UNIPROT:P08758 - FACTA Search

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)

In order to improve the therapeutic efficacy of adoptive immunotherapy of cancer using IL-2-activated NK (A-NK) cells, we developed a bi-specific monoclonal antibody (BimAb) 3.2.3xCC52. One specificity of the BimAb (mAb 3.2.3) was directed against rat CD161A (NKR-P1A) which has been shown to be an activation structure on rat NK cells involved in lysis of target cells and cytokine secretion. The other specificity (mAb CC52) was directed against a tumor associated antigen on the rat colon adenocarcinoma cell line CC531. The hybridomas producing 3.2.3 and CC52 were fused, resulting in a quadroma producing the desired 3.2.3xCC52 BimAb. The hybridomas produced antibodies of different isotypes (IgG2b and IgG1 respectively) which enabled us to pre-select quadromas with a high likelihood for production of BimAb, through testing for the production of bi-isotypic antibodies. Production of functional BimAb by the selected quadromas was demonstrated in an assay showing enhanced conjugate formation between CD161A+ cells and CC531 tumor cells. We also tested the 3.2.3xCC52 BimAb for its capacity to enhance NK cell-mediated lysis of CC531 tumor cells in 4 h and 19 h 51Cr release assays; in a prolonged (2 day) tumor neutralization assay using a tetrazolium salt (MTT)-based assay; and in tests for apoptosis using Annexin V-FITC. Although this BimAb was not demonstrated to cause enhanced lysis of CC531 cells by CD161A+ effector cells in vitro, it might be a useful tool to enhance the number of NK cells at the tumor site and/or prolong contact between tumor cells and NK cells in vivo, thereby probably enhancing the therapeutic efficacy of NK cells.
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PMID:The development of a bi-specific anti-CD161A x anti-tumor antibody for rat NK cell targeting. 1008 94

Ways of restoring an altered drug sensitivity in P-170 glycoprotein (MDR1) positive leukemias are being actively sought for, mostly using MDRI negative regulators together with the MDR1-sensitive anthracycline-type drugs daunorubicin and mitoxantrone. Because idarubicin is less vulnerable to MDR1-mediated transport and could thereby represent a better companion to MDR1 inhibitors, we assessed the ability of the anti-MDR1 agent cyclosporin A to modulate this function in multidrug resistant T-lymphoblastic CEM cells challenged in vitro with either daunorubicin or idarubicin. In order to obtain information of potential interest for the design of a clinical trial, we adopted drug plus metabolite concentrations and exposure times close to the in vivo pharmacokinetics of equimyelotoxic doses of intravenous daunorubicin 45 mg/m2 or idarubicin 10-12 mg/m2, respectively, plus infusional cyclosporin A 16 mg/kg/d. Study methods were cytofluorimetry for the detection of intracellular drug uptake, retention and pro-apoptotic effects (binding of fluoresceinated annexin V), and the standard MTT assay as growth inhibition test. The results showed significantly greater drug uptake (at 30'), retention (at 12 hours), and apoptotic cell rates with idarubicin+/-idarubicinol than daunorubicin+/-daunorubicinol (p<0.05), and a further potentiation of these effects by cyclosporin A. Differing from daunorubicin, idarubicin intracellular accumulation and, by inference, related apoptotic changes were increased by cyclosporin A only in the early phase of drug-cell interaction; a potential advantage towards a reduced toxicity by CsA delivered as short rather than prolonged infusion in the in vivo setting. MTT assay results were also in favour of idarubicin but greatly influenced by cyclosporin A itself. Altogether, study results in MDR1+ cells incubated with CsA 1500 ng/ml plus idarubicin+idarubicinol 100+20 ng/ml, that are peak levels achievable in vivo with an idarubicin dose > or = 12 mg/m2 plus cyclosporin A 16 mg/kg/d, were in the range of those obtained with standard-dose daunorubicin in MDR1- cells (p=n.s.). In summary, an idarubicin plus short-course cyclosporin A combination could be considered for the management of MDR1+ leukemias, where it may represent a more effective and less toxic option than daunorubicin plus continuous infusion cyclosporin A.
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PMID:Cellular uptake and antiproliferative effects of therapeutic concentrations of idarubicin or daunorubicin and their alcohol metabolites, with or without cyclosporin A, in MDR1+ human leukemic cells. 1034 76

The clinical utility of anthracyclines like doxorubicin (DOX) and daunorubicin (DNR) for treatment of multiple myeloma (MM) is limited by the occurrence of multidrug resistance (MDR). Highly lipophilic anthracyclines like idarubicin (IDA) might circumvent MDR and thereby enhance chemotherapeutic efficacy. To determine the efficacy of IDA in myeloma cells, the pharmacokinetics and cytotoxicity of IDA and its major metabolite idarubicinol (IDAol) were compared with those of DNR, DOX, and doxorubicinol (DOXol) in the cell line RPMI 8226-S and two MDR sublines (8226-R7 and 8226-Dox40) that overexpress the drug transporter P-glycoprotein (Pgp). Cytotoxicity assays using MTT (viability) or annexin V (apoptosis) showed a 10-50-fold higher potency of IDA compared with DNR or DOX in the MDR variant cell lines. The difference in cytotoxicity was lower in the sensitive parental cell line (3-fold). These results are explained by a better intracellular uptake of IDA compared to DNR in resistant 8226 cell lines. The Pgp-inhibitor verapamil affected IDA uptake only in the most resistant cell line 8226-Dox40. This indicates that IDA is less sensitive than DNR to transport-mediated MDR. IDAol was at least 32-fold more cytotoxic than DOXol, and more susceptible to Pgp transport than IDA. These studies demonstrate that the efficacy of IDA in MDR MM cell lines is superior to that of DOX or DNR, and that IDA may become an important drug in the treatment of MM, especially in refractory disease.
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PMID:Idarubicin overcomes P-glycoprotein-related multidrug resistance: comparison with doxorubicin and daunorubicin in human multiple myeloma cell lines. 1037 47

Chronic lymphocytic leukemia (CLL) results in the accumulation of mature immunologically defective lymphocytes in GO phase. Lymphocytes from CLL patients were exposed to UVC radiation to determine whether these cells are capable of undergoing apoptosis, as a response to DNA damage. Lymphocytes from CLL patients were found to be readily killed by ultraviolet light-C (UVC) radiation. Cells from healthy donors were minimally affected by doses of UVC ten times higher then those which caused dramatic drops in the metabolism of CLL cells. At four hours after irradiation, the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) had dropped by 50% for CLL cells exposed to a dose of 10 J/m2. In contrast, there was no significant drop for healthy cells exposed to 100 J/m2. Cell death was measured by trypan blue staining, flow cytometry of Annexin V-PI stained cells, and Wright staining. By 24 hours after irradiation, significant amounts of cell death were observed in CLL cells at doses which had no significant effects on viability of healthy lymphocytes. The extreme sensitivity of CLL lymphocytes to UVC indicates that phototherapy should be explored as a potential treatment for this neoplasm.
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PMID:Hypersensitivity of lymphocytes from chronic lymphocytic leukemia patients to ultraviolet light-C radiation. 1061 62

Three oxidized analogs of cholesterol have been characterized for their ability to cause apoptotic cell death in CEM-C7-14 human leukemic cells. In addition to testing 15-ketocholestenol (K15), 15-ketocholestenol hydroxyethyl ether (CK15), and 7-ketocholesterol hydroxyethyl ether (CK7), an oxysterol of known apoptotic response, 25-hydroxycholesterol (25OHC), served as a standard for comparison. Growth studies based on dye exclusion by viable cells while using a sublethal concentration of oxysterols ranked their potency for cell kill as 25OHC > K15 > CK15 > CK7. Both the TUNEL assay (terminal deoxynucleotidyl transferase-mediated dUTP-X nick end labeling), which quantifies the amount of DNA nicks caused by a toxic agent, and the MTT assay, which measures cell metabolism and thus reflects cell viability, substantiated the same rank order. An ELISA assay for evaluating release of DNA fragments into the cytosol after treatment gave a similar potency order. The oncogene c-myc mRNA was suppressed by all three oxysterols, with 25OHC and K15 being the most potent suppressors. Hoechst and Annexin V staining documented that these oxysterols kill cells by an apoptotic pathway as evidenced by condensation of nuclear chromatin and plasma membrane inversion, respectively. From these in vitro studies, we believe that 25OHC, K15, and possibly CK15 have the potential to be chemotherapeutic agents.
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PMID:Structure-apoptotic potency evaluations of novel sterols using human leukemic cells. 1078 8

Prostaglandins of the E-series stimulate B lymphocytes by enhancing immunoglobulin-class switching and antibody production. Little is known about whether or not other prostaglandins affect B lineage cells and perhaps counterbalance the stimulatory effects of PGE2. PGD2 is a major product of cyclooxygenase in bone marrow and in macrophages, suggesting a role for this lipid product in immunological responses. PGD2 undergoes dehydration to the biologically active prostaglandin 15-deoxy-delta 12,14-PGJ2 (15d-PGJ2) that binds to the nuclear receptor known as peroxisome proliferator-activated receptor gamma (PPAR-gamma). We found that normal mouse B cells and a variety of B lymphoma cells (e.g., 70Z/3, WEHI-231, CH12, and J558) express PPAR-gamma mRNA and the 67-kDa PPAR-gamma protein. 15d-PGJ2 had a dose-dependent antiproliferative/cytotoxic effect on normal and malignant B cells, as shown by 3H-thymidine and MTT assays. Only PPAR-gamma agonists (i.e., thiazolidinediones) mimicked the effect of 15d-PGJ2 on B lineage cells, indicating that the mechanism by which 15d-PGJ2 negatively affects B lineage cells involves PPAR-gamma. The mechanism whereby PPAR-gamma agonists induced cytotoxicity is via apoptosis, as shown by Annexin V assay. PPAR-gamma agonists may serve as a counterbalance to the stimulating effects of PGE2, which promotes B-cell differentiation. The use of prostaglandins, such as 15d-PGJ2, and synthetic PPAR-gamma agonists to induce apoptosis in B lineage cells may lead to the development of therapies for fatal PGE2-resistant B lymphomas.
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PMID:PPAR-gamma-mediated regulation of normal and malignant B lineage cells. 1081 46

Oxidized low-density lipoprotein (oxLDL) plays a key role in the development of atherogenesis, partly by causing injury to vascular cells. However, different preparations of LDL, methods of oxidation, and/or active components often produce cellular effects of various degrees. To explore the quantitative relationship between dose and level of oxidation of the oxLDL utilized, we employed combinations of different levels of oxidation and concentrations of oxLDL to induce cell death in cultured vascular smooth muscle cells (VSMC). We also examined the effect of lysophosphatidylcholine (lysoPC), a putative active component of oxLDL, on VSMCs by determining, in parallel with a cytotoxicity test (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay), DNA fragmentation ([3H]thymidine release), and flow cytometric analyses. We found that oxLDL caused cytotoxicity in an oxidative level- and dose-dependent manner, lysoPC also caused dose-dependent cytotoxicity with or without serum. Fragmentation of DNA was observed in both oxLDL- and lysoPC-treated VSMCs. Furthermore, lysoPC-induced DNA ladder was also demonstrated by gel electrophoresis at a concentration of 25 micromol/l or higher. Flow cytometric analysis yielded similar results for oxLDL- and lysoPC-treated VSMC; namely, an accumulation in the fraction of cells in G(0)/G(1) phase with a reciprocal change in S-phase fraction. Membrane phosphatidylserine exposure, detected by annexin V staining, provided additional evidence that lysoPC induced significant apoptosis in VSMC. Taken together, the degree of oxLDL-induced cytotoxicity/apoptosis of VSMC depended on combined effects of oxLDL concentration and oxidative level. Moreover, lysoPC also elicited a dose-dependent apoptosis in addition to cytotoxicity.
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PMID:Lysophosphatidylcholine induces apoptotic and non-apoptotic death in vascular smooth muscle cells: in comparison with oxidized LDL. 1092 25

Estrogen has been shown to protect osteoblastic cells from apoptosis. Similarly, estrogen treatment preceding heat shock elevates heat shock protein 27 (hsp27) expression and increases thermoresistance in the murine estrogen receptor-transformed SMER14 osteoblastic cell line. Forced expression of hsp27 expression in other cell lines limits apoptosis. The purpose of this study was to examine the effects of estrogen on staurosporine-induced apoptosis in the context of hsp27 expression. Cell viability was measured by the MTT assay. Early apoptotic events were examined by fluorescent microscopy by using FITC-conjugated Annexin V staining. TUNEL labeling was used to compare the number of apoptotic nuclei following staurosporine treatment of estrogen pretreated or untreated cells. Estrogen treatment increased SMER14 cell viability, but not ROS17/2.8 cell viability, in the presence of staurosporine. Estrogen treatment also reduced annexin V staining and DNA fragmentation. Similar treatment increased SMER14 cell hsp27 levels. The concurrent reduction in induced apoptosis suggests a possible estrogenic mechanism for increasing and/or maintaining the number of viable osteoblasts in bone.
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PMID:Estrogen-induced resistance to osteoblast apoptosis is associated with increased hsp27 expression. 1105 10

Pseudomonas aeruginosa has been shown to enter into human endothelial cells in vitro. To ascertain the effects of bacterial intracellular (IC) infection, endothelial cells were exposed to PAK and PAO-1 strains for 1 h and treated with gentamicin in culture medium for different periods. P. aeruginosa induced a significant production of superoxide and hydrogen peroxide by endothelial cells. Concentrations of IC bacteria were reduced progressively with time and no viable PAO-1 was detected at 24 h after infection. However, IC infection led to killing of 32.2%+/-2.9 and 51.8%+/-3.5 of the cells infected with PAK and PAO-1, respectively, as determined by the MTT assay. By three criteria (transmission electron microscopy, DNA electrophoresis and reactivity with annexin V) infected cells exhibited features of apoptosis. Treatment of infected cells with anti-oxidants (catalase, tocopherol and N -acetyl-L-cysteine) significantly decreased the percentage of cell death. In contrast, treatment with aminoguanidine, an inhibitor of inducible NO synthase, increased significantly the killing of PAO-1 infected cells. Based on these results we speculate that in response to P. aeruginosa infection, endothelial cells increase the production of reactive oxygen intermediates to eliminate IC pathogens, but cells do not resist the oxidative stress and die by apoptosis.
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PMID:Pseudomonas aeruginosa induces apoptosis in human endothelial cells. 1109 19

Several studies have shown that ionizing radiation induces transcription of the TNFRSF6 (Fas) gene, leading to augmented TNFRSF6 protein levels at the surface of irradiated cells. We have examined TNFRSF6 expression in an apparently normal lymphocyte line and in a lymphocyte cell line derived from a patient with ataxia telangiectasia (AT) before and after exposure to radiation (0-10 Gy). Plasma membranes were isolated from normal lymphocytes and AT cells and subjected to Western blot analysis, using a TNFRSF6-specific monoclonal antibody to probe resolved proteins transferred onto nitrocellulose membranes. In both cell types, the presence of a 48-kDa band corresponding to the molecular mass of TNFRSF6 was revealed. Analysis of FITC-conjugated anti-TNFRSF6 antibody-stained normal lymphocytes and AT cells confirmed TNFRSF6 expression in both cell types. In MTT assays, AT cells treated with agonistic anti-TNFRSF6 Ab (CH.11) displayed a 25.9% decrease in cell viability, relative to cells treated with isotype-matched IgM Ab, suggesting the presence of a biologically active TNFRSF6 receptor at the AT cell surface. Exposure to cycloheximide (0-5 microg/ml), a metabolic inhibitor, enhanced sensitivity of AT cells to CH.11. Normal lymphocytes exhibited increased levels of apoptosis (approximately 34% cell death relative to cells treated with isotype-matched IgM Ab) when exposed to CH.11; however, the degree of cell death was not altered significantly with increasing concentrations of cycloheximide. When AT cells were exposed to 0.1, 0.5, 2 and 10 Gy, the activities of caspases 3 and 8 increased in a dose-dependent manner at 24 h postirradiation and reached a plateau by 72 h. A similar trend for activation of caspase 3 and 8 was observed in normal lymphocytes after irradiation. To assess the roles of TNFRSF6 and/or caspase 8 in radiation-induced cell death of AT and normal lymphocytes, and to determine whether hyper-radiosensitivity in AT cells is correlated with increased activity of these two components of the TNFRSF6 pathway, AT and normal lymphocytes were irradiated in the presence of ZB4, an anti-TNFRSF6 blocking antibody, and a caspase 8 inhibitor (Z-IETD-FMK). Apoptosis was determined by Annexin V staining using flow cytometry. Incubation with ZB4 anti-TNFRSF6 antibody did not alter the fraction of apoptotic cells in either AT cells or normal lymphocytes treated with doses of radiation ranging from 0-10 Gy. In contrast, apoptosis was significantly reduced in both cell lines in the presence of Z-IETD-FMK when samples were exposed to low-dose (< or = 2 Gy) radiation. Relative to control samples (those not incubated with Z-IETD-FMK), no difference in the level of apoptosis was observed in AT or normal lymphocytes treated with 10 Gy. These data indicate that: (a) despite radiation-induced up-regulation of TNFRSF6 at the cell surface, the death-promoting receptor does not play a role in radiation-mediated cytotoxicity; (b) apoptosis in lymphocytes irradiated with low (< or = 2 Gy) but not high doses (>2 Gy) proceeds at least in part through activation of caspase 8; and (3) since blocking anti-TNFRSF6 antibody (ZB4) did not reduce levels of apoptosis in irradiated AT cells to those of normal lymphocytes, TNFRSF6 is unlikely to play a significant role in the hyper-radiosensitivity exhibited by cells having the AT phenotype.
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PMID:Regulation of TNFRSF6 (Fas) expression in ataxia telangiectasia cells by ionizing radiation. 1109 18

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