ATF4 Cancer Research Results

ATF4, Activating Transcription Factor 4: Click to Expand ⟱

Source:

Type: protein

ATF4 (Activating Transcription Factor 4) is a protein that plays a crucial role in various cellular processes, including stress response, cell growth, and differentiation.
ATF4 is overexpressed in several types of cancer, including breast, lung, colon, and pancreatic cancer. The overexpression of ATF4 can contribute to cancer cell growth, survival, and resistance to chemotherapy.
ATF4 promotes cancer cell growth by regulating the expression of genes involved in cell proliferation, angiogenesis, and metastasis. It also inhibits apoptosis (programmed cell death) by regulating the expression of anti-apoptotic genes.

Scientific Papers found: Click to Expand⟱

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.

2631-

Api,

Apigenin Induces Autophagy and Cell Death by Targeting EZH2 under Hypoxia Conditions in Gastric Cancer Cells

in-vivo,

GC,

mice

in-vitro,

GC,

AGS

ER Stress↑, We further show that APG induces ER stress- and autophagy-related cell death through the inhibition of HIF-1α and Ezh2 under normoxia and hypoxia.
Hif1a↓, APG Inhibits HIF-1α and Induces Cell Death under Hypoxia in GC Cells
EZH2↓,
HDAC↓, Apigenin, a flavonoid found in traditional medicine, fruits, and vegetables and an HDAC inhibitor, is a powerful anti-cancer agent against various cancer cell lines.
TumAuto↑, APG Induces Autophagic Cell Death in GC Cells
p‑mTOR↓, APG decreased the phosphorylation of mTOR and increased the activation of AMPKα and ULK1
AMPKα↑,
GRP78/BiP↑, APG mediates the up-regulation of GRP78 through exosomes, and that this effect causes ER stress-induced cell death in APG-treated GC cells.
ROS↑, APG generates intracellular ROS release in colorectal cancer cells, and it causes various cell death types, including cell cycle arrest, chromatin condensation, MMP loss, intracellular Ca2+, annexin-v-positive cells, and ER stress-related cell death
MMP↓,
Ca+2↑, we found that APG exerts intracellular Ca2+ release in a dose- and time-dependent manner
ATF4↑, APG also increased ATF4 and CHOP in a time-dependent manner
CHOP↑,

2632-

Api,

Apigenin inhibits migration and induces apoptosis of human endometrial carcinoma Ishikawa cells via PI3K-AKT-GSK-3β pathway and endoplasmic reticulum stress

in-vitro,

EC,

 20–60 μM

45.55 μM

TumCP↓, We found that API could inhibit the proliferation of Ishikawa cells at IC50 of 45.55 μM, arrest the cell cycle at G2/M phase, induce apoptosis by inhibiting Bcl-xl and increasing Bax, Bak and Caspases.
TumCCA↑,
Apoptosis↑,
Bcl-2↓,
BAX↑,
Bak↑,
Casp↑,
ER Stress↑, Further, API could induce apoptosis by activating the endoplasmic reticulum (ER) stress pathway by increasing the Ca2+, ATF4, and CHOP.
Ca+2↑, after API treatment for 48 h, the intracellular Ca2+ concentration increased in cells in a dose-dependent manner.
ATF4↑,
CHOP↑,
ROS↑, the level of intracellular ROS increased gradually with the increase of API concentration.
MMP↓, mitochondrial membrane potential of 30 μM, 50 μM, and 70 μM groups decreased by 2.19%, 11.32%, and 14.91%, respectively.
TumCMig↓, API inhibits the migration and invasion of Ishikawa cells and the migration and invasion related gene and protein.
TumCI↓,
eff↑, In our study, API restrained the viability of Ishikawa cells, and the inhibition effect of API on Ishikawa cells was better than that of 5-FU.
P53↑, API induces p53 tumor suppressor proteins at the translational level and the induces p21
P21↑,
Cyt‑c↑, After the mitochondria release the Cyto-c, the Caspase-9 is activated, resulting in increased activity of Caspases
Casp9↑, In our study, the expression levels of Bad, Bax, Cyto-c, Caspase-9 and Caspase-3 proteins were up-regulated,
Casp3↑,
Bcl-xL↓, while the expression level of Bcl-xl was down-regulated

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

3345-

ART/DHA,

Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells

in-vitro,

GBM,

ROS↑, Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death
Ferroptosis↑, DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation.
lipid-P↑,
HSP70/HSPA5↑, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5)
ER Stress↑, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4)
ATF4↑,
GRP78/BiP↑, HSPA5
MDA↑, DHA significantly increased lipid ROS and MDA levels in glioma cells in a dose- and time-dependent manner.
GSH↓, As an important antioxidant, reduced form GSH was exhausted by DHA
eff↑, Inhibitor of HSPA5 synergistically enhanced anti-tumor effects of DHA
GPx4↑, DHA induced-ER stress in turn activated cell protection against ferroptosis through PERK-ATF4- HSPA5 activation, which promoted the expression of GPX4 to detoxify peroxidized membrane lipids

3160-

Ash,

Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal

Review,

Var,

TumCCA↑, withaferin A suppressed cell proliferation in prostate, ovarian, breast, gastric, leukemic, and melanoma cancer cells and osteosarcomas by stimulating the inhibition of the cell cycle at several stages, including G0/G1 [86], G2, and M phase
H3↑, via the upregulation of phosphorylated Aurora B, H3, p21, and Wee-1, and the downregulation of A2, B1, and E2 cyclins, Cdc2 (Tyr15), phosphorylated Chk1, and Chk2 in DU-145 and PC-3 prostate cancer cells.
P21↑,
cycA1/CCNA1↓,
CycB/CCNB1↓,
cycE/CCNE↓,
CDC2↓,
CHK1↓,
Chk2↓,
p38↑, nitiated cell death in the leukemia cells by increasing the expression of p38 mitogen-activated protein kinases (MAPK)
MAPK↑,
E6↓, educed the expression of human papillomavirus E6/E7 oncogenes in cervical cancer cells
E7↓,
P53↑, restored the p53 pathway causing the apoptosis of cervical cancer cells.
Akt↓, oral dose of 3–5 mg/kg withaferin A attenuated the activation of Akt and stimulated Forkhead Box-O3a (FOXO3a)-mediated prostate apoptotic response-4 (Par-4) activation,
FOXO3↑,
ROS↑, the generation of reactive oxygen species, histone H2AX phosphorylation, and mitochondrial membrane depolarization, indicating that withaferin A can cause the oxidative stress-mediated killing of oral cancer cells [
γH2AX↑,
MMP↓,
mitResp↓, withaferin A inhibited the expansion of MCF-7 and MDA-MB-231 human breast cancer cells by ROS production, owing to mitochondrial respiration inhibition
eff↑, combination treatment of withaferin A and hyperthermia induced the death of HeLa cells via a decrease in the mitochondrial transmembrane potential and the downregulation of the antiapoptotic protein myeloid-cell leukemia 1 (MCL-1)
TumCD↑,
Mcl-1↓,
ER Stress↑, . Withaferin A also attenuated the development of glioblastoma multiforme (GBM), both in vitro and in vivo, by inducing endoplasmic reticulum stress via activating the transcription factor 4-ATF3-C/EBP homologous protein (ATF4-ATF3-CHOP)
ATF4↑,
ATF3↑,
CHOP↑,
NOTCH↓, modulating the Notch-1 signaling pathway and the downregulation of Akt/NF-κB/Bcl-2 . withaferin A inhibited the Notch signaling pathway
NF-kB↓,
Bcl-2↓,
STAT3↓, Withaferin A also constitutively inhibited interleukin-6-induced phosphorylation of STAT3,
CDK1↓, lowering the levels of cyclin-dependent Cdk1, Cdc25C, and Cdc25B proteins,
β-catenin/ZEB1↓, downregulation of p-Akt expression, β-catenin, N-cadherin and epithelial to the mesenchymal transition (EMT) markers
N-cadherin↓,
EMT↓,
Cyt‑c↑, depolarization and production of ROS, which led to the release of cytochrome c into the cytosol,
eff↑, combinatorial effect of withaferin A and sulforaphane was also observed in MDA-MB-231 and MCF-7 breast cancer cells, with a dramatic reduction of the expression of the antiapoptotic protein Bcl-2 and an increase in the pro-apoptotic Bax level, thus p
CDK4↓, downregulates the levels of cyclin D1, CDK4, and pRB, and upregulates the levels of E2F mRNA and tumor suppressor p21, independently of p53
p‑RB1↓,
PARP↑, upregulation of Bax and cytochrome c, downregulation of Bcl-2, and activation of PARP, caspase-3, and caspase-9 cleavage
cl‑Casp3↑,
cl‑Casp9↑,
NRF2↑, withaferin A binding with Keap1 causes an increase in the nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels, which in turn, regulates the expression of antioxidant proteins that can protect the cells from oxidative stress.
ER-α36↓, Decreased ER-α
LDHA↓, inhibited growth, LDHA activity, and apoptotic induction
lipid-P↑, induction of oxidative stress, increased lipid peroxidation,
AP-1↓, anti-inflammatory qualities of withaferin A are specifically attributed to its inhibition of pro-inflammatory molecules, α-2 macroglobulin, NF-κB, activator protein 1 (AP-1), and cyclooxygenase-2 (COX-2) inhibition,
COX2↓,
RenoP↑, showing strong evidence of the renoprotective potential of withaferin A due to its anti-inflammatory activity
PDGFR-BB↓, attenuating the BB-(PDGF-BB) platelet growth factor
SIRT3↑, by increasing the sirtuin3 (SIRT3) expression
MMP2↓, withaferin A inhibits matrix metalloproteinase-2 (MMP-2) and MMP-9,
MMP9↓,
NADPH↑, but also provokes mRNA stimulation for a set of antioxidant genes, such as NADPH quinone dehydrogenase 1 (NQO1), glutathione-disulfide reductase (GSR), Nrf2, heme oxygenase 1 (HMOX1),
NQO1↑,
GSR↑,
HO-1↑,
*SOD2↑, cardiac ischemia-reperfusion injury model. Withaferin A triggered the upregulation of superoxide dismutase SOD2, SOD3, and peroxiredoxin 1(Prdx-1).
*Prx↑,
*Casp3?, and ameliorated cardiomyocyte caspase-3 activity
eff↑, combination with doxorubicin (DOX), is also responsible for the excessive generation of ROS
Snail↓, inhibition of EMT markers, such as Snail, Slug, β-catenin, and vimentin.
Slug↓,
Vim↓,
CSCs↓, highly effective in eliminating cancer stem cells (CSC) that expressed cell surface markers, such as CD24, CD34, CD44, CD117, and Oct4 while downregulating Notch1, Hes1, and Hey1 genes;
HEY1↓,
MMPs↓, downregulate the expression of MMPs and VEGF, as well as reduce vimentin, N-cadherin cytoskeleton proteins,
VEGF↓,
uPA↓, and protease u-PA involved in the cancer cell metastasis
*toxicity↓, A was orally administered to Wistar rats at a dose of 2000 mg/kg/day and had no adverse effects on the animals
CDK2↓, downregulated the activation of Bcl-2, CDK2, and cyclin D1
CDK4↓, Another study also demonstrated the inhibition of Hsp90 by withaferin A in a pancreatic cancer cell line through the degradation of Akt, cyclin-dependent kinase 4 Cdk4,
HSP90↓,

3511-

Bor,

Boron

Review,

NA,

*memory↑, In boron-deprived humans, boron supplementation improved mental alertness, attention, short-term memory, and motor speed and dexterity.
*motorD↑,
*neuroP↑,
Ca+2↓, human prostate cells, boric acid acts as a reversible noncompetitive inhibitor of cADPR leading to decreased endoplasmic reticulum Ca2+
ATF4↑, The decreased Ca2+ results in the E74 like ETS transcription factor 2α activating transcription factor 4 (ATF4) and nuclear factor erythroid 2 like 2 (Nrf2),
NRF2↑,
*Inflam↓, a dietary boron intake >0.4 mg/d may be useful for bone and brain health and in modulating inflammatory and oxidative stress
*ROS↓,

3512-

Bor,

Activation of the EIF2α/ATF4 and ATF6 Pathways in DU-145 Cells by Boric Acid at the Concentration Reported in Men at the US Mean Boron Intake

in-vitro,

Pca,

DU145

TumCP↓, Treatment of DU-145 prostate cancer cells with physiological concentrations of BA inhibits cell proliferation without causing apoptosis and activates eukaryotic initiation factor 2 (eIF2α).
eIF2α↑, Phosphorylation of eIF2α occurs following BA treatment of DU-145 and LNCaP prostate cells
ATF4↑, post-treatment increases in eIF2α protein at 30 min and ATF4 and ATF6 proteins at 1 h and 30 min, respectively
ATF6↑,
GADD34↑, The increase in ATF4 was accompanied by an increase in the expression of its downstream genes growth arrest and DNA damage-induced protein 34 (GADD34) and homocysteine-induced ER protein (Herp),
CHOP↓, but a decrease in GADD153/CCAAT/enhancer-binding protein homologous protein (CHOP), a pro-apoptotic gene.
GRP78/BiP↑, The increase in ATF6 was accompanied by an increase in expression of its downstream genes GRP78/BiP, calreticulin, Grp94, and EDEM.
GRP94↑,
Risk↓, Low boron status has been associated with increased cancer risk, low bone mineralization, and retinal degeneration
*BMD↑,
Ca+2↓, LNCaP and DU-145: BA binds to cADPR and inhibits cADPR-activated Ca2+ release from the endoplasmic reticulum (ER) in a dose-dependent manner [15, 16] and lowers ER luminal Ca2+ concentrations
*Half-Life↝, lood levels of BA are dynamic, rising rapidly after a meal with an elimination half-life from 4 to 27.8 h depending on dose
IRE1∅, BA does not activate IRE1
chemoP↑, Dietary boron has been connected to three seemingly unconnected observations, increased bone mass and strength [10, 74, 75], chemoprevention

767-

Bor,

Boric acid induces cytoplasmic stress granule formation, eIF2α phosphorylation, and ATF4 in prostate DU-145 cells

in-vitro,

Pca,

DU145

ER Stress↑,
eIF2α↑,
GRP78/BiP↑,
ATF4↑,

737-

Bor,

Boric Acid Activation of eIF2α and Nrf2 Is PERK Dependent: a Mechanism that Explains How Boron Prevents DNA Damage and Enhances Antioxidant Statu

in-vitro,

Pca,

DU145

10uM

Risk↓, intake is associated with reduced risk of cancer and DNA damage and increased antioxidant status.
p‑eIF2α↑,
ATF4↑,
GADD34↑,

726-

Bor,

Redox Mechanisms Underlying the Cytostatic Effects of Boric Acid on Cancer Cells—An Issue Still Open

Review,

NA,

NAD↝, high affinity for the ribose moieties of NAD+
SAM-e↝, high affinity for S-adenosylmethione
PSA↓,
IGF-1↓,
Cyc↓, reduction in cyclins A–E
P21↓,
p‑MEK↓,
p‑ERK↓, ERK (P-ERK1/2)
ROS↑, induce oxidative stress by decreasing superoxide dismutase (SOD) and catalase (CAT)
SOD↓,
Catalase↓,
MDA↑,
GSH↓,
IL1↓, IL-1α
IL6↓,
TNF-α↓,
BRAF↝,
MAPK↝,
PTEN↝,
PI3K/Akt↝,
eIF2α↑,
ATF4↑,
ATF6↑,
NRF2↑,
BAX↑,
BID↑,
Casp3↑,
Casp9↑,
Bcl-2↓,
Bcl-xL↓,

3032-

CA,

Carnosic Acid Induces Apoptosis Through Reactive Oxygen Species-mediated Endoplasmic Reticulum Stress Induction in Human Renal Carcinoma Caki Cells

in-vitro,

Kidney,

Caki-1

cl‑PARP↑, Carnosic acid induced sub-diploid DNA content, sub-G1, population and poly (ADP-ribose) polymerase (PARP) cleavage and activated caspase-3.
ROS↑, Carnosic acid promoted intracellular ROS production,
ER Stress↑, carnosic acid also induced expression of ER stress marker proteins, including activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-homologous protein (CHOP), in a dose- and time-dependent manner.
ATF4↑,
CHOP↑,
selectivity↑, Carnosic acid induced apoptosis in other cancer cells, but not normal cells

5862-

carbop,

Cisplatin,

Molecular Mechanisms of Resistance and Toxicity Associated with Platinating Agents

Review,

Var,

DNAdam↑, It is generally agreed that DNA is the preferential and cytotoxic target for cisplatin and other platinating agents. able to induce similar numbers of single-strand and double-strand breaks on DNA
ER Stress↑, shown to cause activation of apoptotic caspases through activation of the endoplasmic reticulum (ER) stress pathway (
UPR↑, When the ER experiences stress such as starvation or treatment with inhibitors of N-glycosylation (e.g. tunicamycin), it cannot fold or transport proteins correctly, and the UPR is activated.
ATF4↑, regulatory components of the ER stress pathway, including ATF4, ATF6, XBP1, and BiP (Grp78), are upregulated
ATF6↑,
XBP-1↑,
GRP78/BiP↑,
NP/CIPN↝, Carboplatin is notably less neurotoxic than cisplatin at conventional doses, with a similar sensory neuropathy occurring in approximately 6% of patients
toxicity↝, Carboplatin rarely results in nephrotoxicity and peripheral neuropathy, with its major toxicity being myelosuppression
eff↑, exposure to buthiomine sulfoximine (BSO), which significantly depleted cellular glutathione concentration, resulted in a significant enhancement in cisplatin cytotoxicity [151].
TrxR1⇅, Both cisplatin and transplatin show this inhibition of TxrR1 [161], as does oxaliplatin but not carboplatin [162]

5818-

CBD,

Cannabidiol's cytotoxicity in pancreatic cancer is induced via an upregulation of ceramide synthase 1 and ER stress

in-vivo,

PC,

PANC1

GRP78/BiP↑, Upon CBD treatment, CerS1 was upregulated and downstream this led to the GRP78/ATF4/CHOP arm of the unfolded protein response (UPR) pathway being activated.
ATF4↑,
CHOP↑,
UPR↑,
TumCG↓, Cannabidiol reduces pancreatic cancer growth in a dose and time dependent manner
ER Stress↑, activation of GRP78, ATF4 arm of the UPR pathway further resulting in elevated CHOP expression which induces ER stress leading to apoptosis
eff↓, Additionally, drug-drug interactions are a problem with CBD intake as it involves metabolism by a competitive inhibitor of CYP450 enzymes

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

118-

CUR,

Curcumin analog WZ35 induced cell death via ROS-dependent ER stress and G2/M cell cycle arrest in human prostate cancer cells

in-vitro,

Pca,

PC3

 2.2 μM

 for WZ35 analog. For Curcumin it is 20.9μM

in-vitro,

Pca,

DU145

ROS↑, WZ35 treatment for 30 min significantly induced reactive oxygen species (ROS) production in PC-3 cells.
Bcl-2↓,
PARP↑,
cDC2↓, decreased expression of CDC2, cyclinB1, and MDM2
CycB/CCNB1↓,
MDM2↓,
eff↓, Co-treatment with the ROS scavenger NAC completely abrogated the induction of WZ35 on cell apoptosis,
eIF2α↑, WZ35 treatment also induced a constant increase in the level of phosphorylated eIF2α 3 to 12 h after WZ35 treatment
ATF4↑, ATF4 expression also increased in a similar manner with p-eIF2α
CHOP↑, CHOP protein expression apparently increased 9-24 h after WZ35 treatment and peaked at 12 h
ER Stress↑, results suggest that WZ35 can induce ER stress in prostate cancer cells
TumCCA↑, WZ35 induced cell cycle arrest in G2/M phase in PC-3 cells

462-

CUR,

Curcumin promotes cancer-associated fibroblasts apoptosis via ROS-mediated endoplasmic reticulum stress

in-vitro,

Pca,

PC3

10, 20 and 30 μM, 8, 12 and 24 h

Bcl-2↓,
MMP↓,
cl‑Casp3↑,
BAX↑,
BIM↑,
p‑PARP↑,
PUMA↑,
p‑P53↑,
ROS↑,
p‑ERK↑,
p‑eIF2α↑,
CHOP↑,
ATF4↑,

2272-

dietMet,

Methionine restriction - Association with redox homeostasis and implications on aging and diseases

Review,

Nor,

*OS↑, MR seems to be an approach to prolong lifespan which has been validated extensively in various animal models
*mt-ROS↓, Mitochondrial ROS reduction by methionine restriction (MR) maintains redox balance
*H2S↑, MR ameliorates oxidative stress by autophagy activation and hepatic H2S generation.
*FGF21↑, MR impact on cognition by upregulation of FGF21 and alterations of gut microbiome.
*cognitive↑,
*GutMicro↑,
*IGF-1↓, long-term, low-fat, whole-food vegan diet may increase life expectancy in humans by down-regulating IGF-I activity
*mTOR↓, Suppression of the mTOR pathway by MR can also lead to increased H2S production,
*GSH↑, 80% MR increases the GSH content in erythrocytes of rats,
*SOD↑, A diet restricting methionine to 80% (0.17% Met) significantly increases plasma SOD and decreases MDA levels while increasing mRNA expression of Nrf2, HO-1, and NQO-1 in the heart of HFD-fed mice with cardiovascular impairment
*MDA↓,
*NRF2↑,
*HO-1↑,
*NQO1↑,
*GLUT4↑, In skeletal muscle, MR improved expression and transport of GLUT4 and glycogen levels and increased the expression of glycolysis-related genes (HK2, PFK, PKM) in HFD-fed mice
*Glycolysis↑,
*HK2↑,
*PFK↑,
*PKM2↑,
*GlucoseCon↑, promoting glucose uptake and glycogen synthesis, glycolysis, and aerobic oxidation in skeletal muscle.
*ATF4↑, MR can increase the expression of hepatic FGF21 by activating GCN2/ATF4/PPARα signaling in liver cells, thereby improving insulin sensitivity, accelerating energy expenditure, and promoting fat oxidation and glucose metabolism
*PPARα↑,
GSH↓, MR was able to decrease GSH in HepG2 cells, thereby regulating the activation state of protein tyrosine phosphatases such as PTEN.
GSTs↑, decrease of GSH by MR also triggers upregulation of glutathione S-transferase
ROS↑, Double deprivation of methionine and cystine both in vitro and in vivo resulted in a decrease in GSH content, an increase in ROS levels, and an induction of autophagy in glioma cells
*neuroP↑, A neuroprotective role of FGF21

5190-

dietMet,

Methionine restriction activates the integrated stress response in triple-negative breast cancer cells by a GCN2- and PERK-independent mechanism

in-vitro,

BC,

MDA-MB-231

in-vitro,

BC,

MDA-MB-468

p‑eIF2α↑, methionine restriction induces eIF2α phosphorylation and enhances ATF4 gene expression and protein levels of ATF4 and Sestrin-2 in triple (ER/PR/HER2)-negative breast cancer (TNBC) cells.
ATF4↑,
SESN2↑,
TumCCA↑, Methionine restriction or replacement of methionine with homocysteine selectively induces cell cycle blockade or apoptosis in cancer cells
Apoptosis↑,
other↑, Methionine deprivation activates the integrated stress response in TNBC cells

677-

EGCG,

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↑,

3203-

EGCG,

(-)- Epigallocatechin-3-gallate induces GRP78 accumulation in the ER and shifts mesothelioma constitutive UPR into proapoptotic ER stress

NA,

MM,

ROS↑, We have previously shown that (-)-epigallocatechin-3-gallate (EGCG) enhances ROS production and alters Ca2+ homeostasis in cell lines deriving from therapy-recalcitrant malignant mesothelioma (MMe).
Ca+2↝,
GRP78/BiP↑, Exposure to EGCG further increased GRP78 in the ER, and induced ATF4, spliced XBP1, CHOP, and EDEM expressions, combined with a reduction of cell surface GRP78 and a rise in caspase 3 and 8 activities.
ATF4↑,
XBP-1↑,
CHOP↑,
Casp3↑,
Casp8↑,
*GRP78/BiP↓, n non-cancer mouse retinal pigment epithelial cells,EGCG has been found to downregulate GRP78 and UPR signaling (Karthikeyan et al., 2017).
*UPR↓,
UPR↑, However, if ER homeostasiscannot be re-established, the UPR switches its signaling toward irreversible ER stress with the activation of apoptosis (

3205-

EGCG,

The Role of Epigallocatechin-3-Gallate in Autophagy and Endoplasmic Reticulum Stress (ERS)-Induced Apoptosis of Human Diseas

Review,

Var,

Review,

AD,

Beclin-1↑, EGCG not only regulates autophagy via increasing Beclin-1 expression and reactive oxygen species generation,
ROS↑,
Apoptosis↑, Apoptosis is a common cell function in biology and is induced by endoplasmic reticulum stress (ERS)
ER Stress↑,
*Inflam↓, EGCG has health benefits including anti-tumor [15], anti-inflammatory [16], anti-diabetes [17], anti-myocardial infarction [18], anti-cardiac hypertrophy [19], anti-atherosclerosis [20], and antioxidant
*cardioP↑,
*antiOx↑,
*LDL↓, These effects are mainly related to (LDL) cholesterol inhibition, NF-κB inhibition, MPO activity inhibition, decreased levels of glucose and glycated hemoglobin in plasma, decreased inflammatory markers, and reduced ROS generation
*NF-kB↓,
*MPO↓,
*glucose↓,
*ROS↓,
ATG5↑, EGCG induced autophagy by enhancing Beclin-1, ATG5, and LC3B and promoted mitochondrial depolarization in breast cancer cells.
LC3B↑,
MMP↑,
lactateProd↓, 20 mg kg−1 EGCG significantly decreased glucose, lactic acid, and vascular endothelial growth factor (VEGF) levels
VEGF↓,
Zeb1↑, (20 uM) inhibited the proliferation through activating autophagy via upregulating ZEB1, WNT11, IGF1R, FAS, BAK, and BAD genes and inhibiting TP53, MYC, and CASP8 genes in SSC-4 human oral squamous cells [
Wnt↑,
IGF-1R↑,
Fas↑,
Bak↑,
BAD↑,
TP53↓,
Myc↓,
Casp8↓,
LC3II↑, increasing the LC3-II expression levels and induced apoptosis via inducing ROS in mesothelioma cell lines,
NOTCH3↓, but also could reduce partially Notch3/DLL3 to reduce drug-resistance and the stemness of tumor cells
eff↑, In combination therapies, low-intensity pulsed electric field (PEF) can improve EGCG to affect tumor cells; ultrasound (US) with tumor cells is the application of physical stimulation in cancer therapy.
p‑Akt↓, 20 μM EGCG increased intracellular ROS levels and LC3-II, and inhibited p-Akt in PANC-1 cells
PARP↑, 100 μM EGCG increased LC3-II, activated caspase-3 and PARP, and reduced p-Akt in HepG2
*Cyt‑c↓, EGCG protected neuronal cells against human viruses by inhibiting cytochrome c and Bax translocations, and reducing autophagy with increased LC3-II expression and decreased p62 expression
*BAX↓,
*memory↑, EGCG restored autophagy in the mTOR/p70S6K pathway to weaken memory and learning disorders induced by CUMS
*neuroP↑, Finally, EGCG increased the neurological scores through inhibiting cell death
*Ca+2?, EGCG treatment, [Ca2+]m and [Ca2+]i expressions were reduced and oxyhemoglobin-induced mitochondrial dysfunction lessened.
GRP78/BiP↑, MMe cells with EGCG treatment improved GRP78 expression in the endoplasmic reticulum, and induced EDEM, CHOP, XBP1, and ATF4 expressions, and increased the activity of caspase-3 and caspase-8.
CHOP↑, GRP78 accumulation converted UPR of MMe cells into pro-apoptotic ERS
ATF4↑,
Casp3↑,
Casp8↑,
UPR↑,

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

2855-

FIS,

Fisetin Induces Apoptosis Through p53-Mediated Up-Regulation of DR5 Expression in Human Renal Carcinoma Caki Cells

in-vitro,

RCC,

Caki-1

TumCCA↑, Fisetin markedly induced sub-G1 population and cleavage of poly (ADP-ribose) polymerase (PARP), which is a marker of apoptosis, and increased caspase activation.
cl‑PARP↑,
Apoptosis↑,
Casp↑,
P53↑, fisetin induced p53 protein expression
DR5↑, fisetin-induced DR5 expression.
CHOP↑, fisetin induced up-regulation of CHOP expression and reactive oxygen species production, which had no effect on fisetin-induced apoptosis.
ROS↑,
ER Stress↑, Fisetin induced expression of ER stress-related proteins, including CHOP and activating ATF4
ATF4↑,
XBP-1↑, fisetin also increased the spliced form of the X-box binding protein (XBP)-1 mRNA
eff∅, In our study, NAC did not enhance fisetin-induced apoptosis, and the ROS scavenger, GEE, also had no effect on apoptosi

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↑,

2825-

FIS,

Exploring the molecular targets of dietary flavonoid fisetin in cancer

Review,

Var,

*Inflam↓, present in fruits and vegetables such as strawberries, apple, cucumber, persimmon, grape and onion, was shown to possess anti-microbial, anti-inflammatory, anti-oxidant
*antiOx↓, fisetin possesses stronger oxidant inhibitory activity than well-known potent antioxidants like morin and myricetin.
*ERK↑, inducing extracellular signal-regulated kinase1/2 (ERK)/c-myc phosphorylation, nuclear NF-E2-related factor-2 (Nrf2), glutamate cystine ligase and glutathione (GSH) levels
*p‑cMyc↑,
*NRF2↑,
*GSH↑,
*HO-1↑, activate Nrf2 mediated induction of hemeoxygenase-1 (HO-1) important for cell survival
mTOR↓, in our studies on fisetin in non-small lung cancer cells, we found that fisetin acts as a dual inhibitor PI3K/Akt and mTOR pathways
PI3K↓,
Akt↓,
TumCCA↑, fisetin treatment to LNCaP cells resulted in G1-phase arrest accompanied with decrease in cyclins D1, D2 and E and their activating partner CDKs 2, 4 and 6 with induction ofWAF1/p21 and KIP1/p27
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
P21↑,
p27↑,
JNK↑, fisetin could inhibit the metastatic ability of PC-3 cells by suppressing of PI3 K/Akt and JNK signaling pathways with subsequent repression of matrix metalloproteinase-2 (MMP-2) and MMP-9
MMP2↓,
MMP9↓,
uPA↓, fisetin suppressed protein and mRNA levels of MMP-2 and urokinase-type plasminogen activator (uPA) in an ERK-dependent fashion.
NF-kB↓, decrease in the nuclear levels of NF-B, c-Fos, and c-Jun was noted in fisetin treated cells
cFos↓,
cJun↓,
E-cadherin↑, upregulation of E-cadherin and down-regulation of vimentin and N-cadherin.
Vim↓,
N-cadherin↓,
EMT↓, EMT inhibiting potential of fisetin has been reported in melanoma cells
MMP↓, The shift in mitochondrial membrane potential was accompanied by release of cytochrome c and Smac/DIABLO resulting in activation of the caspase cascade and cleavage of PARP
Cyt‑c↑,
Diablo↑,
Casp↑,
cl‑PARP↑,
P53↑, fisetin with induction of p53 protein
COX2↓, Fisetin down-regulated COX-2 and reduced the secretion of prostaglandin E2 without affecting COX-1 protein expression.
PGE2↓,
HSP70/HSPA5↓, It was shown that the induction of HSF1 target proteins, such as HSP70, HSP27 and BAG3 were inhibited in HCT-116 cells exposed to heat shock at 43 C for 1 h in the presence of fisetin
HSP27↓,
DNAdam↑, DNA fragmentation, an increase in the number of sub-G1 phase cells, mitochondrial membrane depolarization and activation of caspase-9 and caspase-3.
Casp3↑,
Casp9↑,
ROS↑, This was associated with production of intracellular ROS
AMPK↑, Fisetin induced AMPK signaling
NO↑, fisetin induced cytotoxicity and showed that fisetin induced apoptosis of leukemia cells through generation of NO and elevated Ca2+ activating the caspase
Ca+2↑,
mTORC1↓, Fisetin was shown to inhibit the mTORC1 pathway and its downstream components including p70S6 K, eIF4B and eEF2 K.
p70S6↓,
ROS↓, Others have also noted a similar decrease in ROS with fisetin treatment.
ER Stress↑, Induction of ER stress upon fisetin treatment, evident as early as 6 h, and associated with up-regulation of IRE1, XBP1s, ATF4 and GRP78, was followed by autophagy which was not sustained
IRE1↑,
ATF4↑,
GRP78/BiP↑,
eff↑, Combination of fisetin and the BRAF inhibitor sorafenib was found to be extremely effective in inhibiting the growth of BRAF-mutated human melanoma cells
eff↑, synergistic effect of fisetin and sorafenib was observed in human cervical cancer HeLa cells,
eff↑, Similarly, fisetin in combination with hesperetin induced apoptosis
RadioS↑, pretreatment with fisetin enhanced the radio-sensitivity of p53 mutant HT-29 cancer cells,
ChemoSen↑, potential of fisetin in enhancing cisplatin-induced cytotoxicity in various cancer models
Half-Life↝, intraperitoneal (ip) dose of 223 mg/kg body weight the maximum plasma concentration (2.53 ug/ml) of fisetin was reached at 15 min which started to decline with a first rapid alpha half-life of 0.09 h and a longer half-life of 3.12 h.

2839-

FIS,

Dietary flavonoid fisetin for cancer prevention and treatment

Review,

Var,

DNAdam↑, Fisetin induced DNA fragmentation, ROS generation, and apoptosis in NCI-H460 cells via a reduction in Bcl-2 and increase in Bax expression
ROS↑,
Apoptosis↑,
Bcl-2↓,
BAX↑,
cl‑Casp9↑, Fisetin treatment increased cleavage of caspase-9 and caspase-3 thereby increasing caspase-3 activation
cl‑Casp3↑,
Cyt‑c↑, leading to cytochrome-c release
lipid-P↓, Fisetin (25 mg/kg body weight) decreased histological lesions and levels of lipid peroxidation and modulated the enzymatic and nonenzymatic anti-oxidants in B(a)P-treated Swiss Albino mice
TumCG↓, We observed that fisetin treatment (5–20 μM) inhibits cell growth and colony formation in A549 NSC lung cancer cells.
TumCA↓, Another study showed that fisetin inhibits adhesion, migration, and invasion in A549 lung cancer cells by downregulating uPA, ERK1/2, and MMP-2
TumCMig↓,
TumCI↓,
uPA↓,
ERK↓,
MMP9↓,
NF-kB↓, Treatment with fisetin also decreased the nuclear levels of NF-kB, c-Fos, c-Jun, and AP-1 and inhibited NF-kB binding.
cFos↓,
cJun↓,
AP-1↓,
TumCCA↑, Our laboratory has previously shown that treatment of LNCaP cells with fisetin caused inhibition of PCa by G1-phase cell cycle arrest
AR↓, inhibited androgen signaling and tumor growth in athymic nude mice
mTORC1↓, induced autophagic cell death in PCa cells through suppression of mTORC1 and mTORC2
mTORC2↓,
TSC2↑, activated the mTOR repressor TSC2, commonly associated with inhibition of Akt and activation of AMPK
EGF↓, Fisetin also inhibits EGF and TGF-β induced YB-1 phosphorylation and EMT in PCa cells
TGF-β↓,
EMT↓, Fisetin also inhibits EGF and TGF-β induced YB-1 phosphorylation and EMT in PCa cells
P-gp↓, decrease the P-gp protein in multidrug resistant NCI/ADR-RES cells.
PI3K↓, Fisetin also inhibited the PI3K/AKT/NFkB signaling
Akt↓,
mTOR↓, Fisetin inhibited melanoma progression in a 3D melanoma skin model with downregulation of mTOR, Akt, and upregulation of TSC
eff↑, combinational treatment study of melatonin and fisetin demonstrated enhanced antitumor activity of fisetin
ROS↓, Fisetin inhibited ROS and augmented NO generation in A375 melanoma cells
ER Stress↑, induction of ER stress evidenced by increased IRE1α, XBP1s, ATF4, and GRP78 levels in A375 and 451Lu cells.
IRE1↑,
ATF4↑,
GRP78/BiP↑,
ChemoSen↑, combination of fisetin with sorafenib effectively inhibited EMT and augmented the anti-metastatic potential of sorafenib by reducing MMP-2 and MMP-9 proteins in melanoma cell xenografts
CDK2↓, Fisetin (0–60 μM) was shown to inhibit activity of CDKs dose-dependently leading to cell cycle arrest in HT-29 human colon cancer cells
CDK4↓, Fisetin treatment decreased activities of CDK2 and CDK4 via decreased levels of cyclin-E, cyclin-D1 and increase in p21 (CIP1/WAF1) levels.
cycE/CCNE↓,
cycD1/CCND1↓,
P21↑,
COX2↓, fisetin (30–120 μM) induces apoptosis in colon cancer cells by inhibiting COX-2 and Wnt/EGFR/NF-kB -signaling pathways
Wnt↓,
EGFR↓,
β-catenin/ZEB1↓, Fisetin treatment inhibited Wnt/EGFR/NF-kB signaling via downregulation of β-catenin, TCF-4, cyclin D1, and MMP-7
TCF-4↓,
MMP7↓,
RadioS↑, fisetin treatment was found to radiosensitize human colorectal cancer cells which are resistant to radiotherapy
eff↑, Combined treatment of fisetin with NAC increased cleaved caspase-3, PARP, reduced mitochondrial membrane potential with induction of caspase-9 in COLO25 cells

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

2832-

FIS,

Fisetin's Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies

Review,

Var,

MMP↓, fraction of cells with reduced mitochondrial membrane potential also increased, indicating that fisetin-induced apoptosis also destroys mitochondria.
mtDam↑,
Cyt‑c↑, Cytochrome c and Smac/DIABLO levels are also released when the mitochondrial membrane potential changes, and this results in the activation of the caspase cascade and the cleavage of poly [ADP-ribose] polymerase (PARP)
Diablo↑,
Casp↑,
cl‑PARP↑,
Bak↑, Fisetin induced apoptosis in HCT-116 human colon cancer cells by upregulating proapoptotic proteins Bak and BIM and downregulating antiapoptotic proteins B cell lymphoma (BCL)-XL and -2.
BIM↑,
Bcl-xL↓,
Bcl-2↓,
P53↑, fisetin through the activation of p53
ROS↑, over generation of ROS, which is also directly initiated by fisetin, the stimulation of AMPK
AMPK↑,
Casp9↑, activating caspase-9 collectively, then activating caspase-3, leading to apopotosis
Casp3↑,
BID↑, Bid, AIF and the increase of the ratio of Bax to Bcl-2, causing the activation of caspase 3–9
AIF↑,
Akt↓, The inhibition of the Akt/mTOR/MAPK/
mTOR↓,
MAPK↓,
Wnt↓, Fisetin has been shown to degrade the Wnt/β/β-catenin signal
β-catenin/ZEB1↓,
TumCCA↑, fisetin triggered G1 phase arrest in LNCaP cells by activating WAF1/p21 and kip1/p27, followed by a reduction in cyclin D1, D2, and E as well as CDKs 2, 4, and 6
P21↑,
p27↑,
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
TumMeta↓, reduces PC-3 cells' capacity for metastasis
uPA↓, fisetin decreased MMP-2 protein, messenger RNA (mRNA), and uPA levels through an ERK-dependent route
E-cadherin↑, Fisetin can upregulate the epithelial marker E-cadherin, downregulate the mesenchymal marker vimentin, and drastically lower the EMT regulator twist protein level at noncytotoxic dosages, studies have revealed.
Vim↓,
EMT↓,
Twist↓,
DNAdam↑, Fisetin induces apoptosis in the human nonsmall lung cancer cell line NCI-H460, which causes DNA breakage, the growth of sub-G1 cells, depolarization of the mitochondrial membrane, and activation of caspases 9, 3, which are involved in prod of iROS
ROS↓, fisetin therapy has been linked to a reduction in ROS, according to other research.
COX2↓, Fisetin lowered the expression of COX-1 protein, downregulated COX-2, and decreased PGE2 production
PGE2↓,
HSF1↓, Fisetin is a strong HSF1 inhibitor that blocks HSF1 from binding to the hsp70 gene promoter.
cFos↓, NF-κB, c-Fos, c-Jun, and AP-1 nuclear levels were also lowered by fisetin treatment
cJun↓,
AP-1↓,
Mcl-1↓, inhibition of Bcl-2 and Mcl-1 all contribute to an increase in apoptosis
NF-kB↓, Fisetin's ability to prevent NF-κB activation in LNCaP cells
IRE1↑, fisetin (20–80 µM) was accompanied by brief autophagy and the production of ER stress, which was shown by elevated levels of IRE1 α, XBP1s, ATF4, and GRP78 in A375 and 451Lu cells
ER Stress↑,
ATF4↑,
GRP78/BiP↑,
MMP2↓, lowering MMP-2 and MMP-9 proteins in melanoma cell xenografts
MMP9↓,
TCF-4↓, fisetin therapy reduced levels of β-catenin, TCF-4, cyclin D1, and MMP-7,
MMP7↓,
RadioS↑, fisetin treatment could radiosensitize human colorectal cancer cells that are resistant to radiotherapy.
TOP1↓, fisetin blocks DNA topoisomerases I and II in leukemia cells.
TOP2↓,

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∅,

150-

NRF,

CUR,

docx,

Subverting ER-Stress towards Apoptosis by Nelfinavir and Curcumin Coexposure Augments Docetaxel Efficacy in Castration Resistant Prostate Cancer Cells

in-vitro,

Pca,

C4-2B

 NFR (5 µM), CUR (5 µM),DTX 10nM

 CRPC

p‑Akt↓,
p‑eIF2α↑, phosphorylated
ER Stress↑, Acute exposure (3–9 hrs) to this 3-drug combination intensified ER-stress induced pro-apoptotic markers, i.e. ATF4, CHOP, and TRIB3.
ATF4↑, 3-drug combination rapidly enhances ER-stress associated death sensors, CHOP, ATF-4 and TRIB3 in C4-2B cells
CHOP↑,
TRIB3↑,
ChemoSen↑, subverting ER-stress towards apoptosis using adjuvant therapy with NFR and CUR can chemosensitize the CRPC cells to DTX therapy.
Casp3↑, NFR or CUR alone could increase Caspase-3 activity in DTX exposed cells
cl‑PARP↑, PARP cleavage assays further confirmed this differential effect of drug combination on apoptotic cell death. In C4-2B cells, a 9-fold increase was observed
BID↑, 3-drug combination rapidly increases ER-stress transducers, BiP, eIF2µ and Xbp-1 in C4-2B cells
XBP-1↑,

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

2948-

PL,

The promising potential of piperlongumine as an emerging therapeutics for cancer

Review,

Var,

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

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

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.

4912-

Sal,

Salinomycin induces cell death with autophagy through activation of endoplasmic reticulum stress in human cancer cells

in-vitro,

Lung,

A549

2.5 μM

in-vitro,

Lung,

H460

in-vitro,

Lung,

Calu-1

in-vitro,

Lung,

H157

CSCs↓, Salinomycin is perhaps the first promising compound that was discovered through high throughput screening in cancer stem cells.
TumAuto↑, salinomycin induced autophagy in human non-small cell lung cancer (NSCLC) cells
ER Stress↑, salinomycin stimulated endoplasmic reticulum stress and mediated autophagy via the ATF4-DDIT3/CHOP-TRIB3-AKT1-MTOR axis.
TumCD↑, salinomycin effectively decreased the survival of the indicated cells in a dose-dependent manner
ATF4↑, Salinomycin induces autophagy via ER stress-dependent upregulation of ATF4 and DDIT3
CHOP↑,
AKT1↓, salinomycin via AKT1-MTOR inhibition in human NSCLC cells.
mTOR↓,

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 42 of 42

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 42

Pathway results for Effect on Cancer / Diseased Cells:

Infection & Microbiome ⓘ

Bacteria↓, 1,
Total Targets: 292

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx↓, 1, antiOx↑, 3, GSH↑, 4, HO-1↑, 3, lipid-P↓, 1, MDA↓, 1, MPO↓, 1, NQO1↑, 2, NRF2↑, 3, Prx↑, 1, ROS↓, 5, mt-ROS↓, 1, SOD↑, 2, SOD2↑, 1,

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1, p‑cMyc↑, 1, FGF21↑, 1, glucose↓, 1, GlucoseCon↑, 1, Glycolysis↑, 1, H2S↑, 1, HK2↑, 1, LDHA↑, 1, LDL↓, 1, lipidLev↓, 1, PFK↑, 1, PKM2↑, 1, PPARα↑, 1,

Cell Death ⓘ

Akt↓, 1, BAX↓, 1, Casp3?, 1, Cyt‑c↓, 1,

Protein Folding & ER Stress ⓘ

GRP78/BiP↓, 1, UPR↓, 1,

Autophagy & Lysosomes ⓘ

Beclin-1↓, 1,

Proliferation, Differentiation & Cell State ⓘ

EMT↑, 1, ERK↑, 1, IGF-1↓, 1, mTOR↓, 1, PI3K↓, 1,

Migration ⓘ

Ca+2?, 1,

Angiogenesis & Vasculature ⓘ

ATF4↑, 1,

Barriers & Transport ⓘ

GLUT4↑, 1,

Immune & Inflammatory Signaling ⓘ

IL1β↓, 1, IL2↓, 1, IL6↓, 1, Inflam?, 1, Inflam↓, 6, NF-kB↓, 1, TNF-α↓, 2,

Drug Metabolism & Resistance ⓘ

BioAv↓, 2, Half-Life↝, 1,

Clinical Biomarkers ⓘ

ALAT↓, 1, AST↓, 1, BMD↑, 1, GutMicro↑, 1, IL6↓, 1,

Functional Outcomes ⓘ

cardioP↑, 2, cognitive↑, 2, hepatoP↑, 2, memory↑, 2, motorD↑, 1, neuroP↑, 5, OS↑, 1, RenoP↑, 1, toxicity↓, 1, toxicity∅, 1,
Total Targets: 67

Scientific Paper Hit Count for: ATF4, Activating Transcription Factor 4

6 Fisetin
5 Boron
4 EGCG (Epigallocatechin Gallate)
3 Artemisinin
3 Curcumin
2 Apigenin (mainly Parsley)
2 diet Methionine-Restricted Diet
2 Luteolin
2 Piperlongumine
2 Shikonin
1 Silver-NanoParticles
1 Ashwagandha(Withaferin A)
1 Carnosic acid
1 carboplatin
1 Cisplatin
1 Cannabidiol
1 Chrysin
1 nelfinavir/Viracept
1 Docetaxel
1 Pterostilbene
1 Resveratrol
1 salinomycin
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#:730  State#:%  Dir#:2
  wNotes=on  sortOrder:rid,rpid

ATF4 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 ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

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