Database Query Results : , , xCT

xCT, SLC7A11: Click to Expand ⟱

Source:

Type: protein

SLC7A11 (also known as xCT) xenobiotic transporter.
XCT (xenobiotic transporter) is a protein that plays a crucial role in the transport of xenobiotics, including chemotherapeutic agents, across cell membranes.
xCT overexpressed in: breast, lung, colon, prostate, GBM, Pancreatic (with poor prognosis) Cancer cells often experience high levels of oxidative stress; upregulation of SLC7A11 helps to counteract this stress and supports cell survival.

Targeting SLC7A11 can sensitize tumor cells to oxidative damage and ferroptosis, offering a potential therapeutic avenue.

SLC7A11 encodes the light chain subunit of the cystine/glutamate antiporter system X_c⁻. This transporter imports cystine into the cell and exports glutamate out. The imported cystine is then used to synthesize glutathione (GSH), a major antioxidant that helps control intracellular ROS levels.

Many cancer cells experience elevated oxidative stress due to increased metabolic activity and stress conditions within the tumor microenvironment. Upregulation of SLC7A11 can provide a survival advantage by boosting GSH synthesis, thereby neutralizing ROS and preventing oxidative damage.

High SLC7A11 activity helps prevent ferroptosis by ensuring continuous glutathione production. Glutathione is a cofactor for glutathione peroxidase 4 (GPX4), a key enzyme that detoxifies lipid peroxides.
Mechanism: When SLC7A11 is inhibited, cystine uptake is reduced. This leads to glutathione depletion, compromised GPX4 activity, and eventually the accumulation of lipid peroxides that trigger ferroptosis.
Inducing ferroptosis has become a promising anticancer strategy. Inhibitors targeting SLC7A11 (or related pathways) can lower glutathione levels, increasing susceptibility to ferroptotic cell death. This is especially attractive in cancers with high SLC7A11 expression, where blocking its function may selectively induce ferroptosis and overcome drug resistance.

Scientific Papers found: Click to Expand⟱

5263-

3BP,

CET,

3-Bromopyruvate overcomes cetuximab resistance in human colorectal cancer cells by inducing autophagy-dependent ferroptosis

in-vitro,

CRC,

DLD1

NA,

HCT116

eff↑, Our results demonstrated that the co-treatment of 3-BP and cetuximab synergistically induced an antiproliferative effect in both CRC cell lines
Ferroptosis↓, co-treatment induced ferroptosis, autophagy, and apoptosis.
TumAuto↑,
Apoptosis↑,
FOXO3↑, co-treatment inhibited FOXO3a phosphorylation and degradation and activated the FOXO3a/AMPKα/pBeclin1 and FOXO3a/PUMA pathways, leading to the promotion of ferroptosis, autophagy, and apoptosis in DLD-1
AMPKα↑,
p‑Beclin-1↑,
HK2↓, 3-Bromopyruvate (3-BP), also known as hexokinase II inhibitor II, has shown promise as an anticancer agent against various types of cancer
ATP↓, 3-BP exerts its anticancer effects by manipulating cell energy metabolism and regulating oxidative stress, as evidenced by the accumulation of reactive oxygen species (ROS) [13,14,15,16].
ROS↑,
Dose↝, Eight days postinoculation, xenografted mice were randomly divided into four groups and intraperitoneally injected with PBS, 3-BP, cetuximab, or a combination of 3-BP and cetuximab every four days for five injections.
TumVol↓, 3-BP alone or co-treatment with 3-BP and cetuximab significantly reduced the tumor volume and tumor weight on Day 28, but co-treatment showed a greater reduction than 3-BP alone
TumW↓,
xCT↑, The protein level of SLC7A11 was significantly upregulated in all three cell lines following co-treatment (Fig. 2B).
GSH↓, co-treatment with 3-BP and cetuximab led to glutathione (GSH) depletion (Fig. 2D), reactive oxygen species (ROS) production
eff↓, Knockdown of either ATG5 or Beclin1 attenuated the cell death and MDA production induced by co-treatment
MDA↑,

5431-

AG,

Advances in research on the anti-tumor mechanism of Astragalus polysaccharides

Review,

Var,

AntiTum↑, APS has been increasingly used in cancer therapy owing to its anti-tumor ability as it prevents the progression of prostate, liver, cervical, ovarian, and non-small-cell lung cancer by suppressing tumor cell growth and invasion and enhancing apoptosi
TumCG↓,
TumCI↓,
Apoptosis↑, after APS treatment, the apoptosis of HepG2 cells is accelerated (57).
Imm↑, APS enhances the sensitivity of tumors to antineoplastic agents and improves the body’s immunity
Bcl-2↓, Huang et al. proposed that APS induces H22 (a hepatocellular cancer [HCC] cell line) apoptosis by downregulating Bcl-2 and upregulating Bax expression (56).
BAX↑,
Wnt↓, downregulating the Wnt/β-catenin signaling pathway.
β-catenin/ZEB1↓,
TumCG↓, APS effectively inhibited the growth of MDA-MB-231 (a human breast cancer [BC] cell line) graft tumor (58)
miR-133a-3p↑, apoptosis rate of human osteosarcoma MG63 cells increased owing to the upregulation of miR-133a and inactivation of the JNK signaling pathways (71).
JNK↓,
Fas↑, Li and Shen found that APS can induce apoptosis by activating the Fas death receptor pathway.
P53↑, Zhang et al. showed that APS could activate p53 and p21 and inhibit the expression of Notch1 and Notch3 in vitro, ultimately inhibiting cell proliferation and promoting their apoptosis
P21↑,
NOTCH1↓,
NOTCH3↓,
TumCP↓,
TumCCA↑, Liu et al. found that APS induced the cell cycle of bladder cancer UM-UC-3 to stop in the G0/G1 phase, thus inhibiting its proliferation
GPx4↓, APS was found to reduce GPX4 expression, inhibit the activity of the light chain subunit SLC7A11 (xCT), and promote the formation of BECN1-xCT complex by activating AMPK/BECN1 signaling.
xCT↓,
AMPK↑,
Beclin-1↑,
NF-kB↓, APS could control the proliferation of lung cancer cells (A549 and NCI-H358 cells) by inhibiting the NF-κB signaling pathway (97)
EMT↓, APS treatment led to reduced EMT markers (vimentin, AXL) and MIF levels in cells.
Vim↓,
TumMeta↓, APS inhibits Lewis lung cancer growth and metastasis in mice by significantly reducing VEGF and EGFR expression in cancerous tissues
VEGF↓,
EGFR↓,
eff↑, Nano-drug delivery systems can increase efficiency and reduce toxicity
eff↑, Jiao et al. developed selenium nanoparticles modified with macromolecular weight APS and observed positive results in hepatoma treatment
MMP↓, Subsequent investigations revealed that APS can decrease the ΔΨm values and Bcl-2, p-PI3K, P-gp, and p-AKT levels while elevating Bax expression.
P-gp↓,
MMP9↓, downregulation of MMP-9 expression,
ChemoSen↑, Li et al. observed that APS could enhance the sensitivity of SKOV3 ovarian cancer cells to CDDP treatment by activating the mitochondrial apoptosis pathway and JNK1/2 signaling pathway
SIRT1↓, APS significantly suppressed SIRT1 and SREBP1 expression, decreased cholesterol and triglyceride levels in PC3 and DU145, and attenuated cell proliferation.
SREBP1↓,
TumAuto↑, APS can induce autophagy in colorectal cancer cells by inhibiting the PI3K/AKT/mTOR axis and the development of cancer cells.
PI3K↓,
mTOR↓,
Casp3↑, Shen found that APS elevated caspase-9, caspase-3, and Bax protein levels, decreased Bcl-2 protein expression, and inhibited CD133 and CD44 co-positive colon cancer stem cell proliferation time
Casp9↑,
CD133↓,
CD44↓,
CSCs↓,
QoL↑, QOL was significantly improved as indicated by the reduction in pain and improvement in appetite

1349-

And,

Andrographolide promoted ferroptosis to repress the development of non-small cell lung cancer through activation of the mitochondrial dysfunction

in-vitro,

Lung,

H460

33.16 μM

in-vitro,

Lung,

H1650

32.45 μM

TumCG↓,
TumMeta↓,
Ferroptosis↑,
ROS↑,
MDA↑,
Iron↑,
GSH↓, lipid ROS reduced glutathione (GSH) accumulation
GPx4↓,
xCT↓, SLC7A11
MMP↓,
ATP↓,

575-

ART/DHA,

Dihydroartemisinin initiates ferroptosis in glioblastoma through GPX4 inhibition

in-vitro,

GBM,

U87MG

GPx4↓,
xCT∅, constant expression of xCT and ACSL4, suggesting GPX4 was a pivotal target for DHA-activated ferroptosis
ROS↑, lipid ROS levels were increased
Ferroptosis↑,
ACSL4∅,

1410-

CUR,

Curcumin induces ferroptosis and apoptosis in osteosarcoma cells by regulating Nrf2/GPX4 signaling pathway

vitro+vivo,

OS,

MG63

tumCV↓,
Apoptosis↑,
TumCG↓,
NRF2↓, after treatment with curcumin, Nrf2 and GPX4 levels were significantly decreased
GPx4↓,
HO-1↓,
xCT↓, SLC7A11
ROS↑, our results revealed that after treatment with curcumin, ROS and MDA levels were significantly increased while GSH levels were decreased
MDA↑,
GSH↓,

2455-

erastin,

Discovery of the Inhibitor Targeting the SLC7A11/xCT Axis through In Silico and In Vitro Experiments

in-vitro,

Cerv,

HeLa

xCT↓, targeted inhibitors have been developed, such as erastin
GSH↓, erastin significantly reduced intracellular GSH levels in HeLa cells
ROS↑, erastin significantly increased intracellular ROS levels in HeLa cells
TumCMig↓, erastin significantly inhibited the migration activity of HeLa cells,

5046-

erastin,

SAS,

The structure of erastin-bound xCT–4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis

Study,

Var,

xCT↓, reduced by the system xc– inhibitors, erastin and sulfasalazine
ROS↑, moreover, inhibiting xCT impairs cystine uptake, causing an accumulation of ROS and suppressing tumor growth.
TumCG↓,
GSH↓, Erastin functions by inhibiting the import of cystine, thereby depleting intracellular glutathione (GSH), which serves as a necessary cofactor for the enzyme glutathione peroxidase 4 (GPX4) in eliminating lipid peroxides
Ferroptosis↑, erastin is commonly used to induce ferroptosis, particularly in cultured cells.

5047-

erastin,

The ferroptosis inducer erastin irreversibly inhibits system xc− and synergizes with cisplatin to increase cisplatin’s cytotoxicity in cancer cells

in-vitro,

Ovarian,

xCT↓, erastin was reported to target and inhibit system xc−, leading to cysteine starvation, glutathione depletion and consequently ferroptotic cell death.
GSH↓,
Ferroptosis↑,
ChemoSen↑, More importantly, short exposure of tumor cells with erastin strongly potentiated the cytotoxic effects of cisplatin to efficiently eradicate tumor cells.
eff↑, only a very short pre-treatment of erastin suffices to synergize with cisplatin to efficiently induce cancer cell death

5048-

erastin,

How erastin assassinates cells by ferroptosis revealed

Review,

Var,

Ferroptosis↑, erastin can induce a form of iron-dependent cell death by inhibiting system Xc−-mediated cystine import; they further coined a term ferroptosis to highlight the iron-dependent nature of this cell death
xCT↓,
lipid-P↑, When erastin blocks the transporter activity of system Xc−, the collapse of ferroptosis defense systems leads to the excessive accumulation of lipid peroxides on cell membranes and subsequent ferroptotic cell death

1204-

MET,

Metformin induces ferroptosis through the Nrf2/HO-1 signaling in lung cancer

in-vitro,

Lung,

A549

in-vitro,

Lung,

H1299

MDA↑,
ROS↑,
Iron↑, iron ions
GSH↓,
T-SOD↓,
Catalase↓,
GPx4↓,
xCT↓,
NRF2↓,
HO-1↓,

2054-

PB,

Sodium butyrate induces ferroptosis in endometrial cancer cells via the RBM3/SLC7A11 axis

in-vitro,

EC,

ISH

in-vitro,

EC,

HEC1B

Ferroptosis↑, Sodium butyrate promotes endometrial cancer cell ferroptosis.
xCT↓, NaBu indirectly downregulates the expression of SLC7A11 by promoting the expression of RBM3, thereby promoting ferroptosis in endometrial cancer cells
RBM3↑,
HDAC↓, Butyric acid is an important histone deacetylase inhibitor
ROS↑, NaBu increased the levels of ROS, lipid ROS and intracellular Fe2 + in Ishikawa and HEC-1B cells

1489-

RES,

Molecular mechanisms of resveratrol as chemo and radiosensitizer in cancer

Review,

Var,

RadioS↑,
ChemoSen↑,
*BioAv↓, However, in vivo experimental models have demonstrated that RSV is rapidly metabolized and eliminated, which leads to low bioavailability of the compound. 75% of RSV has been shown to be absorbed orally, only 1% is detected in the blood plasma
*BioAv↑, nanocarrier of RSV-loaded poly (ε-caprolactone)-poly (ethylene glycol) nanoparticles with an erythrocyte membrane. This system improved RSV’s poor water solubility
Ferroptosis↑, SV could induce ferroptotic cell death in colorectal cancer by initiating lipid peroxidation and suppressing the expression of SLC7A11 and GPX4
lipid-P↑,
xCT↓,
GPx4↓,
*BioAv↑, Bioactive or bioenhancer compounds have also been used (piperine, quercetin, biflavone ginkgetin) that, in combination with RSV, improve bioavailability, solubility, absorption, and cellular permeability
COX2↓, inhibiting Cyclooxygenase-COX
cycD1/CCND1↓,
FasL↓,
FOXP3↓,
HLA↑,
p‑NF-kB↓, decrease NF-ĸB phosphorylation
BAX↑,
Bcl-2↓,
MALAT1↓, decrease the expression of the lncRNA MALAT1 in colorectal and gastric cancer cells through the Wnt/β-catenin signaling pathway

5139-

SAS,

Sulfasalazine induces ferroptosis in osteosarcomas by regulating Nrf2/SLC7A11/GPX4 signaling axis

in-vitro,

OS,

MG63

in-vitro,

OS,

U2OS

*Inflam↓, Sulfasalazine (SAS), a commonly used anti-inflammatory drug prescribed for nonspecific gastrointestinal diseases, autoimmune rheumatic diseases, ankylosing spondylitis, and various skin conditions
TumCP↓, Our results demonstrate that SAS significantly inhibited the proliferation and migration of OS cells, inducing apoptosis and effectively attenuating their malignant progression.
TumCMig↓,
Apoptosis↑,
Ferroptosis↑, Notably, SAS-treated OS cells displayed hallmarks of ferroptosis, including iron accumulation, elevated levels of malondialdehyde and reactive oxygen species, and reduced levels of glutathione and superoxide dismutase
Iron↑,
MDA↑,
ROS↑,
GSH↓,
SOD↓,
MMP↓, SAS decreased mitochondrial membrane potential in OS cells, potentially indicating mitochondrial damage during ferroptosis.
NRF2↓, Mechanistically, we found that SAS induced ferroptosis by downregulating the expression of NRF2,
xCT↓, subsequently decreasing the expression of the light chain subunit of the cysteine/glutamate transporter system Xc- (SLC7A11) and glutathione peroxidase 4.
GPx4↓,
FTH1↓, SAS treatment decreased FTH1 protein expression

5045-

SAS,

Sulfasalazine, a potent cystine-glutamate transporter inhibitor, enhances osteogenic differentiation of canine adipose-derived stem cells

in-vivo,

Var,

50 µM and 100 µM

xCT↓, Sulfasalazine (SSZ), a drug used to treat rheumatoid arthritis, suppresses xCT expression in cancer cells.
GSH↓, this treatment decreased the intracellular glutathione concentration.
BMPs↑, significantly increased alizarin red staining and its quantification, as well as the concentration-dependent osteogenic differentiation markers (BMP1 and SPP) mRNA expression.
Diff↑, SSZ treatment of CADSCs increased the efficiency of osteogenic differentiation induction in vitro.

5044-

SAS,

xCT inhibitor sulfasalazine depletes paclitaxel-resistant tumor cells through ferroptosis in uterine serous carcinoma

in-vitro,

Var,

xCT↓, Thus, the present study investigated the effect of the xCT inhibitor, sulfasalazine (SAS) on cytotoxicity in paclitaxel-sensitive and -resistant USC cell lines.
Ferroptosis↑, SAS-mediated cell death was induced through ferroptosis
ROS↑, ROS production was increased in paclitaxel-resistant but not in -sensitive cells, even at low SAS concentration
IL1↓, inhibit leukocyte motility and interleukin (IL)-1 and IL-2 production (18), and inhibit nuclear factor κ B (NFκB)
IL2↓,
NF-kB↓,
GSH↓, SAS has also been reported to effectively induce GSH depletion (90%) and arrest growth
TumCG↓,
ChemoSen↑, and to enhance sensitivity to chemotherapeutic agents in pancreatic, prostate and mammary cancer

5043-

SAS,

Chronic Sulfasalazine Treatment in Mice Induces System xc− - Independent Adverse Effects

in-vivo,

Nor,

160 mg/kg twice daily or 320 mg/kg once daily, i.p.)

*toxicity↝, on the market for decades as an anti-inflammatory drug, serious side effects due to its use have been reported.
*xCT↓, it needs to reach the systemic circulation in its intact form to allow inhibition of system xc−.
toxicity↓, we were unable to identify any undesirable system xc−-dependent effect of chronic administration of SAS.

5042-

SAS,

xCT: A Critical Molecule That Links Cancer Metabolism to Redox Signaling

Review,

Var,

xCT↓, It is also unclear why solid tumors are more sensitive to xCT inhibitors such as sulfasalazine, as compared to hematological malignancies.
GSH↓, xCT inhibition by sulfasalazine was shown to decrease tumor growth through GSH depletion.
TumCG↓, Similarly, inhibition of xCT also disrupted glioma, melanoma, and prostate cancer cell growth, and it decreased cell proliferation and tumor progression in non-small-cell lung cancer, suggesting a critical role of xCT in solid tumor growth as well
TumCI↓, The xCT inhibitor sulfasalazine suppressed cell invasion of KYSE150, a cell line of esophageal squamous cell carcinoma (ESCC), likely through ROS-induced p38 mitogen-activated protein kinase (MAPK) activation.
ROS↑,
RadioS↑, However, the xCT inhibitor sulfasalazine and radiation synergistically increased glioma cell death,
eff↓, which could be reversed by the antioxidant N-acetyl-l-cysteine (NAC).7

5041-

SAS,

Cisplatin,

Xc− inhibitor sulfasalazine sensitizes colorectal cancer to cisplatin by a GSH-dependent mechanism

in-vitro,

CRC,

xCT↓, Sulfasalazine (SSZ) is an anti-inflammatory drug that has been demonstrated to induce apoptosis and tumor regression through inhibition of plasma membrane cystine transporter xc−
Inflam↓,
Apoptosis↓,
GSH↓, Cysteine is a rate-limiting precursor for intracellular glutathione (GSH) synthesis
ROS↑, SSZ effectively depleted cellular GSH, leading to significant accumulation of reactive oxygen species and growth inhibition in CRC cells.
TumCG↓,
selectivity↑, In contrast, the normal epithelial cells of colon origin were less sensitive to SSZ, showing a moderate ROS elevation.
eff↑, Importantly, SSZ effectively enhanced the intracellular platinum level and cytotoxicity of CDDP in CRC cells.
eff↓, synergistic effect of SSZ and CDDP was reversed by antioxidant N-acetyl-L-cysteine (NAC).

5040-

SAS,

Structure-Activity-Relationship-Aided Design and Synthesis of xCT Antiporter Inhibitors

in-vitro,

GBM,

A172

in-vitro,

Melanoma,

A375

in-vitro,

GBM,

U87MG

in-vitro,

BC,

MCF-7

GSH↓, Depletion of glutathione levels varied among the compounds as well as among the cell lines.
toxicity↓, demonstrated minimal toxicity in normal human astrocytes
xCT↓, Sulfasalazine was previously reported to be an efficient inhibitor of the xCT antiporte

5039-

SAS,

Regulatory network of ferroptosis and autophagy by targeting oxidative stress defense using sulfasalazine in triple-negative breast cancer

vitro+vivo,

BC,

xCT↓, using sulfasalazine (SASP), which is a widely employed xCT inhibitor.
ROS↑, SASP significantly attenuated oxidative stress resistance in MDA-MB-231
GSH↓, through decreased glutathione levels, causing a marked iron-dependent ferroptotic cell death induction.
Ferroptosis↑,
TumCG↓, SASP suppressed tumor growth and metastasis progression through total glutathione reduction in the primary tumor, indicating high anticancer activity against TNBC without liver injury in vivo.
toxicity↓,
lipid-P↑, graphical abstract

5038-

SAS,

Rad,

Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma

in-vivo,

Melanoma,

B16-F10

xCT↓, Sulfasalazine is an inhibitor of xCT that is known to increase cellular oxidative stress, giving it anti-tumor potential.
ROS↑,
RadioS↓, radio-sensitizing effect of sulfasalazine using a B16F10 melanoma model.
GSH↓, Sulfasalazine decreased glutathione concentrations and resistance to H2O2 in B16F10 melanoma cells, but not in mouse embryonic fibroblasts.
selectivity↑,
DNArepair↓, It inhibited cellular DNA damage repair and prolonged cell cycle arrest after X-irradiation.
TumCCA↑,
H2O2↑, SAS decreases cellular GSH and increases H2O2 cytotoxicity in B16F10 cells
Dose↝, At lower SAS concentrations (10–100 μM), we did not observe any increase in intracellular ROS. At higher concentrations of SAS (800–1,000 μM), intracellular ROS increased approximately 2.3-fold in B16F10 cells

5037-

SAS,

Inhibition of xCT by sulfasalazine alleviates the depression-like behavior of adult male mice subjected to maternal separation stress

in-vivo,

Nor,

mice

xCT↓, the inhibition of xCT by SSZ could alleviate depression-like behavior partly via modulating the homeostasis of the glutamate system and dampening neuroinflammation.
Mood↑,
Inflam↓,
glut↓, and the levels of glutamate and pro-inflammatory factors were decreased.

5036-

SAS,

Targeting xCT with sulfasalazine suppresses triple-negative breast cancer growth via inducing autophagy and coordinating cell cycle and proliferation

vitro+vivo,

BC,

MDA-MB-231

in-vitro,

BC,

MDA-MB-468

xCT↓, we demonstrated that sulfasalazine (SAS), like erastin (a known xCT inhibitor), effectively suppressed the expression and transport function of xCT, resulting in a depletion of glutathione levels in MDA-MB-231 and MDA-MB-468 cells.
GSH↓,
OS↑, We unveiled a positive correlation between xCT and the autophagy-related molecule p62, their co-expression indicating poor survival outcomes in breast cancer patients.
Myc↓, Treatment with SAS or xCT knockdown led to the inhibition of MYC, CDK1, and CD44 expression.
CDK1↓,
CD44↓,
eff↑, Significantly, the combined administration of SAS and rapamycin exhibited a synergistic inhibitory effect on the growth of transplanted breast tumor in mouse models constructed from murine-derived 4T1 cells.
TumCG↓,

5035-

SAS,

Sulfasalazine, a potent suppressor of gastric cancer proliferation and metastasis by inhibition of xCT: Conventional drug in new use

Human,

GC,

in-vitro,

GC,

NCI-N87

in-vitro,

GC,

SGC-7901

other?, higher expression of xCT is associated with advanced tumour stage and poor overall survival of gastric cancer.
TumCP↓, Sulfasalazine can attenuate the proliferation, colony formation, metastasis and invasion of gastric cancer in vitro
TumMeta↓,
TumCI↓,
xCT↓, Sulfasalazine, a conventional drug, which is widely utilized in treating inflammatory diseases and rheumatoid arthritis, can also inhibit the expression and function of xCT
OS↑, higher xCT expression in gastric cancer under adjuvant chemotherapy possessed lower progression‐free survival and overall survival than patients with lower xCT expression,

2410-

SIL,

Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF

in-vitro,

GBM,

U87MG

in-vitro,

GBM,

U251

in-vivo,

NA,

nude mice

TumAuto↑, Mechanistically, silibinin activates autophagy through depleting ATP by suppressing glycolysis.
ATP↓,
Glycolysis↓, Silibinin suppressed glycolysis in glioma cells
H2O2↑, Then, autophagy improves intracellular H2O2 via promoting p53-mediated depletion of GSH and cysteine and downregulation of xCT
P53↑,
GSH↓,
xCT↓,
BNIP3↝, The increased H2O2 promotes silibinin-induced BNIP3 upregulation and translocation to mitochondria
MMP↑, silibinin-induced mitochondrial depolarization, accumulation of mitochondrial superoxide
mt-ROS↑,
mtDam↑, Autophagy contributed to silibinin-induced mitochondria damage
HK2↓, protein levels of HK II, PFKP, and PKM2 were all downregulated time-dependently by silibinin in U87, U251, SHG-44, and C6 glioma cells
PFKP↓,
PKM2↓, silibinin suppressed glycolysis via downregulation of HK II, PFKP, and PKM2.
TumCG↓, Silibinin inhibited glioma cell growth in vivo

2198-

SK,

Shikonin suppresses proliferation of osteosarcoma cells by inducing ferroptosis through promoting Nrf2 ubiquitination and inhibiting the xCT/GPX4 regulatory axis

in-vitro,

OS,

MG63

 0.75 uM, 1.5 uM and 3 uM

1.432 uM

in-vitro,

OS,

143B

1.638 uM

TumCP↓, shikonin significantly suppressed OS cells proliferation and blocked the cell cycle progression in vitro.
TumCCA↑,
Ferroptosis↑, ferroptosis in OS cells by promoting the Fe2+ accumulation, reactive oxygen species and lipid peroxidation formation, malondialdehyde production and mitochondrial damage
Iron↑,
ROS↑,
lipid-P↑,
MDA↑,
mtDam↑,
NRF2↓, influenced Nrf2 stability via inducing ubiquitin degradation, which suppressed the expression of Nrf2 downstream targets xCT and GPX4, and led to stimulating ferroptosis. Promoted Nrf2 degradation
xCT↓,
GPx4↓,
GSH/GSSG↓, GSH/GSSG ratio declined after shikonin (1.5 uM) treatment
Keap1↑, shikonin (1.5 uM) significantly downregulated the expression of Nrf2 and upregulated the expression of Keap1

5091-

SSE,

Superoxide-mediated ferroptosis in human cancer cells induced by sodium selenite

in-vitro,

GBM,

U87MG

in-vitro,

Cerv,

HeLa

in-vitro,

BC,

MCF-7

in-vitro,

Pca,

PC3

in-vitro,

CRC,

HT-29

in-vitro,

Nor,

SVGp12

Ferroptosis↑, In this study, for the first time, we demonstrate that sodium selenite (SS), a well-established redox-active selenium compound, is a novel inducer of ferroptosis in a variety of human cancer cells.
xCT↓, SS down-regulates ferroptosis regulators; solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), and glutathione peroxidase 4 (GPx4), while it up-regulates iron accumulation and lipid peroxidation (LPO).
GSH↓,
GPx4↓,
Iron↑, SS induces iron accumulation via O2•−-dependent process
lipid-P↑,
ROS↑, SS-induced ferroptotic responses are achieved via ROS, in particular superoxide (O2•−) generation.
eff↓, Antioxidants such as superoxide dismutase (SOD) and Tiron not only scavenged O2•− production, but also markedly rescued SLC7A11 down-regulation, GSH depletion, GPx4 inactivation, iron accumulation, LPO, and ferroptosis.
TumCP↓, SS inhibits the proliferation of human cancer cells
TumCD↑, SS induces non-apoptotic, non-autophagic and non-necroptotic cell death in human cancer cells

5096-

SSE,

xCT_Pathway">Selenium Toxicity Accelerated by Out-of-Control Response of Nrf2-xCT Pathway

in-vitro,

BC,

MCF-7

xCT↑, Expression of xCT mRNA was remarkably increased in MCF-7 cells after Se treatment, which may further increase Se uptake and oxidative stress.
ROS↑,
NRF2↑, Oxidative stress activates Nrf2 regulon containing GSH biosynthesis enzymes and xCT. Therefore, further Se is taken into the cell, more ROS is generated, and xCT is induced again.

5094-

SSE,

Sodium Selenite Prevents Matrine-Induced Nephrotoxicity by Suppressing Ferroptosis via the GSH-GPX4 Antioxidant System

vitro+vivo,

Nor,

NRK52E

explored the involvement of ferroptosis in MT-induced kidney injury and evaluated the potential efficacy and underlying mechanism of sodium selenite (SS) in attenuating MT-induced nephrotoxicity.

*GPx4↑, SS also reversed the MT-induced reduction in GPX4, CTH and xCT protein levels.
*xCT↑,
*GSH↑, SS is a promising therapeutic drug for alleviating MT-induced renal injury by activating the GSH-GPX4 axis.
*RenoP↑,

5088-

SSE,

Superoxide-mediated ferroptosis in human cancer cells induced by sodium selenite

in-vitro,

BC,

MCF-7

in-vitro,

GBM,

U87MG

in-vitro,

Pca,

PC3

in-vitro,

Cerv,

HeLa

in-vitro,

GBM,

A172

Ferroptosis↑, Sodium selenite selectively induces ferroptosis in multiple human cancer cells.
ROS↑, Superoxide is the ROS molecule responsible for the sodium selenite-induced ferroptosis.
Iron↑, Sodium selenite induces iron accumulation via superoxide dependent mechanism
xCT↓, SS down-regulates ferroptosis regulators; solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), and glutathione peroxidase 4 (GPx4), while it up-regulates iron accumulation and lipid peroxidation (LPO)
GSH↓,
GPx4↓,
lipid-P↑,
TumCP↓, SS inhibits the proliferation of human cancer cells
selectivity↑, Surprisingly, SS had minimal toxicity on SVG P12 cells compared to U87MG human malignant glioma cells

2454-

Trip,

Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ

in-vitro,

HNSCC,

HaCaT

in-vivo,

NA,

 xenograft tumors in nude mice

GSDME-N↑, Triptolide eliminates head and neck cancer cells through inducing gasdermin E (GSDME) mediated pyroptosis.
Pyro↑,
cMyc↓, TPL treatment suppresses expression of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells
HK2↓,
BAD↑, leading to activation of the BAD/BAX-caspase 3 cascade and cleavage of GSDME by active caspase 3.
BAX↑,
Casp3↑,
NRF2↓, TPL treatment suppresses NRF2/SLC7A11 (also known as xCT) axis
xCT↓,
ROS↑, and induces reactive oxygen species (ROS) accumulation, regardless of the status of GSDME.
eff↑, Combination of TPL with erastin, an inhibitor of SLC7A11, exerts robust synergistic effect in suppression of tumor survival in vitro and in a nude mice model.
Glycolysis↓, TPL treatment repressed c-Myc/HK-II axis and aerobic glycolysis in head and neck cancer cells
GlucoseCon↓, as evidenced by reduced glucose consumption, lactate production and cellular ATP content following TPL treatment
lactateProd↓,
ATP↓,
xCT↓, TPL (50 nM) treatment decreased the protein levels of NRF2 and SLC7A11 (
eff↑, combination of TPL with erastin is a promising strategy for head and neck cancer therapy.

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 31

Pathway results for Effect on Cancer / Diseased Cells:

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

GPx4↑, 1, GSH↑, 1, xCT↓, 1, xCT↑, 1,

Immune & Inflammatory Signaling ⓘ

Inflam↓, 1,

Drug Metabolism & Resistance ⓘ

BioAv↓, 1, BioAv↑, 2,

Functional Outcomes ⓘ

RenoP↑, 1, toxicity↝, 1,
Total Targets: 9

Scientific Paper Hit Count for: xCT, SLC7A11

13 Sulfasalazine
4 erastin
4 Selenite (Sodium)
1 3-bromopyruvate
1 cetuximab
1 Astragalus
1 Andrographis
1 Artemisinin
1 Curcumin
1 Metformin
1 Phenylbutyrate
1 Resveratrol
1 Cisplatin
1 Radiotherapy/Radiation
1 Silymarin (Milk Thistle) silibinin
1 Shikonin
1 triptolide

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

Database Query Results : , , xCT

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 ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Functional Outcomes ⓘ

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