,
ATF4↑,

3387-

ART/DHA,

Ferroptosis: A New Research Direction of Artemisinin and Its Derivatives in Anti-Cancer Treatment

Review,

Var,

BioAv↓, Artemisinin, extracted from Artemisia annua L., is a poorly water-soluble antimalarial drug
lipid-P↑, promote the accumulation of intracellular lipid peroxides to induce cancer cell ferroptosis, alleviating cancer development and resulting in strong anti-cancer effects in vitro and in vivo.
Ferroptosis↑,
Iron↑, Artemisinin and Its Derivatives Upregulate Fe2+ Levels in Cancer Cells
GPx4↓, GPX4-dependent defense system is significantly inhibited
GSH↓, , leading to a significant decrease in GSH, GPX4, and SLC7A11 protein expression
P53↑, ARTEs can upregulate p53 protein expression in multiple cancer cells
ER Stress↑, ARTEs can trigger ERS in cancer cells to activate the PERK-ATF4 pathway and upregulate GRP78 expression
PERK↑,
ATF4↑,
GRP78/BiP↑,
CHOP↑, which activates CHOP
ROS↑, promoting the accumulation of intracellular ROS, and leading to ferroptosis
NRF2↑, ARTEs can activate the nuclear factor erythroid-derived 2-like 2 (Nrf2) -γ-glutamyl-peptide pathway in cancer cells, resulting in cancer cell ferroptosis resistance

2001-

Ash,

Withania somnifera: from prevention to treatment of cancer

Review,

Var,

toxicity↓, Some sedation, ptosis and ataxia were observed in Sprague-Dawley rats 15–20 minutes of administering a herbal concoction that contained WS at a large dose of 1–2 g/kg body weight [36]
TumW↓, Induction of apoptosis by WA has been noted in some in vivo models where treatment with 4 mg/kg WA, i.p. 5 times for 2 weeks markedly reduced MDA-MB-231 tumor weights in nude mice as well as increased apoptosis compared to tumors in control mice [56
Dose?, 20 mg/kg, oral 3X/wk for 14 wk Hamster Head and Neck Example
eff↝, showed that this chemopreventive capacity was dependent on a circadian pattern where hamsters dosed with WA at 8 AM and 12 PM showed 100% protection from oral tumor formation while those treated at 12 AM showed 50% incidence in oral tumors
Ki-67↓, WA treatment resulted in retarded tumor growth; reduction in cell proliferation marker Ki-67, survivin, and XIAP,
survivin↓,
XIAP↓,
PERK↑, higher protein expression of pERK, pRSK, CHOP and DR-5 was also observed in the WA-treated group compared to control.
p‑RSK↑,
CHOP↑,
DR5↑,
Dose↝, Clinically diagnosed schizophrenia patients who had received antipsychotic medications for 6 months or more received either a capsule with 400 mg of WS extract (n=15), three times daily, for 1 month [80]
BG↓, Results after one month showed significant reduction in serum triglycerides and fasting blood glucose levels in the WS extract- treated group compared to the placebo
DNMTs↓, in MCF7 and MDA-MB-231 breast cancer cells WA treatment suppressed transcription of DNMT.

2296-

Ba,

The most recent progress of baicalein in its anti-neoplastic effects and mechanisms

Review,

Var,

CDK1↓, graphical abstract
Cyc↓,
p27↑,
P21↑,
P53↑,
TumCCA↑, Cell cycle arrest
TumCI↓, Inhibit invastion
MMP2↓,
MMP9↓,
E-cadherin↑,
N-cadherin↓,
Vim↓,
LC3A↑,
p62↓,
p‑mTOR↓,
PD-L1↓,
CAFs/TAFs↓,
VEGF↓,
ROCK1↓,
Bcl-2↓,
Bcl-xL↓,
BAX↑,
ROS↑,
cl‑PARP↑,
Casp3↑,
Casp9↑,
PTEN↑, A549, H460
MMP↓, ↓mitochondrial transmembrane potential, redistribution of cytochrome c,
Cyt‑c↑,
Ca+2↑, ↑Ca2+
PERK↑, ↑PERK, ↑IRE1α, ↑CHOP,
IRE1↑,
CHOP↑,
Copper↑, ↑Cu+2
Snail↓, ↓Snail, ↓vimentin, ↓Twist1,
Vim↓,
Twist↓,
GSH↓, ↑ROS, ↓GSH, ↑MDA, ↓MMP, ↓NRF2, ↓HO-1, ↓GPX4, ↓FTH1, ↑TFR1, ↓p-JAK2, ↓p-STAT3
NRF2↓,
HO-1↓,
GPx4↓,
XIAP↓, ↓Bcl-2, ↓Bcl-xL, ↓XIAP, ↓surviving
survivin↓,
DR5↑, ↑ROS, ↑DR5

5542-

BBM,

Pharmacological profiling of a berbamine derivative for lymphoma treatment

vitro+vivo,

lymphoma,

CaMKII ↓, PA4 is a potent CAMKIIγ inhibitor.
TumCG↓, PA4 significantly impeded tumor growth in vivo in a xenograft T-cell lymphoma mouse model.
cMyc↓, PA4 reduced c-Myc levels and induced ROS in lymphoma cells
ROS↑,
UPR↑, Unfolded protein response (UPR) was elevated after PA4 treatment
ER Stress↑, UPR induces ER stress
PERK↑, PA4 treatment significantly increased protein kinase RNA-like ER kinase (PERK)
BioAv↑, Both BBM and PA4 were rapidly absorbed into the blood and detected 5 minutes after oral administration.
toxicity↓, mice received oral gavage with 50 mg/kg PA4 daily for 12 consecutive days (n = 6). After 12 days, there were no mortalities and no significant reductions in body weight (Figure 7D). Serum alanine aminotransferase and aspartate aminotransferase levels

5591-

BetA,

Advances and challenges in betulinic acid therapeutics and delivery systems for breast cancer prevention and treatment

Review,

BC,

IC50 values ranging from 1 to 13.0 μg mL−1

BioAv↓, However, its poor water solubility limits its optimal therapeutic potential.
BioAv↑, nano-drug delivery systems (NDDSs) have gained significant attention as a method to substantially improve low solubility and poor drug bioavailability, enhance targeted drug delivery, and reduce side effects.
selectivity↑, reviews by Simone Fulda23,24 strengthened BA's potential for cancer treatment and prevention, particularly its ability to selectively trigger apoptosis in cancer cells while causing minimal harm to normal cells.
eff↑, It is important to note that the anticancer effects of BA on different types of tumors are more potent at a pH lower than 6.8.34
angioG↓, figure 3
*antiOx↑,
*Inflam↓,
MMP↓, BA-induced mitochondrial depolarization
Bcl-2↓, BA treatment has been shown to lower Bcl-2 expression and increase Bax, resulting in the activation of caspase-9 and caspase-3 through the mitochondrial pathway.63
BAX↑,
Casp9↑,
Casp3↑,
GRP78/BiP?, BA directly targets GRP78, triggering ER stress by activating the PERK-eIF2α-CHOP apoptotic cascade
ER Stress↑,
PERK↑,
CHOP↑,
ChemoSen↑, BA's ability to chemosensitize BC cells to taxanes highlights its importance in situations of drug resistance
SESN2↑, Under hypoxia, BA strongly increases SESN2 expression.
ROS↑, Reducing SESN2 levels enhances BA-induced ROS production, DNA damage, and radiosensitivity, while decreasing autophagic flux, indicating that SESN2-mediated autophagy serves as a protective adaptive response.68
MOMP↓, decreases the mitochondrial outer membrane potential (MOMP),
MAPK↑, This leads to the activation of p38 Mitogen-activated protein kinase (p38 MAPK), the release of cytochrome C, apoptosis-inducing factor (AIF),
Cyt‑c↑,
AIF↑,
STAT3↓, BA suppresses the signal transducer and activator of transcription (STAT) 3 signaling pathways
FAK↓, BA's inhibition of STAT3, as well as FAK, leads to decreased expression of MMPs and elevated TIMP-2, thereby impairing cancer cell migration and invasion
TIMP2↑,
TumCMig↓,
TumCI↓,
Sp1/3/4↓, Sp inhibition reduces cancer gene expression, inhibiting cancer cell growth.
TumCCA↑, It increases cell numbers in the G2/M phase, leading to cell cycle arrest.
DNAdam↑, causes DNA damage, thereby inhibiting the progression and invasion of cancer cells.

2729-

BetA,

Betulinic acid in the treatment of tumour diseases: Application and research progress

Review,

Var,

ChemoSen↑, Betulinic acid can increase the sensitivity of cancer cells to other chemotherapy drugs
mt-ROS↑, BA has antitumour activity, and its mechanisms of action mainly include the induction of mitochondrial oxidative stress
STAT3↓, inhibition of signal transducer and activator of transcription 3 and nuclear factor-κB signalling pathways.
NF-kB↓,
selectivity↑, A main advantage of BA and its derivatives is that they are cytotoxic to different human tumour cells, while cytotoxicity is much lower in normal cells.
*toxicity↓, It can kill cancer cells but has no obvious effect on normal cells and is also nontoxic to other organs in xenograft mice at a dose of 500 mg/kg
eff↑, BA combined with chemotherapy drugs, such as platinum and mithramycin A, can induce apoptosis in tumour cells
GRP78/BiP↑, In animal xenograft tumour models, BA enhanced the expression of glucose-regulated protein 78 (GRP78)
MMP2↓, reduced the levels of matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, in lung metastatic lesions of breast cancer, indicating that BA can reduce the invasiveness of breast cancer in vivo and block epithelial mesenchymal transformation (EMT
P90RSK↓,
TumCI↓,
EMT↓,
MALAT1↓, MALAT1, a lncRNA, was downregulated in hepatocellular carcinoma (HCC) cells treated with BA in vivo,
Glycolysis↓, Suppressing aerobic glycolysis of cancer cells by GRP78/β-Catenin/c-Myc signalling pathways
AMPK↑, activating AMPK signaling pathway
Sp1/3/4↓, inhibiting Sp1. BA at 20 mg/kg/d, the tumour volume and weight were significantly reduced, and the expression levels of Sp1, Sp3, and Sp4 in tumour tissues were lower than those in control mouse tissues
Hif1a↓, Suppressing the hypoxia-induced accumulation of HIF-1α and expression of HIF target genes
angioG↓, PC3: Having anti-angiogenesis effect
NF-kB↑, LNCaP, DU145 — Inducing apoptosis and NF-κB pathway
NF-kB↓, U266 — Inhibiting NF-κB pathway.
MMP↓, BA produces ROS and reduces mitochondrial membrane potential; the mitochondrial permeability transition pore of the mitochondrial membrane plays an important role in apoptosis signal transduction.
Cyt‑c↑, Mitochondria release cytochrome C and increase the levels of Caspase-9 and Caspase-3, inducing cell apoptosis.
Casp9↑,
Casp3↑,
RadioS↑, BA could be a promising drug for increasing radiosensitization in oral squamous cell carcinoma radiotherapy.
PERK↑, BA treatment increased the activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptosis pathway and decreased the expression of Sp1.
CHOP↑,
*toxicity↓, BA at a concentration of 50 μg/ml did not inhibit the growth of normal peripheral blood lymphocytes, indicating that the toxicity of BA was at least 1000 times less than that of doxorubicin

2732-

BetA,

Chemo,

Betulinic acid chemosensitizes breast cancer by triggering ER stress-mediated apoptosis by directly targeting GRP78

in-vitro,

BC,

MCF-7

18.411

in-vitro,

BC,

MDA-MB-231

20.465 μM

in-vitro,

Nor,

MCF10

ChemoSen↑, Here in, we found that BA has synergistic effects with taxol to induce breast cancer cells G2/M checkpoint arrest and apoptosis induction,
selectivity↑, but had little cytotoxicity effects on normal mammary epithelial cells.
GRP78/BiP↑, identified glucose-regulated protein 78 (GRP78) as the direct interacting target of BA.
ER Stress↑, BA administration significantly elevated GRP78-mediated endoplasmic reticulum (ER) stress and resulted in the activation of protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2a/CCAAT/enhancer-binding protein homologous protein apopt
PERK↑,
Ca+2↑, We found that BA significantly elevated intracellular free calcium concentration
Cyt‑c↑, increased Cytochrome c and Bax, and the downregulation of Bcl-2
BAX↑,
Bcl-2↓,

2738-

BetA,

Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway

in-vitro,

BC,

MDA-MB-231

in-vitro,

BC,

BT549

in-vivo,

NA,

mice

TumCI↓, BA inhibited invasion and migration of highly aggressive breast cancer cells.
TumCMig↓,
Glycolysis↓, Moreover, BA could suppress aerobic glycolysis of breast cancer cells presenting as a reduction of lactate production, quiescent energy phenotype transition, and downregulation of aerobic glycolysis-related proteins.
lactateProd↓, lactate production in both MDA-MB-231 and BT-549 cells was significantly reduced following BA administration
GRP78/BiP↑, (GRP78) was also identified as the molecular target of BA in inhibiting aerobic glycolysis. BA treatment led to GRP78 overexpression, and GRP78 knockdown abrogated the inhibitory effect of BA on glycolysis.
ER Stress↑, Further studies demonstrated that overexpressed GRP78 activated the endoplasmic reticulum (ER) stress sensor PERK.
PERK↑,
p‑eIF2α↑, Subsequent phosphorylation of eIF2α led to the inhibition of β-catenin expression, which resulted in the inhibition of c-Myc-mediated glycolysis.
β-catenin/ZEB1↓,
cMyc↓, These findings suggested that BA inhibited the β-catenin/c-Myc pathway by interrupting the binding between GRP78 and PERK and ultimately suppressed the glycolysis of breast cancer cells.
ROS↑, (i) the induction of cancer cell apoptosis via the mitochondrial pathway induced by the release of soluble factors or generation of reactive oxygen species (ROS)
angioG↓, (ii) the inhibition of angiogenesis [24];
Sp1/3/4↓, (iii) the degradation of transcription factor specificity protein 1 (Sp1)
DNAdam↑, (iv) the induction of DNA damage by suppressing topoisomerase I
TOP1↓,
TumMeta↓, BA Inhibits Metastasis of Highly Aggressive Breast Cancer Cells
MMP2↓, BA significantly decreased the expression of MMP-2 and MMP-9 secreted by breast cancer cells
MMP9↓,
N-cadherin↓, BA downregulated the levels of N-cadherin and vimentin as the mesenchymal markers, while increased E-cadherin which is an epithelial marker (Figure 2(c)), validating the EMT inhibition effects of BA in breast cancer cells.
Vim↓,
E-cadherin↑,
EMT↓,
LDHA↓, the levels of glycolytic enzymes, including LDHA and p-PDK1/PDK1, were all decreased in a dose-dependent manner by BA
p‑PDK1↓,
PDK1↓,
ECAR↓, extracellular acidification rate (ECAR), which reflects the glycolysis activity, was retarded following BA administration.
OCR↓, oxygen consumption rate (OCR), which is a marker of mitochondrial respiration, was also decreased simultaneously
Hif1a↓, BA could reduce prostate cancer angiogenesis via inhibiting the HIF-1α/stat3 pathway [39]
STAT3↓,

5674-

BTZ,

Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic, anti-tumor effects

in-vivo,

GBM,

in-vivo,

HNSCC,

ER Stress↑, Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK and IRE1α
GRP78/BiP↑,
CHOP↑,
PERK↑,
IRE1↑,
UPR↑, and the UPR (induction of hsp40, 70 and 90)
HSP70/HSPA5↑,
HSP90↑,
eff↑, combination of bortezomib and 34.5ENVE significantly enhanced anti-tumor efficacy in multiple different tumor models in vivo.

2782-

CHr,

Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives

Review,

Var,

Review,

Stroke,

Review,

Park,

*antiOx↑, antioxidant, anti-inflammatory, hepatoprotective, neuroprotective
*Inflam↓, inhibitory effect of chrysin on inflammation and oxidative stress is also important in Parkinson’s disease
*hepatoP↑,
*neuroP↑,
*BioAv↓, Accumulating data demonstrates that poor absorption, rapid metabolism, and systemic elimination are responsible for poor bioavailability of chrysin in humans that, subsequently, restrict its therapeutic effects
*cardioP↑, cardioprotective [69], lipid-lowering effect [70]
*lipidLev↓,
*RenoP↑, Renoprotective
*TNF-α↓, chrysin reduces levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2).
*IL2↓,
*PI3K↓, induction of the PI3K/Akt signaling pathway by chrysin contributes to a reduction in oxidative stress and inflammation during cerebral I/R injury
*Akt↓,
*ROS↓,
*cognitive↑, Chrysin (25, 50, and 100 mg/kg) improves cognitive capacity, inflammation, and apoptosis to ameliorate traumatic brain injury
eff↑, chrysin and silibinin is beneficial in suppressing breast cancer malignancy via decreasing cancer proliferation
cycD1/CCND1↓, chrysin and silibinin induced cell cycle arrest via down-regulation of cyclin D1 and hTERT
hTERT/TERT↓,
VEGF↓, Administration of chrysin is associated with the disruption of hypoxia-induced VEGF gene expression
p‑STAT3↓, chrysin is capable of reducing STAT3 phosphorylation in hypoxic conditions without affecting the HIF-1α protein level.
TumMeta↓, chrysin is a potent agent in suppressing metastasis and proliferation of breast cancer cells during hypoxic conditions
TumCP↓,
eff↑, combination therapy of breast cancer cells using chrysin and metformin exerts a synergistic effect and is more efficient compared to chrysin alone
eff↑, combination of quercetin and chrysin reduced levels of pro-inflammatory factors, such as IL-1β, Il-6, TNF-α, and IL-10, via NF-κB down-regulation.
IL1β↓,
IL6↓,
NF-kB↓,
ROS↑, after chrysin administration, an increase occurs in levels of ROS that, subsequently, impairs the integrity of the mitochondrial membrane, leading to cytochrome C release and apoptosis induction
MMP↓,
Cyt‑c↑,
Apoptosis↑,
ER Stress↑, in addition to mitochondria, ER can also participate in apoptosis
Ca+2↑, Upon chrysin administration, an increase occurs in levels of ROS and cytoplasmic Ca2+ that mediate apoptosis induction in OC cells
TET1↑, In MKN45 cells, chrysin promotes the expression of TET1
Let-7↑, Chrysin is capable of promoting the expression of miR-9 and Let-7a as onco-suppressor factors in cancer to inhibit the proliferation of GC cells
Twist↓, Down-regulation of NF-κB, and subsequent decrease in Twist/EMT are mediated by chrysin administration, negatively affecting cervical cancer metastasis
EMT↓,
TumCCA↑, nduction of cell cycle arrest and apoptosis via up-regulation of caspase-3, caspase-9, and Bax are mediated by chrysin
Casp3↑,
Casp9↑,
BAX↑,
HK2↓, Chrysin administration (15, 30, and 60 mM) reduces the expression of HK-2 in hepatocellular carcinoma (HCC) cells to impair glucose uptake and lactate production.
GlucoseCon↓,
lactateProd↓,
Glycolysis↓, In addition to glycolysis metabolism impairment, the inhibitory effect of chrysin on HK-2 leads to apoptosis
SHP1↑, upstream modulator of STAT3 known as SHP-1 is up-regulated by chrysin
N-cadherin↓, Furthermore, N-cadherin and E-cadherin are respectively down-regulated and up-regulated upon chrysin administration in inhibiting melanoma invasion
E-cadherin↑,
UPR↑, chrysin substantially diminishes survival by ER stress induction via stimulating UPR, PERK, ATF4, and elF2α
PERK↑,
ATF4↑,
eIF2α↑,
RadioS↑, Irradiation combined with chrysin exerts a synergistic effect
NOTCH1↑, Irradiation combined with chrysin exerts a synergistic effect
NRF2↓, in reducing Nrf2 expression, chrysin down-regulates the expression of ERK and PI3K/Akt pathways—leading to an increase in the efficiency of doxorubicin in chemotherapy
BioAv↑, chrysin at the tumor site by polymeric nanoparticles leads to enhanced anti-tumor activity, due to enhanced cellular uptake
eff↑, Chrysin- and curcumin-loaded nanoparticles significantly promote the expression of TIMP-1 and TIMP-2 to exert a reduction in melanoma invasion

2792-

CHr,

Chrysin induces death of prostate cancer cells by inducing ROS and ER stress

in-vitro,

Pca,

DU145

0, 5, 10, 20, 50 and 100 Î¼M

in-vitro,

Pca,

PC3

DNAdam↑, chrysin induced apoptosis of cells evidenced by DNA fragmentation and increasing the population of both DU145 and PC-3 cells in the sub-G1 phase of the cell cycle
TumCCA↑,
MMP↓, chrysin induced loss of mitochondria membrane potential (MMP), while increasing production of reactive oxygen species (ROS) and lipid peroxidation in a dose-dependent manner
ROS↑,
lipid-P↑,
ER Stress↑, Also, it induced endoplasmic reticulum (ER) stress through activation of unfolded protein response (UPR) proteins including PRKR-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), and 78 kDa glucose-regulated protein (GRP78)
UPR↑,
PERK↑,
eIF2α↑,
GRP78/BiP↑,
PI3K↓, chrysin-mediated intracellular signaling pathways suppressed phosphoinositide 3-kinase (PI3K) and the abundance of AKT, P70S6K, S6, and P90RSK proteins, but stimulated mitogen-activated protein kinases (MAPK) and activation of ERK1/2 and P38 proteins
Akt↓,
p70S6↓,
MAPK↑,

677-

EGCG,

PERKp-eIF2_a_ATF4_and_IRE1_a">Induction of Endoplasmic Reticulum Stress Pathway by Green Tea Epigallocatechin-3-Gallate (EGCG) in Colorectal Cancer Cells: Activation of PERK/p-eIF2 α /ATF4 and IRE1 α

in-vitro,

CRC,

HT-29

ER Stress↑,
GRP78/BiP↑,
PERK↑,
eIF2α↑,
ATF4↑,
IRE1↑, IRE1 α
Apoptosis↑,

3208-

EGCG,

Induction of Endoplasmic Reticulum Stress Pathway by Green Tea Epigallocatechin-3-Gallate (EGCG) in Colorectal Cancer Cells: Activation of PERK/p-eIF2α/ATF4 and IRE1α

in-vitro,

Colon,

HT29

in-vitro,

Nor,

3T3

TumCD↓, EGCG treatment was toxic to the HT-29 cell line
ER Stress↑, EGCG induced ER stress in HT-29 by upregulating immunoglobulin-binding (BiP), PKR-like endoplasmic reticulum kinase (PERK), phosphorylation of eukaryotic initiation factor 2 alpha subunit (eIF2α), activating transcription 4 (ATF4), and IRE1α
GRP78/BiP↑,
PERK↑,
eIF2α↑,
ATF4↑,
IRE1↑,
Apoptosis↑, Apoptosis was induced in HT-29 cells after the EGCG treatment, as shown by the Caspase 3/7 activity.
Casp3↑,
Casp7↑,
Wnt↓, (CRC) via suppression of the Wnt/β-catenin pathway
β-catenin/ZEB1↓,
*toxicity∅, This embryonic fibroblast cell line (3T3) has shown that the EGCG was not toxic to normal healthy cells, given the treatment at any concentration even at the highest concentration of EGCG (1000 μM).
UPR↑, ER stress is induced by EGCG and activates UPR proteins

2860-

FIS,

Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways

in-vitro,

PC,

PANC1

in-vitro,

PC,

Bxpc-3

in-vitro,

Nor,

hTERT-HPNE

in-vivo,

NA,

mice

AMPK↑, We found that the AMPK/mTOR signaling pathway was enhanced after fisetin treatment
mTOR↑,
UPR↑, RNA-seq analysis revealed that the unfolded protein response pathway, which is activated by ER stress, was enriched
ER Stress↑, Fisetin induced ER stress in pancreatic cancer cells
selectivity↑, results showed that fisetin was less cytotoxic to normal cells compared with pancreatic cancer cells
TumCP↓, fisetin inhibited the proliferation of PANC-1 cells
PERK↑, expression of PERK, ATF4, and ATF6 were also upregulated by fisetin
ATF4↑,
ATF6↑,

2841-

FIS,

Fisetin, an Anti-Inflammatory Agent, Overcomes Radioresistance by Activating the PERK-ATF4-CHOP Axis in Liver Cancer

in-vitro,

Nor,

RAW264.7

LPS-induced Raw264.7 cells

in-vitro,

Liver,

HepG2

10, 25, 100, and 200 μM, 24 h

in-vitro,

Liver,

Hep3B

in-vitro,

Liver,

HUH7

*Inflam↓, fisetin reduced the LPS-induced production of pro-inflammation markers, such as TNF-α, IL-1β, and IL-6, demonstrating the anti-inflammatory effects of fisetin
*TNF-α↓,
*IL1β↓,
*IL6↓,
Apoptosis↓, fisetin induced apoptotic cell death and ER stress through intracellular calcium (Ca2+) release, the PERK-ATF4-CHOP signaling pathway, and induction of GRP78 exosomes.
ER Stress↑,
Ca+2↑,
PERK↑, inducing the GRP78-PERK-ATF4-CHOP pathway in fisetin-treated radioresistant liver cancer cells.
ATF4↑, fisetin treatment of HepG2 and Hep3B cells resulted in the upregulation of ATF4 and CHOP in a time-dependent manner
CHOP↑,
GRP78/BiP↑,
tumCV↓, fisetin decreased the cell viability and increased LDH activity in HepG2, Hep3B, and Huh7 cells in a concentration-dependent manner
LDH↑,
Casp3↑, caspase-3 activity was significantly enhanced
cl‑Casp3↑, fisetin treatment significantly increased the pro-apoptotic markers, including cleaved caspase-3, caspase-8, and caspase-9
cl‑Casp8↑,
cl‑Casp9↑,
p‑eIF2α↑, fisetin treatment increased CHOP, p-eIF2α, ATF4, p-PERK, and GRP78 levels
RadioS↑, Radiation Combined with Fisetin Overcomes Radioresistance

1968-

GamB,

Gambogic Acid Shows Anti-Proliferative Effects on Non-Small Cell Lung Cancer (NSCLC) Cells by Activating Reactive Oxygen Species (ROS)-Induced Endoplasmic Reticulum (ER) Stress-Mediated Apoptosis

in-vitro,

Lung,

A549

0, 0.5, and 1.0 μmol/l

tumCV↓, GA treatment significantly reduced cell viabilities of NSCLC cells in a concentration-dependent manner.
ROS↑, GA treatment increased intracellular ROS level,
GRP78/BiP↑, expression levels of GRP (glucose-regulated protein) 78
CHOP↑, CHOP (C/EBP-homologous protein),
ATF6↑, ATF (activating transcription factor) 6 and caspase 12,
Casp12↑,
p‑PERK↑, phosphorylation levels of PERK
ER Stress↑, Induced Endoplasmic Reticulum (ER) Stress-Mediated Apoptosis

839-

Gra,

Functional proteomic analysis revels that the ethanol extract of Annona muricata L. induces liver cancer cell apoptosis through endoplasmic reticulum stress pathway

in-vitro,

Liver,

HepG2

tumCV↓,
Apoptosis↑,
HSP70/HSPA5↑,
GRP94↑,
ER Stress↑, evidenced by the up-regulation of HSP70, GRP94 and PDI-related protein 5
p‑PERK↑,
p‑eIF2α↑,
GRP78/BiP↑,
CHOP↑,

2868-

HNK,

Honokiol: A review of its pharmacological potential and therapeutic insights

Review,

Var,

Review,

Sepsis,

*P-gp↓, reduction in the expression of defective proteins like P-glycoproteins, inhibition of oxidative stress, suppression of pro-inflammatory cytokines (TNF-α, IL-10 and IL-6),
*ROS↓,
*TNF-α↓,
*IL10↓,
*IL6↓,
eIF2α↑, Bcl-2, phosphorylated eIF2Î±, CHOP,GRP78, Bax, cleaved caspase-9 and phosphorylated PERK
CHOP↑,
GRP78/BiP↑,
BAX↑,
cl‑Casp9↑,
p‑PERK↑,
ER Stress↑, endoplasmic reticulum stress and proteins in apoptosis in 95-D and A549 cells
Apoptosis↑,
MMPs↓, decrease in levels of matrix metal-mloproteinases, P-glycoprotein expression, the formation of mammosphere, H3K27 methyltransferase, c-FLIP, level of CXCR4 receptor,pluripotency-factors, Twist-1, class I histone deacetylases, steroid receptor co
cFLIP↓,
CXCR4↓,
Twist↓,
HDAC↓,
BMPs↑, enhancement in Bax protein, and (BMP7), as well as interference with an activator of transcription 3 (STAT3), (mTOR), (EGFR), (NF-kB) and Shh
p‑STAT3↓, secreased the phosphorylation of STAT3
mTOR↓,
EGFR↓,
NF-kB↓,
Shh↓,
VEGF↓, induce apoptosis, and regulate the vascular endothelial growth factor-A expression (VEGF-A)
tumCV↓, human glioma cell lines (U251 and U-87 MG) through inhibition of colony formation, glioma cell viability, cell migration, invasion, suppression of ERK and AKT signalling cascades, apoptosis induction, and reduction of Bcl-2 expression.
TumCMig↓,
TumCI↓,
ERK↓,
Akt↓,
Bcl-2↓,
Nestin↓, increased the Bax expression, lowered the CD133, EGFR, and Nesti
CD133↓,
p‑cMET↑, HKL through the downregulating the phosphorylation of c-Met phosphorylation and stimulation of Ras,
RAS↑,
chemoP↑, Cheng and coworker determined the chemopreventive role of HKL against the proliferation of renal cell carcinoma (RCC) 786â0 cells through multiple mechanism
*NRF2↑, , HKL also effectively activate the Nrf2/ARE pathway and reverse this pancreatic dysfunction in in vivo and in vitro model
*NADPH↓, (HUVECs) such as inhibition of NADPH oxidase activity, suppression of p22 (phox) protein expression, Rac-1 phosphorylation, reactive oxygen species production, inhibition of degradation of Ikappa-B-alpha, and suppression of activity of of NF-kB
*p‑Rac1↓,
*ROS↓,
*IKKα↑,
*NF-kB↓,
*COX2↓, Furthermore, HKL treatment the inhibited cyclooxygenase (COX-2) upregulation, reduces prostaglandin E2 production, enhanced caspase-3 activity reduction
*PGE2↓,
*Casp3↓,
*hepatoP↑, compound also displayed hepatoprotective action against oxidative injury in tert-butyl hydroperoxide (t-BHP)-injured AML12 liver cells in in vitro model
*antiOx↑, compound reduces the level of acetylation on SOD2 to stimulate its antioxidative action, which results in reduced reactive oxygen species aggregation in AML12 cells
*GSH↑, HKL prevents oxidative damage induced by H2O2 via elevating antioxidant enzymes levels which includes glutathione and catalase and promotes translocation and activation transcription factor Nrf2
*Catalase↑,
*RenoP↑, imilarly, the compound protects renal reperfusion/i-schemia injury (IRI) in adult male albino Wistar rats via reducing theactivities of serum alkaline phosphatase (ALP), aspartate aminotrans- ferase (AST) and alanine aminotransferase (ALT)
*ALP↓,
*AST↓,
*ALAT↓,
*neuroP↑, Several reports and works have shown that HKL displays some neuroprotective properties
*cardioP↑, Cardioprotection
*HO-1↑, the expression level of heme oxygenase-1 (HO-1)was remarkably up-regulated and miR-218-5p was significantly down-regulated in septic mice treated with HKL
*Inflam↓, anti-inflammatory action of HKL at dose of 10 mg/kg in the muscle layer of mice

2912-

LT,

Luteolin: a flavonoid with a multifaceted anticancer potential

Review,

Var,

ROS↑, induction of oxidative stress, cell cycle arrest, upregulation of apoptotic genes, and inhibition of cell proliferation and angiogenesis in cancer cells.
TumCCA↑,
TumCP↓,
angioG↓,
ER Stress↑, Luteolin induces mitochondrial dysfunction and activates the endoplasmic reticulum stress response in glioblastoma cells, which triggers the generation of intracellular reactive oxygen species (ROS)
mtDam↑,
PERK↑, activate the expression of stress-related proteins by mediating the phosphorylation of PERK, ATF4, eIF2α, and cleaved-caspase 12.
ATF4↑,
eIF2α↑,
cl‑Casp12↑,
EMT↓, Luteolin is known to reverse epithelial-to-mesenchymal transition (EMT), which is associated with the cancer cell progression and metastasis.
E-cadherin↑, upregulating the biomarker E-cadherin expression, followed by a significant downregulation of the N-cadherin and vimentin expression
N-cadherin↓,
Vim↓,
*neuroP↑, Furthermore, luteolin holds potential to improve the spinal damage and brain trauma caused by 1-methyl-4-phenylpyridinium due to its excellent neuroprotective properties.
NF-kB↓, downregulation and suppression of cellular pathways such as nuclear factor kappa B (NF-kB), phosphatidylinositol 3’-kinase (PI3K)/Akt, and X-linked inhibitor of apoptosis protein (XIAP)
PI3K↓,
Akt↑,
XIAP↓,
MMP↓, Furthermore, the membrane action potential of mitochondria depletes in the presence of luteolin, Ca2+ levels and Bax expression upregulate, the levels of caspase-3 and caspase-9 increase, while the downregulation of Bcl-2
Ca+2↑,
BAX↑,
Casp3↑,
Casp9↑,
Bcl-2↓,
Cyt‑c↑, cause the cytosolic release of cytochrome c from mitochondria
IronCh↑, Luteolin serves as a good metal-chelating agent owing to the presence of dihydroxyl substituents on the aromatic ring framework
SOD↓, luteolin further triggered an early phase accumulation of ROS due to the suppression of the activity of cellular superoxide dismutase.
*ROS↓, Luteolin reportedly demonstrated an optimal 43.7% inhibition of the accumulation of ROS, 24.5% decrease in malondialdehyde levels, and 38.7% lowering of lactate dehydrogenase levels at a concentration of 30 µM
*LDHA↑,
*SOD↑, expression of superoxide dismutase ameliorated by 73.7%, while the activity of glutathione improved by 72.3% at the same concentration of luteolin
*GSH↑,
*BioAv↓, Poor bioavailability of luteolin limits its optimal therapeutic efficacy and bioactivity
Telomerase↓, MDA-MB-231 cells with luteolin led to dose dependent arrest of cell cycle in S phase by reducing the levels of telomerase and by inhibiting the phosphorylation of NF-kB inhibitor α along with its target gene c-Myc
cMyc↓,
hTERT/TERT↓, These events led to the suppression of the expression of human telomerase reverse transcriptase (hTERT) encoding for the catalytic subunit of telomerase
DR5↑, luteolin upregulated the expression of caspase cascades and death receptors, including DR5
Fas↑, expression of proapoptotic genes such as FAS, FADD, BAX, BAD, BOK, BID, TRADD upregulates, while the anti-apoptotic genes NAIP, BCL-2, and MCL-1 experience downregulation.
FADD↑,
BAD↑,
BOK↑,
BID↑,
NAIP↓,
Mcl-1↓,
CDK2↓, expression of cell cycle regulatory genes CDK2, CDKN2B, CCNE2, CDKN1A, and CDK4 decreased on incubation with luteolin
CDK4↓,
MAPK↓, expression of MAPK1, MAPK3, MAP3K5, MAPK14, PIK3C2A, PIK3C2B, AKT1, AKT2, and ELK1 downregulated
AKT1↓,
Akt2↓,
*Beclin-1↓, luteolin led to downregulation of the expression of hypoxia-inducible factor-1α and autophagy-associated proteins, Beclin 1, and LC3
Hif1a↓,
LC3II↑, LC3-II is upregulated following the luteolin treatment in p53 wild type HepG2 cells i
Beclin-1↑, Luteolin treatment reportedly increased the number of intracellular autophagosomes, as indicated by an increased expression of Beclin 1, and conversion of LC3B-I to LC3B-II in hepatocellular carcinoma SMMC-7721 cells.

2903-

LT,

Luteolin induces apoptosis by ROS/ER stress and mitochondrial dysfunction in gliomablastoma

in-vitro,

GBM,

U251

in-vitro,

GBM,

U87MG

in-vivo,

NA,

mouse

ER Stress↑, Luteolin induced a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in glioblastoma cells by increasing intracellular reactive oxygen species (ROS) levels.
ROS↑,
PERK↑, Luteolin induced expression of ER stress-associated proteins, including phosphorylation of PERK, eIF2α, ATF4, CHOP and cleaved-caspase 12.
eIF2α↑,
ATF4↑,
CHOP↑,
Casp12↑,
eff↓, Inhibition of ROS production by anti-oxidant N-acetylcysteine could reverse luteolin-induced ER stress and mitochondrial pathways activation as well as apoptosis.
UPR↑, Researches indicate that abnormalities in ER function can cause ER stress, resulting in unfolded protein response (UPR),
MMP↓, integrity of mitochondrial membranes potential decreased in U87MG cells after treatment of 40 uM luteolin
Cyt‑c↑, release of cytochrome C to cytoplasm was elevated in U251MG cells
Bcl-2↓, significantly decreased the expression of anti-apoptotic protein Bcl-2 and increased the expression of pro-apoptotic protein Bax in U251MG and U87MG glioblastoms cells.
BAX↑,
TumCG↓, Luteolin inhibited tumor growth in a xenograft mouse model
Weight∅, luteolin did not affect body weight, alanine aminotransferase (ALT) or aspartate transaminase (AST)
ALAT∅,
AST∅,

1664-

PBG,

Anticancer Activity of Propolis and Its Compounds

Review,

Var,

Apoptosis↑,
TumCMig↓,
TumCCA↑,
TumCP↓,
angioG↓,
P21↑, upregulating p21 and p27 expression
p27↑,
CDK1↓, thanol-extracted Cameroonian propolis increased the amount of DU145 and PC3 cells in G0/G1 phase, down-regulated cell cycle proteins (CDK1, pCDK1, and their related cyclins A and B)
p‑CDK1↓,
cycA1/CCNA1↓,
CycB/CCNB1↓,
P70S6K↓, Caffeic acid phenylethyl ester has been shown to inhibit the S6 beta-1 ribosomal protein kinase (p70S6K),
CLDN2↓, inhibition of NF-κB may be involved in the decrease of claudin-2 mRNA level
HK2↓, Chinese poplar propolis has been shown to significantly reduce the level of glycolysis at the stage of action of hexokinase 2 (HK2), phosphofructokinase (PFK), muscle isozyme pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA)
PFK↓,
PKM2↓,
LDHA↓,
TLR4↓, hinese propolis, as well as CAPE, inhibits breast cancer cell proliferation in the inflammatory microenvironment by inhibiting the Toll-like receptor 4 (TLR4) signal pathway
H3↓, Brazilian red propolis bioactive isoflavonoid, down-regulates the alpha-tubulin, tubulin in microtubules, and histone H3 genes
α-tubulin↓,
ROS↑, CAPE also affects the apoptotic intrinsic pathway by increasing ROS production
Akt↓, CAPE induces apoptosis by decreasing the levels of proteins related to carcinogenesis, including Akt, GSK3b, FOXO1, FOXO3a, NF-kB, Skp2 and cyclin D1
GSK‐3β↓,
FOXO3↓,
NF-kB↓,
cycD1/CCND1↓,
MMP↓, It was found that chrysin caused a loss of mitochondria membrane potential (MMP) while increasing the production of reactive oxygen species (ROS), cytoplasmic Ca2+ levels, and lipid peroxidation
ROS↑,
i-Ca+2↑,
lipid-P↑,
ER Stress↑, Chrysin also induced endoplasmic reticulum (ER) stress by activating unfolded protein response proteins (UPR) such as PRKR-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), and 78 kDa glucose-regulated protein (GRP78)
UPR↑,
PERK↑,
eIF2α↑,
GRP78/BiP↑,
BAX↑, CAPE activated Bax protein
PUMA↑, CAPE also significantly increased PUMA expression
ROS↑, Northeast China causes cell apoptosis in human gastric cancer cells with increased production of reactive oxygen species (ROS) and reduced mitochondrial membrane potential.
MMP↓,
Cyt‑c↑, release of cytochrome C from mitochondria to the cytoplasm is observed, as well as the activation of cleaved caspases (8, 9, and 3) and PARP
cl‑Casp8↑,
cl‑Casp8↑,
cl‑Casp3↑,
cl‑PARP↑,
eff↑, administration of Iranian propolis extract in combination with 5-fluorouracil (5-FU) significantly reduced the number of azaxymethane-induced aberrant crypt foci compared to 5-FU or propolis alone.
eff↑, Propolis may also have a positive effect on the efficacy of photodynamic therapy (PDT). enhances the intracellular accumulation of protoporphyrin IX (PpIX) in human epidermoid carcinoma cells
RadioS↑, breast cancer patients undergoing radiotherapy and supplemented with propolis had a statistically significant longer median disease-free survival time than the control group
ChemoSen↑, confirmed that propolis mouthwash is effective and safe in the treatment of chemo- or radiotherapy-induced oral mucositis in cancer patients.
eff↑, Quercetin, ferulic acid, and CAPE may also influence the MDR of cancer cells by inhibiting P-gp expression

4951-

PEITC,

ROS accumulation by PEITC selectively kills ovarian cancer cells via UPR-mediated apoptosis

in-vitro,

Ovarian,

PA1

5 μM

in-vitro,

Ovarian,

SKOV3

ROS↑, PEITC caused increased ROS-accumulation and inhibited proliferation selectively in ovarian cancer cells, and glutathione (GSH) depletion in SKOV-3.
TumCP↓,
GSH↓, One of the generating ROS mechanisms by PEITC is a depletion of GSH
selectivity↑, However, PEITC did not cause any effect in normal ovarian epithelial cells and peripheral blood mononuclear cells
UPR↑, PEITC Induces Unfolded Protein Response, Attenuated by NAC, in Ovarian Cancer Cells
CHOP↑, The key regulator of UPR-mediated apoptosis, CHOP/GADD153 and endoplasmic reticulum resident chaperone BiP/GRP78 were parallely up-regulated
ER Stress↑,
GRP78/BiP↑,
PERK↑, with activation of two major sensors of the UPR [PERK and ATF-6 in PA-1; PERK, and IRE1α in SKOV-3) in response to ROS accumulation induced by PEITC (5 μM)
ATF6↑,
eff↓, ROS scavenger, N-acetyl-L-cysteine (NAC), attenuated the effect of PEITC on UPR signatures (P-PERK, IRE1α, CHOP/GADD153, and BiP/GRP78)
TumCG↓, PEITC Inhibits Growth of Ovarian Cancer Cells without Inhibiting the Growth of Normal PBMC Cells
Apoptosis↑, PEITC Induces Apoptotic Cell Death in Ovarian Cancer Cell Lines
toxicity↓, IC50 value of PEITC for endothelial cells was more than 100 μM, suggesting cancer cell-specific cell death by PEITC (28). PEITC is a well-known ROS inducer in cancer cells without any potential adverse effect on normal cells (

1944-

PL,

Piperlongumine, a Novel TrxR1 Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cells by ROS-Mediated ER Stress

in-vitro,

HCC,

HUH7

0.625, 2.5, 5, 10, 15, 20, 30, 40, and 50 µM

in-vitro,

HCC,

HepG2

ER Stress↑, PL induces a lethal endoplasmic reticulum (ER) stress response in HCC cells
TrxR1↓, PL treatment reduces TrxR1 activity and tumor cell burden in vivo
ROS↑, and increasing intracellular ROS levels
eff↓, Interestingly, pretreatment with NAC, a specific ROS inhibitor, for 2 h apparently suppressed PL-induced increases in ROS levels
Bcl-2↓, PL treatment decreased the levels of the antiapoptotic proteins Bcl-2 and procaspase3 and increased the levels of the proapoptotic proteins Bax and cleaved caspase-3 in a dose-dependent manner.
proCasp3↓,
BAX↓,
cl‑Casp3↑,
TumCCA↑, PL Induces ROS-Dependent G2/M Cell Cycle Arrest in HCC Cells
p‑PERK↑, PL increased the expression of p-PERK and ATF4 in a dose-dependent manner.
ATF4↑,
TumCG↓, PL Inhibits HUH-7 Xenograft Tumor Growth Accompanied by Increased ROS Levels and Decreased Trxr1 Activity
lipid-P↑, PL treatment increased the levels of the product of lipid peroxidation (MDA) in tumor tissues ( Figure 6H ), suggesting increased ROS levels
selectivity↑, In normal cells, TrxR1 can protect against oxidant stress

4693-

PTS,

Pterostilbene in the treatment of inflammatory and oncological diseases

BioAv↑, PTS is rapidly absorbed, contributing to its superior oral bioavailability of approximately 80%–95%
*Inflam↓, PTS exhibits anti-inflammatory, antioxidant, and antitumour properties, potentially making it a promising candidate for clinical applications
*antiOx↑,
AntiTum↑,
BBB↑, The ability of PTS to cross the blood-brain barrier efficiently not only broadens its therapeutic scope
Half-Life↝, The majority of Pterostilbene’s glucuronide-conjugated metabolites are excreted within 12 h post-administration, indicating rapid renal and total serum clearance
*ROS↓, PTS can reduce oxidative stress and counteract ROS like H2O2 and O2
*NRF2↑, PTS activates the phosphorylation of AMPK and AKT, prompting the shift of Nrf2 from the cytoplasm into the nucleus. This action then heightens the expression of Nrf2-regulated genes, NQO1 and HO-1
*NQO1↑,
*HO-1↑,
PTEN↑, PTS enhances PTEN expression in liver cancer cells by directly inhibiting miR-19a, which leads to reduced cell growth, cell cycle halt at the S phase, increased apoptosis, and decreased cell invasion
miR-19b↓,
TumCCA↑,
ER Stress↑, PTS administration can activate ERS and elevate levels of ERS-associated molecules like p-PERK, ATF4, and CHOP.
PERK↑,
ATF4↑,
CHOP↑,
Ca+2↝, facilitates the transfer of Ca2+ from the endoplasmic reticulum to the cytoplasm,
EMT↓, Pterostilbene inhibits epithelial-mesenchymal transition and apoptosis in tumors
NF-kB↓, downregulates NFκB, Twist1, and Vimentin and amplifies E-cadherin expression
Twist↓,
Vim↓,
E-cadherin↑,
ChemoSen↑, combined use of PTS and autophagy inhibitors has been shown to improve the therapeutic efficacy of chemotherapy drugs against both chemotherapy-sensitive and chemotherapy-resistant cancer cells.
toxicity∅, Remarkably, even at a high dose of 3,000 mg/(kg·d), no observable toxic side effects were detected in animal subjects
toxicity↝, some studies have raised concerns about potential liver toxicity at high doses

3362-

QC,

The effect of quercetin on cervical cancer cells as determined by inducing tumor endoplasmic reticulum stress and apoptosis and its mechanism of action

in-vitro,

Cerv,

HeLa

Apoptosis↑, The apoptosis rate in the quercetin group increased significantly in comparison with the blank control group,
cycD1/CCND1↓, Cyclin D1 showed a tendency to decrease progressively
Casp3↑, Caspase-3, GRP78, and CHOP expression levels in the quercetin intervention group rose significantly in comparison with the blank control group
GRP78/BiP↑,
CHOP↑,
tumCV↓, viability of the cervical cancer HeLe cells was inhibited by quercetin in a dose-dependent manner
IRE1↑, The IRE1, p-Perk, and c-ATF6 levels in the quercetin intervention group (20, 40, and 80 μmol/L) rose gradually in comparison with the blank control group
p‑PERK↑,
c-ATF6↑,
ER Stress↑, quercetin can induce ERS to initiate HeLe cell apoptosis.

3065-

RES,

Resveratrol-induced cytotoxicity in human Burkitt's lymphoma cells is coupled to the unfolded protein response

in-vitro,

lymphoma,

0-200uM

UPR↑, treatment with RES lead to the activation of all 3 branches of the UPR
IRE1↑, with early splicing of XBP-1 indicative of IRE1 activation, phosphorylation of eIF2α consistent with ER resident kinase (PERK) activation, activating transcription factor 6 (ATF6) splicing
p‑eIF2α↑,
PERK↑,
ATF6↑,
GRP78/BiP↑, increase in expression levels of the downstream molecules GRP78/BiP, GRP94 and CHOP/GADD153 in human Burkitt's lymphoma Raji and Daudi cell lines.
GRP94↑,
CHOP↑,
GADD34↑, RES induces a pathway initiated by phosphorylation of eIF2α and followed by the upregulation of GADD34 and ATF4.
ATF4↑,
XBP-1↑, RES increased XBP-1 expression both in Raji and in Daudi cells
Ca+2↑, RES was found to significantly increase cytosolic Ca2+
ER Stress↑, RES was able to induce ER stress and activated all 3 branches of the UPR.

3066-

RES,

Resveratrol triggers ER stress-mediated apoptosis by disrupting N-linked glycosylation of proteins in ovarian cancer cells

GSK‐3β↑, resveratrol suppressed the hexosamine biosynthetic pathway and interrupted protein glycosylation through GSK3β activation
Akt↓, Akt attenuation in response to resveratrol.
CHOP↑, Resveratrol-mediated disruption of protein glycosylation induced cellular apoptosis as indicated by the up-regulation of GADD153, followed by the activation of ER-stress sensors (PERK and ATF6α).
ER Stress↑,
PERK↑,
ATF6↑,
UPR↑, Disruption of protein glycosylation causes the accumulation of aberrant of proteins in the endoplasmic reticulum (ER) which in turn activates unfolded protein responses (UPR) in the ER, leading to severe stressful conditions
GlucoseCon↓, Previous studies have shown that resveratrol (RSV) impairs glucose consumption via Akt/GLUT1 axis in cancer [

3002-

RosA,

Anticancer Effects of Rosemary (Rosmarinus officinalis L.) Extract and Rosemary Extract Polyphenols

Review,

Var,

TumCG↓, SW480 colon cancer cells and found RE to significantly decrease cell growth at a concentration of 31.25 µg/mL (48 h),
TumCP↓, Cell proliferation was dramatically decreased and cell cycle arrest was induced in HT-29 and SW480 c
TumCCA↑,
ChemoSen↑, RE enhanced the inhibitory effects of the chemotherapeutic drug 5-fluorouracil (5-FU) on proliferation and sensitized 5-FU resistant cells
NRF2↑, HCT116 ↑ Nrf2, ↑ PERK, ↑ sestrin-2, ↑ HO-1, ↑ cleaved-casp 3
PERK↑,
SESN2↑,
HO-1↑,
cl‑Casp3↑,
ROS↑, HT-29 ↑ ROS accumulation, ↑ UPR, ↑ ER-stress
UPR↑,
ER Stress↑,
CHOP↑, HT-29: ↑ ROS levels, ↑ HO-1 and CHOP
HER2/EBBR2↓, SK-BR-3: ↑ FOS levels, ↑ PARP cleavage, ↓ HER2, ↓ ERBB2, ↓ ERα receptor.
ER-α36↓,
PSA↓, LNCaP : ↑ CHOP, ↓ PSA production, ↑ Bax, ↑ cleaved-casp 3, ↓ androgen receptor expression
BAX↑,
AR↓,
P-gp↓, A2780: ↓ P-glyco protein, ↑ cytochrome c gene, ↑ hsp70 gene
Cyt‑c↑,
HSP70/HSPA5↑,
eff↑, This study noted that the rosemary essential oil was more potent than its individual components (α-pinene, β-pinene, 1,8-cineole) when tested alone at the same concentrations.
p‑Akt↓, A549: ↓ p-Akt, ↓ p-mTOR, ↓ p-P70S6K, ↑ PARP cleavage
p‑mTOR↓,
p‑P70S6K↓,
cl‑PARP↑,
eff↑, RE containing 10 µM equivalent of CA, or 10 µM CA alone (96 h) potentiated the ability of vitamin D derivatives to inhibit cell viability and proliferation, induce apoptosis and cell cycle arrest and increase differentiation of WEHI-3BD murine leukem

2231-

SK,

Shikonin Exerts Cytotoxic Effects in Human Colon Cancers by Inducing Apoptotic Cell Death via the Endoplasmic Reticulum and Mitochondria-Mediated Pathways

in-vitro,

CRC,

SNU-407

3 µM after 48 h

Apoptosis↑, Shikonin induced apoptotic cell death by activating mitogen-activated protein kinase family members
ER Stress↑, apoptotic process was mediated by the activation of endoplasmic reticulum (ER) stress
PERK↑, leading to activation of the PERK/elF2α/CHOP apoptotic pathway, and mitochondrial Ca2+ accumulation.
eIF2α↑,
CHOP↑,
mt-Ca+2↑,
MMP↓, Shikonin increased mitochondrial membrane depolarization
Bcl-2↓, decrease in B cell lymphoma (Bcl)-2 and an increase in Bcl-2-associated X protein, and subsequently, increased expression of cleaved forms of caspase-9 and -3.
Casp3↑,
Casp9↑,
ERK↑, Shikonin treatment activated ERK, JNK, and p38 MAPK in a time-dependent manner
JNK↑,
p38↓,

2196-

SK,

Research progress in mechanism of anticancer action of shikonin targeting reactive oxygen species

Review,

Var,

*ALAT↓, shikonin was found to mitigate the rise in ALT and AST levels triggered by LPS/GalN
*AST↓,
*Inflam?, demonstrated the anti-inflammatory properties of shikonin within two traditional mouse models frequently employed in pharmacological research to assess anti-inflammatory activities
*EMT↑, Shikonin stimulates EMT by weakening the nuclear translocation of NF-κB p65
ROS?, naphthoquinone framework possesses the capacity to produce ROS, which in turn modulate cellular oxidative stress levels
TrxR1↓, Duan and colleagues demonstrated that shikonin specifically inhibits the physiological function of TrxR1 by targeting its Sec residue
PERK↑, In vivo Western blot of HCT-15(colon cancer) xenografts showed shikonin upregulated PERK/eIF2α/ATF4/CHOP and IRE1α/JNK pathways.
eIF2α↑,
ATF4↑,
CHOP↑,
IRE1↑,
JNK↑,
eff↝, oral shikonin did not demonstrate anti-tumor effects in the colorectal cancer model, intraperitoneal injection significantly inhibited tumor growth.
DR5↑, upregulation of Death Receptor 5 (DR5) in cholangiocarcinoma cells through ROS-induced activation of the JNK signaling cascade.
Glycolysis↓, inhibited glycolysis in HepG2 cells by suppressing the activity of PKM2, a critical enzyme within the glycolytic pathway
PKM2↓,
ChemoSen↑, The combination of shikonin with drugs can reverse drug resistance and enhance therapeutic efficacy
GPx4↓, shikonin conjunction with cisplatin overcame drug resistance in cancer cells, downregulated GPX4, and upregulated haemoglobin oxygenase 1 (HMOX1) inducing iron death in cells.
HO-1↑,

2228-

SK,

Shikonin induced Apoptosis Mediated by Endoplasmic Reticulum Stress in Colorectal Cancer Cells

in-vitro,

CRC,

HCT116

0.25, 0.5, 1, 1.5, 2, 2.5 and 3 μM

in-vitro,

CRC,

HCT15

in-vivo,

NA,

 intraperitoneal injection (3 mg/kg, 3 times per week

mouse

Apoptosis↑, shikonin induced cell apoptosis by down-regulating BCL-2 and activating caspase-3/9 and the cleavage of PARP.
Bcl-2↓,
Casp3↑,
Casp9↑,
cl‑PARP↑,
GRP78/BiP↑, The expression of BiP and the PERK/elF2α/ATF4/CHOP and IRE1α /JNK signaling pathways were upregulated after shikonin treatment.
PERK↑,
eIF2α↑,
ATF4↑,
CHOP↑,
JNK↑,
eff↓, pre-treatment with N-acetyl cysteine significantly reduced the cytotoxicity of shikonin
ER Stress↑, Shikonin induced endoplasmic reticulum stress
ROS↑, Shikonin induced reactive oxygen species-mediated ER stress
TumCG↓, Shikonin suppressed the growth of colorectal cancer cells in vivo

5107-

SSE,

Involvement of p38 in signal switching from autophagy to apoptosis via the PERK/eIF2α/ATF4 axis in selenite-treated NB4 cells

vitro+vivo,

AML,

APL NB4

PERK↑, We found that selenite activated PERK and eIF2α/ATF4 downstream to promote apoptosis.
eIF2α↑,
ATF4↑,
Apoptosis↑,
AntiTum↑, Moreover, selenite exhibited potent antitumor effects in vivo
ER Stress↑, p38 is critical for ATF4 upregulation in response to selenite-induced ER stress
p38↑, Then, activated p38

3416-

TQ,

Thymoquinone induces apoptosis in bladder cancer cell via endoplasmic reticulum stress-dependent mitochondrial pathway

in-vitro,

Bladder,

T24/HTB-9

 TQ (20–100 μM) for 24 h

in-vitro,

Bladder,

253J

in-vitro,

Nor,

SV-HUC-1

TumCP↓, TQ has a significant cytotoxicity on bladder cancer cells and can inhibit their proliferation and induce apoptosis.
Apoptosis↑,
ER Stress↑, The protein changes of Bcl-2, Bax, cytochrome c and endoplasmic reticulum stress-related proteins (GRP78, CHOP, and caspase-12) revealed that the anticancer effect of TQ was associated with mitochondrial dysfunction and the endoplasmic reticulum stre
cl‑Casp3↑, TQ increased the cleaved subunits of caspase-3, caspase-8, caspase-7 and PARP (Fig. 2B) and increased caspase-3 activity (Fig. 2C) in a dose-dependent manner.
cl‑Casp8↑,
cl‑Casp7↑,
cl‑PARP↑,
Cyt‑c↑, can increase the release of cytochrome c
PERK↑, TQ increased the expression of PERK, IRE1 and ATF6 and the expression of downstream molecules such as p-eIF2a and ATF4 in a dose-dependent manner
IRE1↑,
ATF6↑,
p‑eIF2α↑,
ATF4↑,
GRP78/BiP↑, GRP78, IRE1, ATF6, ATF4 and CHOP was significantly increased after TQ treatment
CHOP↑,

Showing Research Papers: 1 to 38 of 38

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 38

Pathway results for Effect on Cancer / Diseased Cells:

Infection & Microbiome ⓘ

Bacteria↓, 1,
Total Targets: 233

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx↑, 4, Catalase↑, 1, GSH↑, 2, HO-1↑, 2, NQO1↑, 1, NRF2↑, 2, ROS↓, 5, SOD↑, 1,

Core Metabolism/Glycolysis ⓘ

ALAT↓, 2, LDHA↑, 1, lipidLev↓, 1, NADPH↓, 1,

Cell Death ⓘ

Akt↓, 1, Casp3↓, 1, JNK↑, 1,

Protein Folding & ER Stress ⓘ

CHOP↑, 1, cl‑eIF2α↑, 1, GRP78/BiP↑, 1, p‑PERK↑, 1,

Autophagy & Lysosomes ⓘ

Beclin-1↓, 1,

Proliferation, Differentiation & Cell State ⓘ

EMT↑, 1, PI3K↓, 1,

Migration ⓘ

p‑Rac1↓, 1,

Barriers & Transport ⓘ

P-gp↓, 1,

Immune & Inflammatory Signaling ⓘ

COX2↓, 1, IKKα↑, 1, IL10↓, 1, IL1β↓, 1, IL2↓, 1, IL6↓, 2, Inflam?, 1, Inflam↓, 5, NF-kB↓, 1, PGE2↓, 1, TNF-α↓, 3,

Drug Metabolism & Resistance ⓘ

BioAv↓, 2,

Clinical Biomarkers ⓘ

ALAT↓, 2, ALP↓, 1, AST↓, 2, IL6↓, 2,

Functional Outcomes ⓘ

cardioP↑, 2, cognitive↑, 1, hepatoP↑, 2, neuroP↑, 3, RenoP↑, 2, toxicity↓, 3, toxicity↝, 1, toxicity∅, 1,

Infection & Microbiome ⓘ

AntiViral↑, 1,
Total Targets: 49

Scientific Paper Hit Count for: PERK, protein kinase-like ER kinase

4 Silver-NanoParticles
4 Betulinic acid
3 Shikonin
2 Artemisinin
2 Chrysin
2 EGCG (Epigallocatechin Gallate)
2 Fisetin
2 Luteolin
2 Resveratrol
1 Vitamin C (Ascorbic Acid)
1 Ashwagandha(Withaferin A)
1 Baicalein
1 Berbamine
1 Chemotherapy
1 Bortezomib
1 Gambogic Acid
1 Graviola
1 Honokiol
1 Propolis -bee glue
1 Phenethyl isothiocyanate
1 Piperlongumine
1 Pterostilbene
1 Quercetin
1 Rosmarinic acid
1 Selenite (Sodium)
1 Thymoquinone

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#:617  State#:%  Dir#:2
  wNotes=on  sortOrder:rid,rpid

PERK Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Metal & Cofactor Biology ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Transcription & Epigenetics ⓘ

Protein Folding & ER Stress ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Hormonal & Nuclear Receptors ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Infection & Microbiome ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Protein Folding & ER Stress ⓘ

Autophagy & Lysosomes ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Infection & Microbiome ⓘ

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