Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08758 (annexin V)
 9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to investigate in vitro the mechanism of toxicity of isoniazid (= INH), the drug most widely used for treatment of tuberculosis. The human hepatoma line HepG2, the human lymphoblastoid line AHH-1 and the murine lymphoma cells YAC-1 were used as test systems. Active cell death (= apoptosis) and necrosis were detected by different flow cytometric methods: the binding of annexin V to the cell membrane and staining with propidium iodide (PI), the TUNEL assay for detection of DNA fragmentation and the occurrence of a sub G1 peak in cell cycle histograms. Mitochondrial membrane potential was analysed with the fluorescent probe JC-1. In addition to cytotoxicity, effects of INH on cell cycle were studied in HepG2 cells. The data of the present investigations indicate that INH induces cytotoxicity via apoptosis both in hepatoma and lymphoma cells. Twenty-four hours of application of INH in concentrations > 26 mM led to a remarkable number of apoptotic cells positive for Annexin V. The induction of apoptosis was accompanied by a break down of the mitochondrial membrane potential and the occurrence of DNA strand breaks. At incubation times from 36 to 48 hours, a sub-G1 peak of late apoptotic cells was detected in cell cycle analysis. Furthermore, cell cycle studies showed a disruption of the cycle at low concentrations of INH which are only mildly cytotoxic. Thus the present study unequivocally demonstrated that INH induces cytotoxicity via apoptosis and can lead to a significant disturbance of the cell cycle in mammalian cells.
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PMID:In vitro studies on the toxicity of isoniazid in different cell lines. 1468 83

We recently reported that chronic lymphocytic leukemia (CLL) cells synthesize and release vascular endothelial growth factor (VEGF) under normoxic and hypoxic conditions. CLL B cells also express VEGF membrane receptors (VEGF-R1 and VEGF-R2), suggesting that they use VEGF as a survival factor. To assess the mechanism of apoptosis resistance related to VEGF, we determined the impact of VEGF on CLL B cells, and we studied the impact of epigallocatechin-3-gallate (EGCG), a known receptor tyrosine kinase (RTK) inhibitor, on VEGF receptor status and viability of CLL B cells. VEGF165 significantly increased apoptotic resistance of CLL B cells, and immunoblotting revealed that VEGF-R1 and VEGF-R2 are spontaneously phosphorylated on CLL B cells. EGCG significantly increased apoptosis/cell death in 8 of 10 CLL samples measured by annexin V/propidium iodide (PI) staining. The increase in annexin V/PI staining was accompanied by caspase-3 activation and poly-adenosine diphosphate ribose polymerase (PARP) cleavage at low concentrations of EGCG (3 microg/mL). Moreover, EGCG suppressed the proteins B-cell leukemia/lymphoma-2 protein (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP), and myeloid cell leukemia-1 (Mcl-1) in CLL B cells. Finally, EGCG (3-25 microg/mL) suppressed VEGF-R1 and VEGF-R2 phosphorylation, albeit incompletely. Thus, these results suggest that VEGF signaling regulates survival signals in CLL cells and that interruption of this autocrine pathway results in caspase activation and subsequent leukemic cell death.
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PMID:VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia. 1499 3

Energy metabolism and amino acid transport and incorporation are important components of the pathophysiology of gliomas, about which molecular imaging is providing regional biologic information that is useful to clinical practice. Imaging hypoxia is straightforward and proliferation imaging with FLT shows significant promise. Neither has been exploited thoroughly enough to allow judgement of their potential benefit to the practice of neuro-oncology. Although cell division is the most distinguishing function of growth in tumors, probing membrane biosynthesis with PET and 1-[11C]acetate or a choline tracer may yield information as helpful as protein or DNA synthesis. Because astrocytic gliomas frequently carry epidermal growth factor receptor mutations at a frequency that is related to grade, a PET tracer that is specific for this mutated receptor could be useful for grading and prognosis [35]. Methods for imaging angiogenesis are being developed; 18F-labeling of a cyclic RGD-containing glycopeptide, cyclo(-Arg-Gly-Asp-D-Phe-Lys(sugar amino acid)-), with 4-nitro-phenyl 2-[18F]fluoropropionate has been reported [136]. 18F-labeled annexin V is being tested as a new PET agent for quantitating tumor cell death and predicting response to therapy. Annexin V binds to surface membranes that have exposed phosphatidyl serine residues resulting from programmed cell destruction. Recently, a Tc-99m-labeled derivative has been shown to accumulate in late stage lung cancer and lymphoma in response to chemotherapy [137]. As molecular pathways leading to and sustaining neoplasia become better understood, so will our capacity improve to measure them in vivo and intervene to the patient's advantage.
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PMID:Positron emission tomography imaging of brain tumors. 1502 57

Many vaccine adjuvants contain surface-active agents, but the immunological roles played by these components have been essentially ignored. The objective of this study was to examine possible apoptotic and necrotic effects of the surface-active agents, Pluronic L121 and Tween 80, which are components of L121-adjuvant (a formulation we synthesized with the aim of representing several commercially produced adjuvants), on EL4 lymphoma cells. Cell viability and cytolytic effects were analyzed using the MTT and LDH release assays, and the distribution of cells in different stages of the cell cycle after treatment with these agents was analyzed by propidium iodide (PI) staining and flow cytometry. L121-adjuvant was shown to induce cell cycle arrest and inhibit cell proliferation. Treatment of EL4 cells with surface-active agents resulted in a concentration-dependent increase in the apoptotic/necrotic cell populations. Fluorescence microscopy using Hoechst 33342 staining demonstrated chromosome condensation and DNA fragmentation in cells treated with surfactants or adjuvant. The apoptotic and necrotic effects of vaccine adjuvant containing surface-active agents were confirmed by Annexin V/propidium iodide staining and flow cytometric analysis. Pretreatment of EL4 cells with zVAD-fmk, a broad range caspase inhibitor, partially prevented apoptosis induced by Pluronic L121, but did not prevent the cell death induced by Tween 80 or L121-adjuvant. These findings suggested that Tween 80 and L121-adjuvant induced apoptosis in EL4 cells via a "non-classical" caspase-independent pathway. Results presented in this study suggest mechanisms of elicitation of CD8(+), class I-restricted CTL response by soluble antigens mediated by the vaccine adjuvant containing surface-active agents.
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PMID:Cell death induced by vaccine adjuvants containing surfactants. 1506 78

L-PHA reactive oligosaccharides are found on the surface of HBL-2 cells, a lymphoma cell line, established from a human diffuse large B cell lymphoma (DLBCL). Swainsonine (SW) is a potent inhibitor of alpha-mannosidase II which catalyzes the biosynthesis of complex type N-linked oligosaccharides in human cells. CD40L stimulation of HBL-2 cells leads to their prolonged survival. Reduction in the expression of N-linked oligosaccharides, including L-PHA reactive oligosaccharides, on the cell surface by SW treatment resulted in enhancement of HBL-2 cell survival by CD40L stimulation. From an Annexin V assay the enhancement of CD40L-mediated HBL-2 cell survival by SW treatment may have resulted from anti-necrotic effects after 48 h of incubation. Bcl-2 enzyme linked immuno sorbent assay (ELISA) data showed that the expression of bcl-2 protein was enhanced by CD40L stimulation alone and also by CD40L stimulation along with SW treatment. However, there were no significant differences in the amount of bcl-2 protein with these treatments. Therefore, the enhancement of CD40L-mediated cell survival by SW treatment did not depend on the enhancement of bcl-2 protein expression. Furthermore, SW treatment of HBL-2 cells led to degradation of the heavy chain of IgM and rescued HBL-2 cells from anti-IgM-induced growth inhibition. Anti-IgM induced growth inhibition of HBL-2 cells prevented the inhibition of cell death by CD40L. From the present results it is possible that reduction of N-glycosylation of the heavy chain of IgM by SW treatment may reduce anti-IgM-induced growth inhibition, and reduction in anti-IgM-induced growth inhibition due to altered N-glycosylation may enhance CD40-CD40L-mediated cell survival through TRAF2 which interacts with both IgM and CD40 in HBL-2 cells.
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PMID:Regulatory roles of N-glycosylation of immunoglobulin M in CD40-CD40L-mediated cell survival of human diffuse large B cell lymphoma. 1506 43

Interest in exploiting traditional medicines for prevention or treatment of cancer is increasing. Extracts from the herb Tripterygium wilfordii hook F have been used in China for centuries to treat immune-related disorders. Recently it was reported that triptolide, a purified compound from Tripterygium, possessed antitumor properties and induced apoptosis in a variety of malignant cell lines. K562 cells are usually resistant to apoptosis induction, probably because of the expression of bcr-abl, the hybrid gene characteristic of the Philadelphia chromosome t (9;22). Present studies demonstrate that triptolide inhibited K562 cells proliferation and induced apoptosis in a dose and time-dependent manner. The growth-inhibitory IC50 value for triptolide treatment was 40 ng/ml. Characteristic apoptotic features were confirmed by morphology, internucleosomal DNA fragmentation, and Annexin V Staining. Significantly, triptolide-induced apoptosis of K562 cells was associated with a decline in bcr-abl expression levels, at the concentrations of 20 ng/ml, 40 ng/ml and 80 ng/ml, triptolide was able to decrease the expression of bcr-abl down to 50%, 30% and 20% respectively of the basal value after 72 h. Our findings strongly suggest that triptolide might be an effective therapeutic agent against CML cells.
Leuk Lymphoma 2004 Feb
PMID:Triptolide down-regulates bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells. 1510 26

Radiolabeled annexin V may provide an early indication of the success or failure of anticancer therapy on a patient-by-patient basis as an in vivo marker of tumor cell killing. An important question that remains is when, after initiation of treatment, should annexin V imaging be performed. To address this issue, we obtained simultaneous in vivo measurements of tumor burden and uptake of radiolabeled annexin V in the syngeneic orthotopic murine BCL1 lymphoma model using in vivo bioluminescence imaging (BLI) and small animal single-photon emission computed tomography (SPECT). BCL1 cells labeled for fluorescence and bioluminescence assays (BCL1-gfp/luc) were injected into mice at a dose that leads to progressive disease within two to three weeks. Tumor response was followed by BLI and SPECT before and after treatment with a single dose of 10 mg/kg doxorubicin. Biodistribution analyses revealed a biphasic increase of annexin V uptake within the tumor-bearing tissues of mice. An early peak occurring before actual tumor cells loss was observed between 1 and 5 hr after treatment, and a second longer sustained rise from 9 to 24 hr after therapy, which heralds the onset of tumor cell loss as confirmed by BLI. Multimodality imaging revealed the temporal patterns of tumor cell loss and annexin V uptake revealing a better understanding of the timing of radiolabeled annexin V uptake for its development as a marker of therapeutic efficacy.
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PMID:Multi-modality imaging identifies key times for annexin V imaging as an early predictor of therapeutic outcome. 1514 7

The ability of fifteen cycloartanes, isolated from Euphorbia species, to reverse multidrug resistance (MDR) and apoptosis induction in L5178Y mouse lymphoma cells, including its multidrug-resistant subline, was studied by flow cytometry. Reversion of MDR was investigated using a standard functional assay with rhodamine 123 as a fluorescent substrate analogue. For the evaluation of apoptosis, the cells were stained with FITC-labeled annexin V and propidium iodide. The majority of the compounds were able to reverse MDR of the tested human MDR1 gene-transfected mouse lymphoma cells. Some of the compounds were able to induce moderate apoptosis in the PAR cell line, but this effect was less effective on multidrug-resistant cells. The results indicate that cycloartanes can be substrates of ABC transporters, which might compete with certain anticancer chemotherapeutics.
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PMID:Effect of cycloartanes on reversal of multidrug resistance and apoptosis induction on mouse lymphoma cells. 1516 Oct 38

The X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis-1 (cIAP-1) are emerging as versatile proteins in programmed cell death with a scope of possible functions reaching far beyond their well known inhibitory effects on caspases. We previously demonstrated that the ability of drugs to modify expression and cleavage of the IAPs are crucial for the synergistic effects achieved by the combinations of different cytotoxic drugs employed to treat malignant lymphomas. In order to more clearly assess the underlying molecular mechanisms, we here evaluated the consequences of drug-induced apoptosis on the localization and aggregation of XIAP and cIAP-1. The influence of drug-induced apoptosis on localization of IAPs was investigated using immunofluorescence microscopy as well as western blot analysis. Apoptosis was induced by chemotherapeutic drugs with different modes of action (bendamustine, cladribine, fludarabine, doxorubicin and mitoxantrone) and assessed by flow-cytometry using Annexin V. We demonstrate that XIAP and cIAP-1 are downregulated and/or cleaved in a dose-dependent manner upon treatment with a variety of anti-cancer drugs. Moreover we provide evidence that in the context of drug-induced apoptosis XIAP, its BIR3-RING cleavage product and cIAP-1 undergo an extensive change of subcellular localization. Immunofluorescence microscopy reveals that XIAP, in contrast to cIAP-1, is located in discrete cytosolic protein aggregates and-upon induction of apoptosis with cytotoxic drugs--redistributes into large nuclear inclusions. This translocation of XIAP and its BIR3-RING cleavage product from the cytosol into the nucleus is confirmed by cell fractionation and western blot analyses. Of note, in this experimental setting putative interaction partners of XIAP-such as Apaf-1, caspase-3 and -7--do not co-localize with XIAP. These results imply a new unknown function of XIAP and its BIR3-RING fragment in the nucleus in the context of drug-induced apoptosis. The localization of cIAP-1 in mitochondria and its liberation from these indicate a profoundly different function of this protein despite its similar modular structure to XIAP.
Leuk Lymphoma 2004 Jul
PMID:Upon drug-induced apoptosis in lymphoma cells X-linked inhibitor of apoptosis (XIAP) translocates from the cytosol to the nucleus. 1535 44

Strategies to enhance the immunogenicity of tumors are urgently needed. Although vaccination with irradiated dying lymphoma cells recruits a tumor-specific immune response, its efficiency as immunogen is poor. Annexin V (AxV) binds with high affinity to phosphatidylserine on the surface of apoptotic and necrotic cells and thereby impairs their uptake by macrophages. Here, we report that AxV preferentially targets irradiated lymphoma cells to CD8+ dendritic cells for in vivo clearance, elicits the release of proinflammatory cytokines and dramatically enhances the protection elicited against the tumor. The response was endowed with both memory, because protected animals rejected living lymphoma cells after 72 d, and specificity, because vaccinated animals failed to reject unrelated neoplasms. Finally, AxV-coupled irradiated cells induced the regression of growing tumors. These data indicate that endogenous adjuvants that bind to dying tumor cells can be exploited to target tumors for immune rejection.
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PMID:Inhibition of phosphatidylserine recognition heightens the immunogenicity of irradiated lymphoma cells in vivo. 1550 19


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