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Leukemia Jun 2022By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a...
By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.
Topics: Cell Line, Tumor; Cysteine; Cystine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Nuclear Proteins; Sulfasalazine
PubMed: 35474100
DOI: 10.1038/s41375-022-01573-6 -
Journal of Medicine and Life Aug 2023Ulcerative colitis is a chronic inflammatory disease with high mortality and morbidity worldwide. It causes inflammation in the lining of the colon, resulting in several...
Ulcerative colitis is a chronic inflammatory disease with high mortality and morbidity worldwide. It causes inflammation in the lining of the colon, resulting in several symptoms that negatively impact the quality of life. Unfortunately, there is currently no known cure for this condition. Therefore, it is crucial to explore alternative treatment approaches. This research aimed to investigate the anti-inflammatory and antioxidative effects of a combination therapy involving Sulfasalazine+Ezetimibe compared to Sulfasalazine alone in a rat model of ulcerative colitis. Forty adult rats were divided into four groups for this study. The groups consisted of a control group (negative control), an acetic acid group (positive control), an acetic acid+Sulfasalazine (100 mg/kg per day) group, and an acetic acid+Sulfasalazine (50 mg/kg)+Ezetimibe (5 mg/kg) group. Rats were treated for one week, and colitis was induced by administering 2 ml of 4% (v/v) acetic acid inter-rectally. After sacrifice, the colonic tissue homogenate was analyzed for several markers, including proinflammatory cytokines (TNF-α, IL-1β, NF-κB), oxidative stress markers (malondialdehyde, myeloperoxidase), and adhesive molecule markers (E-selectin, ICAM-1). Sulfasalazine and the combination of Sulfasalazine+Ezetimibe significantly reduced the colonic levels of TNF-α, IL-1β, NF-κB, MDA, and E-selectin in the homogenate. However, the combination therapy of Sulfasalazine and Ezetimibe demonstrated a superior effect.
Topics: Rats; Animals; Sulfasalazine; Colitis, Ulcerative; E-Selectin; NF-kappa B; Tumor Necrosis Factor-alpha; Quality of Life; Colitis; Colon; Biomarkers; Acetates
PubMed: 38024826
DOI: 10.25122/jml-2023-0194 -
Brazilian Journal of Medical and... 2021We aimed to reveal the anti-convulsant effects sulfasalazine and its mechanism in pentylenetetrazole (PTZ)-induced seizures in rats. Forty-eight male Wistar albino rats...
We aimed to reveal the anti-convulsant effects sulfasalazine and its mechanism in pentylenetetrazole (PTZ)-induced seizures in rats. Forty-eight male Wistar albino rats (200-250 g) were randomly divided into two groups: 24 for electroencephalography (EEG) recording (group A) and 24 for behavioral studies (group B). About 70 mg/kg PTZ was used for behavioral studies after sulfasalazine administration and 35 mg/kg PTZ was used for EEG recording after sulfasalazine administration. Electrodes were implanted on the dura mater over the left frontal cortex and the reference electrode was implanted over the cerebellum for EEG recording. Racine's convulsion scale, first myoclonic jerk onset time, spike percentages, brain malondialdehyde (MDA), superoxide dismutase (SOD), and prostaglandin F2α (PGF2α) levels were evaluated between the groups. First myoclonic jerk onset time was significantly shorter in the saline group than both 250 and 500 mg/kg sulfasalazine groups (P<0.05). Racine's convulsion scores were significantly lower in the 250 and 500 mg/kg sulfasalazine groups than the saline group (P<0.05, P<0.001). The two sulfasalazine groups had lower spike percentages than the saline group (P<0.05). Significantly lower MDA and PGF2α levels were observed in the 250 and 500 mg/kg sulfasalazine groups compared with the saline group (P<0.05, P<0.001, respectively). SOD increased significantly in both sulfasalazine groups compared with the PTZ+saline group (P<0.05). Our study demonstrated that sulfasalazine had protective effects on PTZ-induced convulsions by protecting against oxidative and inflammatory damage associated with PTZ.
Topics: Animals; Male; Rats; Pentylenetetrazole; Rats, Sprague-Dawley; Rats, Wistar; Seizures; Sulfasalazine
PubMed: 34878064
DOI: 10.1590/1414-431X2021e11541 -
Epilepsia Apr 2022Previously, we reported that inhibition of the astrocytic cystine/glutamate antiporter system xc- (SXC), using sulfasalazine (SAS), decreased evoked excitatory signaling...
OBJECTIVE
Previously, we reported that inhibition of the astrocytic cystine/glutamate antiporter system xc- (SXC), using sulfasalazine (SAS), decreased evoked excitatory signaling in three distinct hyperexcitability models ex vivo. The current study expands on this work by evaluating the in vivo efficacy of SAS in decreasing astrogliosis-mediated seizure burden seen in the beta-1 integrin knockout (B1KO) model.
METHODS
Video-EEG (electroencephalography) monitoring (24/7) was obtained using Biopac EEG acquisition hardware and software. EEG spectral analysis was performed using MATLAB. SAS was used at an equivalence of doses taken by Crohn's disease patients. Whole-cell patch-clamp recordings were made from cortical layer 2/3 pyramidal neurons.
RESULTS
We report that 100% of B1KO mice that underwent 24/7 video-EEG monitoring developed spontaneous recurrent seizures and that intraperitoneal administration of SAS significantly reduced seizure frequency in B1KOs compared to B1KOs receiving sham saline. Spectral analysis found an acute reduction in EEG power following SAS treatment in B1KOs; however, this effect was not observed in nonepileptic control mice receiving SAS. Finally, whole-cell recordings from SXC knockout mice had hyperpolarized neurons and SXC-B1 double knockouts fired significantly less action potentials in response to current injection compared to B1KOs with SXC.
SIGNIFICANCE
To devise effective strategies in finding relief for one-in-three patients with epilepsy who experience drug-resistant epilepsy we must continue to explore the mechanisms regulating glutamate homeostasis. This study explored the efficacy of targeting an astrocytic glutamate antiporter, SXC, as a novel antiepileptic drug (AED) target and further characterized a unique mouse model in which chronic astrogliosis is sufficient to induce spontaneous seizures and epilepsy. These findings may serve as a foundation to further assess the potential for SAS or inform the development of more potent and specific compounds that target SXC as a novel treatment for epilepsy.
Topics: Animals; Antiporters; Electroencephalography; Epilepsy; Gliosis; Glutamic Acid; Humans; Mice; Seizures; Sulfasalazine
PubMed: 35132640
DOI: 10.1111/epi.17178 -
Hypertension in Pregnancy Feb 2022
Letter by Lu et al. regarding article, "Esomeprazole and sulfasalazine in combination additively reduce sFlt-1 secretion and diminish endothelial dysfunction: potential for a combination treatment for preeclampsia".
Topics: Esomeprazole; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Sulfasalazine; Vascular Endothelial Growth Factor Receptor-1
PubMed: 34978249
DOI: 10.1080/10641955.2021.2024224 -
Advanced Science (Weinheim,... Jul 2023Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. Due to the insensitivity of advanced HCC...
Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. Due to the insensitivity of advanced HCC cells to traditional chemotherapies, low drug accumulation, and limited drug residence time in the peritoneal cavity, the therapeutic effects of malignant ascites in HCC are not satisfactory. In this study, an injectable hydrogel drug delivery system based on chitosan hydrochloride and oxidized dextran (CH-OD) is designed to load sulfasalazine (SSZ), an FDA-approved drug with ferroptosis-inducing ability, for effective tumor-killing and activation of anti-tumor immunity. Compared to free SSZ, SSZ-loaded CH-OD (CH-OD-SSZ) hydrogel exhibits greater cytotoxicity and induces higher levels of immunogenic ferroptosis. In the preclinical model of hepatoma ascites, intraperitoneal administration of CH-OD-SSZ hydrogel can significantly suppress tumor progression and improve the immune landscape. Both in vitro and in vivo, CH-OD-SSZ hydrogel induces the repolarization of macrophages to an M1-like phenotype and promotes the maturation and activation of dendritic cells. Combination treatment with CH-OD-SSZ hydrogel and anti-programmed cell death protein 1 (PD-1) immunotherapy achieves more than 50% ascites regression and generates long-term immune memory. Collectively, CH-OD-SSZ hydrogel exhibits promising therapeutic potential in the treatment of peritoneal dissemination and malignant ascites in advanced HCC, especially when combined with anti-PD-1 immunotherapy.
Topics: Humans; Carcinoma, Hepatocellular; Hydrogels; Chitosan; Dextrans; Ascites; Ferroptosis; Liver Neoplasms; Sulfasalazine; Immunotherapy
PubMed: 37132587
DOI: 10.1002/advs.202300517 -
Renal Failure Nov 2017Sulfasalazine is a commonly used drug for the treatment of rheumatoid arthritis and inflammatory bowel disease. There are several cases of renal injury encompass...
Sulfasalazine is a commonly used drug for the treatment of rheumatoid arthritis and inflammatory bowel disease. There are several cases of renal injury encompass sulfasalazine administration in humans. The mechanism of sulfasalazine adverse effects toward kidneys is obscure. Oxidative stress and its consequences seem to play a role in the sulfasalazine-induced renal injury. The current investigation was designed to investigate the effect of sulfasalazine on kidney mitochondria. Rats received sulfasalazine (400 and 600 mg/kg/day, oral) for 14 consecutive days. Afterward, kidney mitochondria were isolated and assessed. Sulfasalazine-induced renal injury was biochemically evident by the increase in serum blood urea nitrogen (BUN), gamma-glutamyl transferase (γ-GT), and creatinine (Cr). Histopathological presentations of the kidney in sulfasalazine-treated animals revealed by interstitial inflammation, tubular atrophy, and tissue necrosis. Markers of oxidative stress including an increase in reactive oxygen species (ROS) and lipid peroxidation (LPO), a defect in tissue antioxidant capacity, and glutathione (GSH) depletion were also detected in the kidney of sulfasalazine-treated groups. Decreased mitochondrial succinate dehydrogenase activity (SDA), mitochondrial depolarization, mitochondrial GSH depletion, increase in mitochondrial ROS, LPO, and mitochondrial swelling were also evident in sulfasalazine-treated groups. Current data suggested that oxidative stress and mitochondrial injury might be involved in the mechanism of sulfasalazine-induced renal injury.
Topics: Acute Kidney Injury; Administration, Oral; Animals; Antioxidants; Arthritis, Rheumatoid; Biomarkers; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Glutathione; Humans; Inflammatory Bowel Diseases; Kidney; Lipid Peroxidation; Male; Mitochondria; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Sulfasalazine; gamma-Glutamyltransferase
PubMed: 29214868
DOI: 10.1080/0886022X.2017.1399908 -
Expert Opinion on Pharmacotherapy Aug 2016Rheumatoid arthritis (RA) can spontaneously improve during pregnancy. However, a considerable proportion of patients can experience a flare and high disease activity has... (Review)
Review
INTRODUCTION
Rheumatoid arthritis (RA) can spontaneously improve during pregnancy. However, a considerable proportion of patients can experience a flare and high disease activity has been associated with an increased risk of adverse pregnancy outcome. Thus, the treatment of RA in pregnant women should be selected taking into account both the potential harmful effects of the treatment and the risk associated with discontinuation.
AREAS COVERED
Recent publications regarding safety of the most important disease modifying anti-rheumatic drugs (DMARDs) during pregnancy has been reviewed. A systematic literature search of MEDLINE was conducted using pregnancy, teratogenicity, adverse effects, embryo/foetal-toxicity as key search terms for each DMARD.
EXPERT OPINION
A great body of evidence suggest that hydroxychloroquine, sulfasalazine, and non-fluorinated steroids can be continued throughout pregnancy, while methotrexate and leflunomide should be discontinued 3 months before pregnancy. Continuation of TNFi during the first part of pregnancy should be considered when benefits outweigh the potential risk of teratogenicity. Data regarding other biologics are scant and, at present, they should be stopped before pregnancy.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Female; Humans; Hydroxychloroquine; Isoxazoles; Leflunomide; Methotrexate; Pregnancy; Pregnancy Complications; Sulfasalazine; Treatment Outcome
PubMed: 27283340
DOI: 10.1080/14656566.2016.1197204 -
Oxidative Medicine and Cellular... 2022Glioma is the most common primary brain tumor, with a high rate of recurrence and treatment resistance. Glioblastoma is highly invasive, infiltrating surrounding brain...
Glioma is the most common primary brain tumor, with a high rate of recurrence and treatment resistance. Glioblastoma is highly invasive, infiltrating surrounding brain parenchyma, and is known to cause intracranial metastasis resulting in a dismal prognosis. Hypoxia contributes significantly to chemo- and radiotherapy resistance in cancer. Ferroptosis is a nonapoptotic oxidative cell death that has been identified as a potential anticancer mechanism. Sulfasalazine (SAS) activates ferroptosis and plays a potential role in tumor treatment. However, the relationship between hypoxia and SAS resistance has not been elucidated. This study is aimed at investigating the role of hypoxia in SAS-induced ferroptosis and the underlying mechanisms. Here, we found that hypoxia significantly suppressed SAS-induced ferroptosis by upregulating SLC7A11 expression in the U87 and U251 glioma cell lines. Hypoxia promotes SLC7A11 expression by enhancing the PI3K/AKT/HIF-1 pathway. The AKT inhibitor MK-2206 and HIF-1 inhibitor PX-478 significantly reversed this effect. In addition, under normoxia, PX-478 induced a higher lipid peroxidation level by decreasing SLC7A11 expression in the U87 and U251 cells but could not induce cell death directly; it could significantly enhance the tumor cell killing effect of SAS. In vivo, the combination of PX-478 and SAS had a coordinated synergistic effect on anticancer activity, as revealed by subcutaneous and orthotopic xenograft mouse models. In conclusion, hypoxia enhanced glioma resistance to SAS-induced ferroptosis by upregulating SLC7A11 via activating the PI3K/AKT/HIF-1 axis. Combination therapy with PX-478 and SAS may be a potential strategy against glioma.
Topics: Humans; Animals; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sulfasalazine; Ferroptosis; Signal Transduction; Glioma; Hypoxia; Amino Acid Transport System y+
PubMed: 36439690
DOI: 10.1155/2022/7862430 -
Neuroreport May 2021Sulfasalazine is a recognized therapy for inflammatory bowel disease and is of paramount importance for maintaining intestinal barrier homeostasis. However, its effects...
Sulfasalazine is a recognized therapy for inflammatory bowel disease and is of paramount importance for maintaining intestinal barrier homeostasis. However, its effects on blood-brain barrier (BBB) function and inflammation have not yet been explored. We sought to examine whether sulfasalazine has anti-inflammatory and antiapoptotic effects on the BBB. hCMEC/D3 cells are a well-established BBB in vitro model, were treated with 1 μg/mL Escherichia coli O111:B4 lipopolysaccharide for 12 h. The cell counting kit-8 assay was used to assess cell viability. The cells were also treated with gradient concentrations of sulfasalazine for 12 h. The levels of apoptosis-related proteins and inflammatory factors (IL-1χ and TNF-α IL-6) were measured by western blotting. ZO-1 and F-actin expression was measured by immunofluorescence staining. This study confirmed that 5 mM sulfasalazine improved the maintenance of BBB integrity and relieved lipopolysaccharide-induced inflammatory apoptosis and showed that sulfasalazine might be an effective treatment for BBB disruption.
Topics: Anti-Inflammatory Agents; Blood-Brain Barrier; Cell Line; Cell Survival; Endothelial Cells; Humans; Inflammation; Lipopolysaccharides; Sulfasalazine
PubMed: 33913929
DOI: 10.1097/WNR.0000000000001632