Database Query Results : Sulfasalazine, , xCT

SAS, Sulfasalazine: Click to Expand ⟱

Features:

Sulfasalazine is primarily known as an anti-inflammatory and disease‐modifying antirheumatic drug (DMARD), used for conditions such as rheumatoid arthritis and inflammatory bowel diseases (e.g., ulcerative colitis).

-Inhibit the nuclear factor kappa B (NF-κB) pathway.
-Sulfasalazine has been noted to interfere with the cystine/glutamate antiporter (system x_c⁻), which can reduce glutathione levels in cancer cells, potentially making them more susceptible to oxidative stress.

-Ability to inhibit anti-oxidant production (for ProOxidant effect).

Rank	Pathway / Target Axis	Direction	Primary Effect	Notes / Cancer Relevance	Ref
1	System xC− (xCT/SLC7A11 cystine–glutamate antiporter)	↓ cystine uptake	Limits cystine supply	Sulfasalazine is used as an xCT inhibitor; blocking cystine uptake is the core upstream action in cancer models	(ref)
2	Glutathione biosynthesis / GSH pool	↓ GSH	Loss of redox buffering	In glioma cells, cystine uptake blockade by sulfasalazine leads to glutathione depletion	(ref)
3	ROS accumulation	↑ ROS	Oxidative stress amplification	Glioma study: sulfasalazine increases ROS after GSH depletion (mechanistic sequence shown)	(ref)
4	DNA damage (oxidative/genotoxic stress)	↑ DNA damage	Checkpoint/death signaling	Glioma study: sulfasalazine causes DNA damage as part of the ROS-driven cytotoxic cascade	(ref)
5	Radiosensitization (oxidative vulnerability)	↑ radiation sensitivity	Enhances radiotherapy effect	Melanoma model: sulfasalazine decreases glutathione and synergistically enhances X-irradiation cytotoxicity	(ref)
6	Ferroptosis (system xC− → GSH/GPX4 vulnerability)	↑ ferroptotic death	Iron-dependent oxidative death	Paclitaxel-resistant uterine serous carcinoma model: sulfasalazine (xCT inhibitor) induces ferroptotic cell death signatures	(ref)
7	Mitochondrial apoptosis (caspase pathway)	↑ apoptosis	Programmed cell death	Osteosarcoma work: sulfasalazine blocks system xC− and induces cell death consistent with ferroptosis/apoptosis programs (apoptosis markers reported in the paper’s mechanism set)	(ref)
8	NF-κB activation (IκBα degradation / IKK activity)	↓ NF-κB activation	Reduced pro-survival/inflammatory transcription	Mechanistic paper shows sulfasalazine blocks NF-κB activation by inhibiting IκBα degradation via IKK inhibition	(ref)
9	NF-κB nuclear translocation	↓ nuclear NF-κB	Transcriptional shutdown	Colon cancer cells: sulfasalazine prevents TNFα-induced NF-κB nuclear translocation and NF-κB–dependent transcription	(ref)
10	Chemo-sensitization via xCT inhibition	↑ chemo sensitivity (context-dependent)	Combination benefit	Mechanistic rationale: xCT inhibition lowers GSH and oxidative defense, increasing sensitivity to cytotoxic stress (glioma + radiation shown explicitly)	(ref)
11	Tumor growth suppression in vivo (xCT-targeted stress)	↓ tumor growth	Anti-tumor efficacy	Glioma xenograft model: sulfasalazine plus radiosurgery improves survival compared to control/monotherapy	(ref)
12	Resistance axis: xCT-high / antioxidant-high tumors	↑ vulnerability when xCT-high	Targeted susceptibility	Endometrial/USC model: sulfasalazine shows stronger cytotoxicity in resistant (stress-adapted) cells consistent with xCT dependence	(ref)

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⟱

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.

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

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.

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,

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 13

Pathway results for Effect on Cancer / Diseased Cells:

Functional Outcomes ⓘ

Mood↑, 1, OS↑, 2, toxicity↓, 3,
Total Targets: 45

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

xCT↓, 1,

Immune & Inflammatory Signaling ⓘ

Inflam↓, 1,

Functional Outcomes ⓘ

toxicity↝, 1,
Total Targets: 3

Scientific Paper Hit Count for: xCT, SLC7A11

13 Sulfasalazine
1 erastin
1 Cisplatin
1 Radiotherapy/Radiation

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

Database Query Results : Sulfasalazine, , xCT

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Metal & Cofactor Biology ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Transcription & Epigenetics ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Immune & Inflammatory Signaling ⓘ

Functional Outcomes ⓘ

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