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Protein & Cell Aug 2021The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is... (Review)
Review
The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucose- and glutamine-dependency in SLC7A11 cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11 cancer. In this review, we summarize diverse regulatory mechanisms of SLC7A11 in cancer, discuss ferroptosis-dependent and -independent functions of SLC7A11 in promoting tumor development, explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells, and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment. This review will provide the foundation for further understanding SLC7A11 in ferroptosis, nutrient dependency, and tumor biology and for developing novel effective cancer therapies.
Topics: Amino Acid Transport System y+; Antineoplastic Agents; Cystine; DNA Methylation; Ferroptosis; Gene Expression Regulation, Neoplastic; Glucose; Glutamine; Glutathione; Histones; Humans; Molecular Targeted Therapy; Neoplasms; Piperazines; Signal Transduction; Sorafenib; Sulfasalazine
PubMed: 33000412
DOI: 10.1007/s13238-020-00789-5 -
SAPHO syndrome: pathogenesis, clinical presentation, imaging, comorbidities and treatment: a review.Postepy Dermatologii I Alergologii Dec 2021Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome is a constellation of dermatological and osteoarticular symptoms. The pathogenesis of SAPHO is... (Review)
Review
Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome is a constellation of dermatological and osteoarticular symptoms. The pathogenesis of SAPHO is unknown, but infectious, genetic, immunological and environmental factors may play a role. SAPHO is classified along two different spectrums: pustulo-psoriatic hyperostotic spondyloarthritis and chronic recurrent multifocal osteomyelitis. The typical skin lesions are palmoplantar pustulosis and acne. The sign of arthritis is involvement of the anterior chest wall, most often the sternoclavicular joints. There are no standard treatment recommendations, but nonsteroidal anti-inflammatory drugs, sulfasalazine, methotrexate, antibiotics and biological drugs can be considered.
PubMed: 35125997
DOI: 10.5114/ada.2020.97394 -
Current Osteoporosis Reports Dec 2017Chronic non-bacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder. We summarize... (Review)
Review
PURPOSE OF REVIEW
Chronic non-bacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder. We summarize the clinical presentation, diagnostic approaches, most recent advances in understanding the pathophysiology, and available treatment options and outcomes in CNO/CRMO.
RECENT FINDINGS
Though the exact molecular pathophysiology of CNO/CRMO remains somewhat elusive, it appears likely that variable defects in the TLR4/MAPK/inflammasome signaling cascade result in an imbalance between pro- and anti-inflammatory cytokine expressions in monocytes from CNO/CRMO patients. In this context, we present previously unpublished data on cytokine and chemokine expression in monocytes and tissues. CNO/CRMO is an autoinflammatory bone disorder resulting from imbalanced cytokine expression from innate immune cells. Though the exact molecular pathophysiology remains unclear, variable molecular defects appear to result in inflammasome activation and pro-inflammatory cytokine expression in monocytes from CNO/CRMO patients. Recent advances suggest signaling pathways and single molecules as biomarkers for CNO/CRMO as well as future treatment targets.
Topics: Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bone Density Conservation Agents; Chemokine CCL2; Chemokine CCL4; Chemokine CCL5; Chemokines; Cytokines; Diphosphonates; Disease Models, Animal; Humans; Immunosuppressive Agents; Inflammasomes; Interleukin-12; Interleukin-6; Methotrexate; Mice; Mitogen-Activated Protein Kinases; Monocytes; Osteomyelitis; Receptors, Interleukin-2; Signal Transduction; Sulfasalazine; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 29080202
DOI: 10.1007/s11914-017-0405-9 -
International Journal of Molecular... Jul 2020Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and redox imbalance. Ferroptosis shows specific biological... (Review)
Review
Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and redox imbalance. Ferroptosis shows specific biological and morphological features when compared to the other cell death patterns. The loss of lipid peroxide repair activity by glutathione peroxidase 4 (GPX4), the presence of redox-active iron and the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are considered as distinct fingerprints of ferroptosis. Several pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion, p53, Keap1/Nrf2 and phospholipid biosynthesis, can modify susceptibility to ferroptosis. Through the decades, various diseases, including acute kidney injury; cancer; ischemia-reperfusion injury; and cardiovascular, neurodegenerative and hepatic disorders, have been associated with ferroptosis. In this review, we provide a comprehensive analysis of the main biological and biochemical mechanisms of ferroptosis and an overview of chemicals used as inducers and inhibitors. Then, we report the contribution of ferroptosis to the spectrum of liver diseases, acute or chronic. Finally, we discuss the use of ferroptosis as a therapeutic approach against hepatocellular carcinoma, the most common form of primary liver cancer.
Topics: Animals; Autophagy; Chemical and Drug Induced Liver Injury; Cyclohexylamines; Cysteine; Ferroptosis; Glutathione; Heme; Humans; Iron; Kelch-Like ECH-Associated Protein 1; Lipid Peroxidation; Lipoxygenase; Liver Diseases; Liver Neoplasms; Oxidative Stress; Phenylenediamines; Phospholipid Hydroperoxide Glutathione Peroxidase; Piperazines; Quinoxalines; Reactive Oxygen Species; Reperfusion Injury; Signal Transduction; Sorafenib; Spiro Compounds; Sulfasalazine; Tumor Suppressor Protein p53; alpha-Tocopherol
PubMed: 32664576
DOI: 10.3390/ijms21144908 -
Current Gene Therapy 2019Ferroptosis is a newly discovered form of iron-dependent oxidative cell death characterized by lethal accumulation of lipid-based reactive oxygen species (ROS). It is... (Review)
Review
BACKGROUND
Ferroptosis is a newly discovered form of iron-dependent oxidative cell death characterized by lethal accumulation of lipid-based reactive oxygen species (ROS). It is distinct from other forms of cell death including apoptosis, necrosis, and autophagy in terms of morphology, biochemistry and genetics.
DISCUSSION
Ferroptosis can be induced by system xc- inhibitors or glutathione peroxidase 4 (GPx4) inhibitors, as well as drugs such as sorafenib, sulfasalazine (SAS), and artesunate (ART). Ferroptosis has been recently shown to be critical in regulating growth of tumors, such as hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic carcinoma, and diffuse large B cell lymphoma (DLBCL). Ferroptosis is also associated with resistance to chemotherapeutic drugs and the anti-tumor efficacy of immunotherapy.
CONCLUSION
This review summarizes the mechanism of ferroptosis and its relationship with different types of tumors, to advance our understanding of cell death and to find a novel approach for clinical cancer management.
Topics: Apoptosis; Artesunate; Autophagy; Cell Death; Ferroptosis; Humans; Iron; Neoplasms; Phospholipid Hydroperoxide Glutathione Peroxidase; Reactive Oxygen Species; Sulfasalazine
PubMed: 31264548
DOI: 10.2174/1566523219666190628152137 -
Andrology Jul 2017Beside cytotoxic drugs, other drugs can impact men's fertility through various mechanisms. Via the modification of the hypothalamic-pituitary-gonadal axis hormones or by... (Review)
Review
Beside cytotoxic drugs, other drugs can impact men's fertility through various mechanisms. Via the modification of the hypothalamic-pituitary-gonadal axis hormones or by non-hormonal mechanisms, drugs may directly and indirectly induce sexual dysfunction and spermatogenesis impairment and alteration of epididymal maturation. This systematic literature review summarizes existing data about the negative impact and associations of pharmacological treatments on male fertility (excluding cytotoxic drugs), with a view to making these data more readily available for medical staff. In most cases, these effects on spermatogenesis/sperm maturation/sexual function are reversible after the discontinuation of the drug. When a reprotoxic treatment cannot be stopped and/or when the impact on semen parameters/sperm DNA is potentially irreversible (Sulfasalazine Azathioprine, Mycophenolate mofetil and Methotrexate), the cryopreservation of spermatozoa before treatment must be proposed. Deleterious impacts on fertility of drugs with very good or good level of evidence (Testosterone, Sulfasalazine, Anabolic steroids, Cyproterone acetate, Opioids, Tramadol, GhRH analogues and Sartan) are developed.
Topics: Animals; Cryopreservation; DNA Damage; Drug-Related Side Effects and Adverse Reactions; Fertility; Fertility Preservation; Humans; Infertility, Male; Male; Risk Assessment; Risk Factors; Sexual Behavior; Sperm Banks; Spermatogenesis; Spermatozoa
PubMed: 28622464
DOI: 10.1111/andr.12366 -
Clinical Rheumatology Sep 2023Systematic r eview to evaluate the quality of the clinical practice guidelines (CPG) for rheumatoid arthritis (RA) management and to provide a synthesis of high-quality... (Review)
Review
Systematic r eview to evaluate the quality of the clinical practice guidelines (CPG) for rheumatoid arthritis (RA) management and to provide a synthesis of high-quality CPG recommendations, highlighting areas of consistency, and inconsistency. Electronic searches of five databases and four online guideline repositories were performed. RA management CPGs were eligible for inclusion if they were written in English and published between January 2015 and February 2022; focused on adults ≥ 18 years of age; met the criteria of a CPG as defined by the Institute of Medicine; and were rated as high quality on the Appraisal of Guidelines for Research and Evaluation II instrument. RA CPGs were excluded if they required additional payment to access; only addressed recommendations for the system/organization of care and did not include interventional management recommendations; and/or included other arthritic conditions. Of 27 CPGs identified, 13 CPGs met eligibility criteria and were included. Non-pharmacological care should include patient education, patient-centered care, shared decision-making, exercise, orthoses, and a multi-disciplinary approach to care. Pharmacological care should include conventional synthetic disease modifying anti-rheumatic drugs (DMARDs), with methotrexate as the first-line choice. If monotherapy conventional synthetic DMARDs fail to achieve a treatment target, this should be followed by combination therapy conventional synthetic DMARDs (leflunomide, sulfasalazine, hydroxychloroquine), biologic DMARDS and targeted synthetic DMARDS. Management should also include monitoring, pre-treatment investigations and vaccinations, and screening for tuberculosis and hepatitis. Surgical care should be recommended if non-surgical care fails. This synthesis offers clear guidance of evidence-based RA care to healthcare providers. TRIAL REGISTRATION: The protocol for this review was registered with Open Science Framework ( https://doi.org/10.17605/OSF.IO/UB3Y7 ).
Topics: Adult; Humans; Antirheumatic Agents; Arthritis, Rheumatoid; Hydroxychloroquine; Methotrexate; Sulfasalazine; Practice Guidelines as Topic
PubMed: 37291382
DOI: 10.1007/s10067-023-06654-0 -
Cancer Discovery Dec 2019A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities, including radiotherapy. Here, we demonstrate that...
A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities, including radiotherapy. Here, we demonstrate that radiotherapy induces tumor-cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor-cell ferroptosis. Mechanistically, IFNγ derived from immunotherapy-activated CD8 T cells and radiotherapy-activated ATM independently, yet synergistically, suppresses SLC7A11, a unit of the glutamate-cystine antiporter xc, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy. SIGNIFICANCE: This article describes ferroptosis as a previously unappreciated mechanism of action for radiotherapy. Further, it shows that ferroptosis is a novel point of synergy between immunotherapy and radiotherapy. Finally, it nominates SLC7A11, a critical regulator of ferroptosis, as a mechanistic determinant of synergy between radiotherapy and immunotherapy..
Topics: Amino Acid Transport System y+; Animals; Antineoplastic Agents, Immunological; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Survival; Down-Regulation; Ferroptosis; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Interferon-gamma; Lipid Metabolism; Melanoma, Experimental; Mice; Oxidation-Reduction; Sulfasalazine; Xenograft Model Antitumor Assays
PubMed: 31554642
DOI: 10.1158/2159-8290.CD-19-0338 -
Nature Cell Biology Apr 2020SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with...
SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11 cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11 cancer cells and suppress SLC7A11 tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11 cancers.
Topics: Amino Acid Transport System y+; Animals; Biological Transport; Carcinoma, Renal Cell; Cell Death; Cell Line, Tumor; Cystine; Disulfides; Gastrointestinal Agents; Gene Expression Regulation, Neoplastic; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 3; Glucosephosphate Dehydrogenase; Humans; Kidney Neoplasms; Mice; Mice, Nude; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Pyrazoles; Quinolines; Stress, Physiological; Sulfasalazine; Survival Analysis; Xenograft Model Antitumor Assays
PubMed: 32231310
DOI: 10.1038/s41556-020-0496-x