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PubMed1981

The future research in surgical pathology.

Recent conceptual and methodologic advances have the potential for providing new avenues of investigation for the study of human disease at the cellular and molecular levels. Surgical pathologists, by virtue of their training in the recognition of different disease states at various points in their evolution, are in a unique position to lead research efforts utilizing human tissues as a major investigative resource. Many tissues obtained in the surgical pathology laboratory are available for direct experimental studies without jeopardizing their utilization for routine diagnostic purposes. Moreover, experimental data derived from their study may lead to more accurate and meaningful diagnoses. Advances in tissue culture methodology and xenotransplantation technics, for example, have now made possible the study of mechanisms of carcinogenesis and variations in responses to different carcinogens directly in human tissues. Analysis of the effects of the physical and chemical microenvironments on the expression of various phenotypic characteristics may be performed directly in cultures of normal and neoplastic cells. The application of immunocytochemical technics will have a major impact in many areas of diagnostic and investigative pathology. These methods, which exploit the exquisite sensitivity of antibodies as diagnostic reagents for the visualization of a variety of antigens, permit the pathologist to extent and expand morphologic observations to include a variety of biochemical parameters. Potential applications include the characterization of the entire spectrum of proliferative events preceding the development of overt neoplasms, analysis of fully developed neoplasms with regard to the emergence of tumor subpopulations, and evaluation of new tumor marker systems. Clinically, these technics may be expected to aid in early diagnosis, determination of prognosis, and prediction of response to various forms of therapy. A major challenge for the future depends on the appreciation of the unique importance of human tissues for biomedical research and on the development and expansion of the traditional role of the surgical pathologist in this effort.

Antigens, Neoplasm↗
PubMed2003

Tumors as elusive targets of T-cell-based active immunotherapy.

The understanding of tumor-host interactions remains elusive despite significant progress in the identification of tumor antigens (TAs) recognized by autologous T cells. In particular, most human tumors do not regress and continue to grow in spite of spontaneous or immunization-induced immune responses demonstrated in circulating lymphocytes. Indeed, systemic immune responses might insufficiently address the complexity of tumor-host interactions because of factors, such as (1) the lack of productive T-cell receptor (TCR) engagement with epitope owing to qualitative and/or quantitative defects in the generation and maintenance of the immune response, (2) insufficient costimulation provided by the host, (3) the lack of localization of the immune response in target tissues and (4) the complexity of tumor-host interactions within the tumor microenvironment caused by temporal changes in tumor phenotypes and an array of immune mediators expressed in the tumor microenvironment. Here, we will review current knowledge of the different 'levels' of immune response that might be necessary for immunotherapy to be effective in the treatment of cancer. Furthermore, we will discuss the information still required in order to understand the mechanism(s) governing tumor rejection by the immune system in response to TA-specific immunization.

Animals↗
PubMed1986

Development of immunity in human severe primary T cell deficiency following haploidentical bone marrow stem cell transplantation.

Recent advances in the prevention of graft-vs-host disease (GVHD) have allowed the use of haploidentical bone marrow cells for correction of lethal genetic defects of the immune system. Sequential analyses of blood lymphocyte phenotypes and functions were done before and after transplantation of haploidentical marrow stem cells into 17 infants with severe primary T cell deficiencies. The marrow was depleted of post-thymic T cells and most other mature marrow cells by soy lectin agglutination and sheep erythrocyte rosetting. The studies were performed to define the time course and extent of appearance of immune function, and to identify factors leading to resistance to engraftment. No pretransplant immunosuppression was used. T cell function was detected between 34 and 287 days after transplantation, but a sharp rise usually occurred between 84 and 115 days, and normal function was reached between 113 and 210 days. Fifteen of the patients are alive from 6 to 41 mo post-transplantation, 12 have improved or have normal T lymphocyte function, and nine have proven T cell chimerism. Increased immunoglobulins of several isotypes have been noted in 11 patients and specific antibodies in seven patients, although B cell chimerism has been detected in only one patient. B cell function required 2 to 2.5 yr for normalization. No GVHD occurred in 14 patients, and the other three had only transient mild skin rashes. Two patients died of viral infections. Failure to engraft was correlated with some pre-transplant lymphocyte responses to mitogens and allogeneic cells (three cases), but not with the presence of pre-transplant natural killer cell function (five cases) nor with the presence of purine salvage pathway enzyme deficiencies (four cases). The latter, however, was associated with poor lymphoid function in two patients. These studies indicate that the thymic microenvironment of most infants with severe combined immunodeficiency disease is capable of differentiating donor stem cells to mature and functioning T lymphocytes which can cooperate with apparently normal host B cells for antibody production.

Adenosine Deaminase↗
PubMed2002

Electrochemical monitoring of anticancer compounds on the human ovarian carcinoma cell line A2780 and its adriamycin- and Cisplatin-resistant variants.

A novel electrochemical technique which detects and monitors real-time changes in cell behavior in vitro has been used to examine the effects of recognized anticancer drugs on the human ovarian carcinoma cell line A2780 and its adriamycin (A2780adr)- and cisplatin (A2780cispt)-resistant variants. These cells, adherent to gold electrodes or sensors, modify the extracellular microenvironment at the cell:sensor interface, producing an electrochemical potential that is different from that of the bulk culture medium. Confluent, adherent A2780 cells produced an electrochemical signal, measured as an open circuit potential (OCP), of approximately -100 mV compared to a cell-free value of approximately -15 mV. Exposure of A2780 cells to cisplatin (range 10(-4) to 10(-6) M), adriamycin (range 10(-5) to 10(-7) M), and vinblastine (10(-6) M) all produced positive shifts in the OCP signal relative to untreated control cells during 24 h of culture, but Taxotere (range 10(-5) to 10(-7) M) had no effect. These positive shifts in OCP signal were evident well before observations of reduced cellular adhesion and viability after 24 h, as judged in parallel cultures with a plastic substratum and by scanning electron microscopy. By contrast, the same treatments applied to the A2780adr and A2780cispt variants showed that each demonstrated different sensitivities to the same drugs applied to the parental A2780 cells. The effects of the same four anticancer drugs on ovarian carcinoma (A2780) and breast carcinoma (8701-BC) cell lines showed that the former was far more responsive to adriamycin and cisplatin. Such differences in drug sensitivities between the two cell lines were subsequently confirmed using the conventional MTT assay over 5 days. Although this electrochemical technology readily detects changes in cell adhesion and viability, the modified OCP signals recorded within a few hours of anticancer drug treatments are evident well before microscopic morphological changes become apparent. It is proposed that these early changes in OCP signals, relative to control untreated cells, reflect modifications of physiological/behavioral processes manifested at the cell surface.

Antineoplastic Agents↗
PubMed2004

Inflammatory neuropathies of the enteric nervous system.

Inflammatory neuropathy of the enteric nervous system is emerging as an important topic in the field of neurogastroenterology. Enteric ganglionitis can be either primary or secondary to a wide array of diseases (i.e., paraneoplastic, infectious, and neurological disorders) and is characterized by a dense infiltrate of inflammatory/immune cells mainly confined to the neural microenvironment. The clinical picture reflects the involved segment of the gastrointestinal tract (achalasia, gastroparesis, pseudo-obstruction, and megacolon). In these settings, symptoms may develop either acutely (frequently after a flulike episode in otherwise previously healthy individuals) or more slowly (e.g., in paraneoplastic syndromes). The inflammatory/immune response in enteric ganglionitis leads to neuronal dysfunction and degeneration over time and sometimes results in a complete loss of enteric neurons. The diagnosis of enteric ganglionitis is supported by detection of circulating antineuronal antibodies against select molecular targets, including Hu and Yo proteins, neurotransmitter receptors, and ion channels. Potential mechanisms involved in neuronal dysfunction include viral antigen expression in the enteric neural environment, molecular mimicry (onconeural antigens), and the role exerted by cellular and humoral autoimmunity. A short course of steroid or other immunosuppressive therapy has been shown to be helpful in the treatment of these conditions. This feature reinforces the concept of a cause/effect relationship of the immune-mediated insult damaging the enteric innervation. An increased awareness of the clinical features and the immunologic and neurodegenerative mechanisms of these forms of peripheral neuropathy is important to correctly diagnose this problem during the early stages of the disease process and to provide appropriate immunosuppressive therapies.

Enteric Nervous System↗
PubMed1992

Effects of interleukin-3 on murine fetal liver hemopoiesis in utero.

The normal regulation of primitive hemopoietic stem cells (PHSCS) throughout development involves locally produced factors and humoral factors. While considerable information is available on the effects of candidate hemopoietic growth factors (HGFs) on postnatal hemopoietic tissues, little is known about the regulatory events of developing hemopoietic stem cells within fetal microenvironments. Fetal hemopoiesis represents expanding populations and may be under different regulatory control mechanisms. The microinjection of purified interleukin-3 (IL-3), a candidate HGF, into 13-day-old mouse fetuses via the yolk sac, allowed us to evaluate its effects on morphogenetic events and, more specifically, on fetal liver populations using quantitative in vitro clonal assays for hemopoietic precursors. In view of the sensitivity of fetal development during the early organogenetic period, considerable care was taken to identify the stress effects of the surgical laparotomy and the microinjection procedure. Control studies, required to distinguish stress effects of surgical laparotomy and microinjection, clearly revealed that the fetal liver is a sensitive organ responding with limited tissue disorganization, reduced cellularity and erythropoietic activity, as monitored 24 h after experimental intervention. The microinjection of 15 units of IL-3 promoted a significant expansion of depleted liver hemopoietic-cell populations and had stimulatory effects on the distribution of connective tissue mast cells and absolute cell numbers, including hemopoietic precursors (erythroid, granulocyte, macrophage, megakaryocyte), compared to controls. These studies suggest that (1) fetal liver hemopoiesis is selectively sensitive to maternal stress but has an effective regenerative capacity to maintain essential hemopoiesis in utero, and (2) fetal hemopoietic cells require an ability to respond to IL-3 early in fetal development.

Animals↗
PubMed1999

Immunocytochemical study of cells in the vitreous of proliferative vitreoretretinopathy.

PURPOSE: To identify the cellular components of vitreous samples obtained during vitrectomy for proliferative vitreoretinopathy (PVR). METHODS: With the use of three intermediate filament (IF) proteins, vimentin, glial fibrillary acidic protein (GFAP), and cytokeratin (CK), cytocentrifuge slides of 14 fresh vitreous aspirates were detected with immunohistochemical technique. RESULTS: All the specimens contained epithelial-like proliferative cells with or without pigment and some membrane-like pieces. Immunocytochemical staining showed that 76.0-90.0% cells stained for CK, 17.4-29.6% cells expressed GFAP, and 80.1-91.0% cells were positive for vimentin. CONCLUSIONS: Majority of cells in the vitreous samples originated from retinal pigment epithelial cells (RPE) and glial cells in PVR. Expression of IF proteins may be determined by tissue of origin and local microenvironment.

Adolescent↗
PubMed2005

Cell and tissue responses to genotoxic stress.

Cancers arise as a consequence of the accumulation of multiple genetic mutations in a susceptible cell, resulting in perturbation of regulatory networks that control proliferation, survival, and cellular function. Here, the sources of cellular stress that can cause oncogenic mutations and the responses of cells to DNA damage are reviewed. The role of different repair pathways and the potential for cell- and tissue-specific reliance on individual repair mechanisms are discussed. Evidence for cell- and tissue-specific activation of p53-mediated growth arrest and apoptosis after exposure to an individual genotoxin is assessed and some of the potential mediators of these different responses are provided. These cell- and tissue-specific responses to particular forms of DNA damage are likely to be key determinants of tissue-specific tumour susceptibility, and there is good evidence for genetic variations in these responses. The role that genotoxic agents play in altering the microenvironment to produce indirect effects on tumourigenesis through altered production of free radicals and cytokines that are characteristic of inflammatory-type processes is also evaluated. Changes to the microenvironment as direct or indirect effects of genotoxic stress can be involved in both tumour initiation and progression and may even be a prerequisite for tumourigenesis. Therefore, tumour susceptibility after endogenous or exogenous genotoxic stress represents a balance between cell-intrinsic responses of target cells and changes to the microenvironment. A fuller understanding of cell- and tissue-specific responses, alterations to the microenvironment, and genetic modifiers of these responses could lead to novel prevention and therapeutic strategies for common forms of human malignancy.

Animals↗
PubMed2005

Effects of cytoskeletal prestress on cell rheological behavior.

Normal tissue development requires that cells alter their mechanical behavior in different microenvironments to carry out their diverse functions. During cell spreading, migration, invasion and mitosis, cells exhibit a high degree of deformability, exhibiting almost a fluid-like behavior, whereas within quiescent differentiated tissues, cells must behave like an elastic solid to maintain their structural integrity in the face of an applied mechanical stress. A growing body of experimental evidence suggests that rheological properties of adherent cells depend on pre-existing tensional stress ("prestress") borne by the cytoskeleton. This prestress results from the action of tensional forces borne by actin microfilaments, transmitted over intermediate filaments and resisted by both extracellular matrix adhesions and internal microtubules. Observations that the prestress influences mechanical properties of the cell are intimately related to the cellular tensegrity model. This model depicts the cytoskeleton as an interconnected network of cables that carry pre-existing tension that is balanced by compression-bearing struts and by anchoring forces of the substrate. This paper offers a brief survey of the basic concept of cellular tensegrity model, comparison of model predictions with experimental data obtained from rheological measurements on living cells, and comparison with other models that have been used in studies of rheology of cells.

Cells↗
PubMed2026

Differential cell signaling testing for cell-cell communication inference from single-cell data by dominoSignal.

MOTIVATION: Algorithms for ligand-receptor network inference have emerged as commonly used tools to estimate cell-cell communication from reference single-cell data. Many studies employ these algorithms to compare signaling between conditions and lack methods to statistically identify signals that are significantly different. We previously developed the cell communication inference algorithm Domino, which considers ligand and receptor gene expression in association with downstream transcription factor activity scoring. We developed the dominoSignal software to innovate upon Domino and extend its functionality to test statistically differential cellular signaling. RESULTS: This new functionality includes the compilation of active signals as linkages from multiple subjects in a single-cell data set and testing condition-dependent signaling linkage. The software is applicable for analysis of single-cell data sets with multiple subjects as biological replicates as well as with bootstrapped replicates from data sets with few or pooled subjects. We use simulation studies to benchmark the number of subjects in compared groups and cells within an annotated cell type sufficient to accurately identify differential linkages. We demonstrate the application of the Differential Cell Signaling Test (DCST) in the dominoSignal software to investigate consequences of cancer cell phenotypes and immunotherapy on cell-cell communication in tumor microenvironments. These applications in cancer studies demonstrate the ability of differential cell signaling analysis to infer changes to cell communication networks from therapeutic or experimental perturbations, which is broadly applicable across biological systems. AVAILABILITY: dominoSignal is available through Bioconductor at https://www.bioconductor.org/packages/release/bioc/html/dominoSignal.html.

Cell Communication↗
PubMed2003

Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren's syndrome.

OBJECTIVE: To investigate functional properties of the germinal center (GC)-like structures observed in salivary glands of patients with Sjögren's syndrome (SS) and to determine the frequency with which such structures develop. METHODS: Hematoxylin and eosin-stained sections from 165 minor salivary gland biopsy samples were screened for GC-like structures. Expression of markers for GCs (CD3, CD20, Ki-67, CD35, CD31), adhesion molecules (intercellular adhesion molecule 1, lymphocyte function-associated antigen 1, vascular cell adhesion molecule 1, very late activation antigen 4), chemokines (CXCL13, CCL21, CXCL12), and production of autoantibodies (anti-Ro/SSA and anti-La/SSB) was investigated by immunohistochemistry. Apoptosis was investigated by TUNEL staining. RESULTS: GC-like structures were observed in 28 of 165 patients (17%). When GCs were defined as T and B cell aggregates with proliferating cells with a network of follicular dendritic cells and activated endothelial cells, such microenvironments were found in all patients in whom structures with GC-like morphology were observed. The defined microenvironments were not found in patients without apparent GC-like structures. The GCs formed within the target tissue showed functional features with production of autoantibodies (anti-Ro/SSA and anti-La/SSB) and apoptotic events (by TUNEL staining), and the local production of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly increased (P = 0.04) in patients with GC development. CONCLUSION: Lymphoid neogenesis and functional ectopic GC formation take place in salivary glands of a subset of patients with SS. Our data suggest that the ectopic secondary lymphoid follicles contain all elements needed for driving the autoimmune response. Our findings underscore a key role for the target organ in recruitment of inflammatory cells and propagation of the disease process.

Apoptosis↗
PubMed1998

The cellular basis of tumor progression.

Variability in disease presentation and course is a hallmark of cancer. Variability is seen among similarly diagnosed cancers in different patients or animal hosts and in the same cancer at different periods of time. This latter type of variability, termed "tumor progression," was defined by Foulds in a series of six rules that describe the independent behavior of individual cancers and the independent evolution of different cancer characteristics. Tumor progression is believed to result from variability among subpopulations of tumor cells within individual cancers and from selection of these subpopulations by conditions within the cancer environment, such that different subpopulations come to prominence over the course of cancer development and growth. Interactions among subpopulations, however, modulate tumor behavior as well as tumor evolution. The leading hypothesis for the origin of tumor subpopulations is the genetic instability of cancer cells. There are a number of possible mechanisms of genetic instability, some internal to cancer cells (mutation, amplification, mutator phenotypes, DNA repair deficiencies) and some present in the tumor microenvironment (endogenous mutagens). There are also potential epigenetic mechanisms of variability, including alterations in gene regulation, differentiation, adaptation, and cell fusion. Regardless of mechanism, the heterogeneity of tumor subpopulations poses a number of challenges to the practice of cancer research, including the design of reproducible and meaningful experiments. Tumor heterogeneity also has significant consequences for the clinical assessment of tumor prognosis and the development of effective treatment regimens.

Animals↗
PubMed2006

Early destruction of tumor vasculature in tumor necrosis factor-alpha-based isolated limb perfusion is responsible for tumor response.

Addition of high-dose tumor necrosis factor-alpha to melphalan-based isolated limb perfusion enhances anti-tumor effects impressively. Unfortunately, the mechanism of action of tumor necrosis factor-alpha is still not fully understood. Here, we investigated the effects of tumor necrosis factor-alpha on the tumor microenvironment and on secondary immunological events during and shortly after isolated limb perfusion in soft-tissue sarcoma-bearing rats. Already during isolated limb perfusion, softening of the tumor was observed. Co-administration of tumor necrosis factor-alpha in the isolated limb perfusion with melphalan induced a six-fold enhanced drug accumulation of melphalan in the tumor compared with isolated limb perfusion with melphalan alone. In addition, directly after perfusion with tumor necrosis factor-alpha plus melphalan, over a time-frame of 30 min, vascular destruction, erythrocyte extravasation and hemorrhage was detected. Interstitial fluid pressure and pH in the tumor, however, were not altered by tumor necrosis factor-alpha and no clear immune effects, cellular infiltration or cytokine expression were observed. Taken together, these results indicate that tumor necrosis factor-alpha induces rapid damage to the tumor vascular endothelial lining resulting in augmented drug accumulation. As other important parameters were not changed (e.g. interstitial fluid pressure and pH), we speculate that the tumor vascular changes, and concurrent hemorrhage and drug accumulation are the key explanations for the observed synergistic anti-tumor response.

Animals↗
PubMed2006

p27Kip1 and p130 cooperate to regulate hematopoietic cell proliferation in vivo.

To investigate the potential functional cooperation between p27Kip1 and p130 in vivo, we generated mice deficient for both p27Kip1 and p130. In p27Kip1-/-; p130-/- mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27Kip1-/- counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27Kip1-/-; p130-/- animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1-/- splenocytes. The finding that the p27Kip1-/-; p130-/- splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27Kip1 to regulate hematopoietic cell proliferation in vivo.

Animals↗
PubMed1998

Thymic stromal-cell abnormalities and dysregulated T-cell development in IL-2-deficient mice.

The role that interleukin-2 (IL-2) plays in T-cell development is not known. To address this issue, we have investigated the nature of the abnormal thymic development and autoimmune disorders that occurs in IL-2-deficient (IL-2-/-) mice. After 4 to 5 weeks of birth, IL-2-/- mice progressively develop a thymic disorder resulting in the disruption of thymocyte maturation. This disorder is characterized by a dramatic reduction in cellularity, the selective loss of immature CD4-8- (double negative; DN) and CD4+8+ (double positive; DP) thymocytes and defects in the thymic stromal-cell compartment. Immunohistochemical staining of sections of thymuses from specific pathogen-free and germ-free IL-2-/- mice of various ages showed a progressive loss of cortical epithelial cells, MHC class II-expressing cells, monocytes, and macrophages. Reduced numbers of macrophages were apparent as early as 1 week after birth. Since IL-2-/- thymocyte progenitor populations could mature normally on transfer into a normal thymus, the thymic defect in IL-2-/- mice appears to be due to abnormalities among thymic stromal cells. These results underscore the role of IL-2 in maintaining functional microenvironments that are necessary to support thymocyte growth, development, and selection.

Animals↗
PubMed1988

The chemical logic of a minimum protocell.

Traditional schemes for the origin of cellular life on earth generally suppose that the chance assembly of polymer synthesis systems was the initial event, followed by incorporation into a membrane-enclosed volume to form the earliest cells. Here we discuss an alternative system consisting of replicating membrane vesicles, which we define as minimum protocells. These consist of vesicular bilayer membranes that self-assemble from relatively rare organic amphiphiles present in the prebiotic environment. If some of the amphiphiles are primitive pigment molecules asymmetrically oriented in the bilayer, light energy can be captured in the form of electrochemical ion gradients. This energy could then be used to convert relatively common precursor molecules into membrane amphiphiles, thereby providing an initial photosynthetic growth process, as well as an appropriate microenvironment for incorporation and evolution of polymer synthesis systems.

Cells↗
PubMed1996

Termination by early deletion of V beta 8 + T cells of aged mice in response to staphylococcal enterotoxin B.

The changes in the T cell repertoire of aging BALB/c mice include an increase of V beta 8 + T cells, most of which have a relatively low density of T cell receptors (TCR). We investigated the response of V beta 8 + T cells to staphylococcal enterotoxin B (SEB), a superantigen from a common bacterium, the anamnestic response to which is thought usually to be part of the defense against infection. The injection of an amount of SEB optimum for V beta 8 + T cell proliferation in young mice induced little or no proliferative response in aged mice, and within one or two days they died in shock with apoptotic cells in the spleen, a sign of T cell-shock caused by SEB. Flowcytometry analysis (FCA) 15 h after SEB injection, when cell division had not yet started, revealed the loss of 90% of V beta 8 + T cells in the blood and of 50% in the spleen in mice of all ages tested. However, conspicuous in the remaining V beta 8 + T cells in the spleens of the young mice but not in those of the aged mice, was an increased cellular complexity, as shown by the fact that light was strongly side scattered in FCA, indicating intracellular re-organization. The remaining T cells in the young could include progenitors for the expanding population of V beta 8 + T cells. As seen in lethal shock, V beta 8 + T cells in the aged are not unresponsive to SEB in vitro. They responded to the antigen by increasing the amount of TCR up to the level of that in young mice, but without proliferation. The proliferation arrest of V beta 8 + T cells of aged mice was found to be an intrinsic defect in in vitro cell mixture experiments, in which they were cocultured with young spleen cells which provided a complete immune microenvironment. It was simultaneously found in vitro that most of the V beta 8 + T cells from aged mice disappeared after antigen stimulation and that their disappearance was prevented by the presence of spleen cells from young mice, although they still did not proliferate. Taken all together the findings suggest that V beta 8+ T cells in the aged are at the end state of maturation and terminate by apoptotic death, causing T-cell shock in response to SEB.

Age Factors↗
PubMed2026

Mapping the covalent cysteine interactome of Ebselen reveals high-sensitivity target engagement and redox proteome remodeling.

Ebselen is a covalent organoselenium compound with broad pharmacological activity, yet its cellular cysteine targets and downstream proteomic consequences remain incompletely defined. Here, we integrated competitive gel-based activity-based protein profiling, reactivity-dependent tandem orthogonal proteolysis-activity-based protein profiling, and TMT-based quantitative proteomics to map Ebselen-induced cysteine engagement and proteome remodeling in living cancer cells. Ebselen exhibited dose-dependent cytotoxicity and markedly perturbed intracellular thiol-redox balance, as reflected by glutathione depletion and altered reactive oxygen species-associated fluorescence readouts. Competitive gel-based profiling confirmed concentration-dependent engagement of protein cysteine residues in live cells. Quantitative rdTOP-ABPP further identified hundreds of dose-responsive cysteine sites in HeLa and HepG2 cells and revealed a preference for cysteine microenvironments enriched with basic residues. Cross-cell-line comparison highlighted CDK5 Cys53, SMU1 Cys298, and RPSA2 Cys163 as conserved covalent nodes, among which CDK5 Cys53 showed high sensitivity to Ebselen treatment, a finding validated by competitive labeling and MS-based site assignment. Global TMT proteomics revealed extensive remodeling of redox-related and cell-survival-associated pathways, including compensatory upregulation of selenoproteins such as TXNRD1 and GPX family members. Together, these results define a chemical proteomic atlas of Ebselen-cysteine interactions and provide a framework for understanding and optimizing covalent organoselenium therapeutics.

Humans↗