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)

Recent data have renewed the interest for arsenic-containing compounds as anticancer agents. In particular, arsenic trioxide (As2O3) has been demonstrated to be an effective drug in the treatment of acute promyelocytic leukemia by inducing programmed cell death in leukemic cells both in vitro and in vivo. This prompted us to study the in vitro effects of As2O3 and of another arsenical derivative, the organic compound melarsoprol, on human myeloma cells and on the plasma cell differentiation of normal B cells. At pharmacological concentrations (10(-8) to 10(-6) mol/L), As2O3 and melarsoprol caused a dose- and time-dependent inhibition of survival and growth in myeloma cell lines that was, in some, similar to that of acute promyelocytic leukemia cells. Both arsenical compounds induced plasma cell apoptosis, as assessed by 4',6-diamidino-2-phenylindole staining, detection of phosphatidylserine at the cell surface using annexin V, and by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay. As2O3 and melarsoprol also inhibited viability and growth and induced apoptosis in plasma-cell enriched preparations from the bone marrow or blood of myeloma patients. In nonseparated bone marrow samples, both arsenical compounds triggered death in myeloma cells while sparing most myeloid cells, as demonstrated by double staining with annexin V and CD38 or CD15 antibodies. In primary myeloma cells as in cell lines, interleukin 6 did not prevent arsenic-induced cell death or growth inhibition, and no synergistic effect was observed with IFN-alpha. In contrast to As2O3, melarsoprol only slightly reduced the plasma cell differentiation of normal B cells induced by pokeweed mitogen. Both pokeweed mitogen-induced normal plasma cells and malignant plasma cells showed a normal nuclear distribution of PML protein, which was disrupted by As2O3 but not by melarsoprol, suggesting that the two arsenical derivatives acted by different mechanisms. These results point to the use of arsenical derivatives as investigational drugs in the treatment of multiple myeloma.
Cancer Res 1999 Mar 01
PMID:Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines and in plasma cells from myeloma patients. 1007 Sep 61

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

Prostatic cancers are well-known to be sensitive to heat stress. However, the mechanism by which the cancer cells are killed by high temperature remains poorly understood. The present study was undertaken to determine the anti-proliferative effects of heat stress on the prostatic cancer cells in culture. Heat shock at 43 degrees C inhibited the cell growth of three different prostatic cell lines. Flow cytometrical analysis using BrdU and PI showed a decrease in the proportion of cells in an S phase, accompanied by cell accumulation in G1 and G2, in both JCA-1 and PC-3 but not in LNcap. Both JCA-1 and PC-3 presented a strong expression of hsp70 at 37 degrees C. The heat shock caused apparent enhancement of the expression of hsp70 through the cell cycle. A treatment at 43 degrees C for 8 hours resulted in not only an apparent increment of positive hsp70 cells, but cells with subdiploid DNA content in LNcap. Flow cytometrical analysis by FITC-labeled Annexin V showed increment of apoptotic cells at 43 degrees C for 8 hours in LNcap cells. The results suggest that apoptosis is an important pathway of heat-induced killing of these cells. In conclusion, the cell growth of prostatic cancers may be affected by the temperature through relationship of the cell cycle and hsp70.
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PMID:[Anti-proliferative effects of heating on the human prostatic carcinoma cells in culture]. 1008 78

Two erythroleukemia cell lines have been established from the splenic lesions of red blood cell-type pyruvate kinase (R-PK) activity-deficient mice of CBA/N origin infected with a polycythemic strain of Friend leukemia virus complex (FVp). Ten to 30% of the cells of these cell lines undergo apoptotic changes in routine passage, as shown by nuclear fragmentation, DNA laddering, DNA content (propidium iodide (PI) staining), and annexin V binding assay. In these cells, however, although adenosine 5'-triphosphate (ATP) levels were lower than in the control cells, the mitochondrial inner transmembrane potential (delta psi m), detected by rhodamine 123 (R123) and diSC3(5) staining, remained unchanged until the final stage of apoptosis. No evidence was obtained to relate this finding to R-PK mutation due to difficulty in cloning stable, conditionally inducible R-PK gene transfectants. However, low delta psi m in the apoptotic cell population of the control T3-K-1 (K-1) and T3-CI-2-0 (2-0) Friend erythroleukemia cells supports a possible relationship, as do results obtained in two Friend erythroleukemia cells recently isolated from normal CBA/N mice. These cell lines are expected to be useful for clarifying both the primary apoptotic changes independent of mitochondrial dysfunction and the PK-isozyme changes during erythrodifferentiation, for example, the decreased muscle type 2 (M2) PK level. Modification of growth signals in these cell lines may modulate differentiation and/or apoptosis and allow further elucidation of the signaling networks.
Jpn J Cancer Res 1999 Feb
PMID:Apoptotic changes precede mitochondrial dysfunction in red cell-type pyruvate kinase mutant mouse erythroleukemia cell lines. 1018 87

Fresh, superficial transitional cell carcinomas (TCCs) of low-grade atypia (3 grade I, Ta; 6 grade II, Ta), as well as primary cultures derived from them were labeled with [35S]methionine for 16 h, between 2 and 6 days after inoculation. Whole protein extracts were subjected to IEF (isoelectric focusing) two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) followed by autoradiography. Proteins were identified by a combination of proteomic technologies that included microsequencing, mass spectrometry, 2-D PAGE immunoblotting and comparison with the bladder TCC protein database available on the internet (http://biobase.dk/cgi-bin/celis). Comparison of the IEF 2-D gel protein profiles of fresh tumors and their primary cultures showed that the overall expression profiles were strikingly similar, although differing significantly in the levels of several proteins whose rate of synthesis was differentially regulated in at least 85% of the tumor/culture pairs as a result of the short-term culturing. Most of the proteins affected by culturing were upregulated and among them we identified components of the cytoskeleton (keratin 18, gelsolin and tropomyosin 3), a molecular chaperone (hsp 28), aldose reductase, GST pi, metastasin, synuclein, the calreticulin precursor and three polypeptides of unknown identity. Only four major proteins were downregulated, and these included two fatty acid-binding proteins (FABP:FABP5 and A-FABP) which are thought to play a role in growth control, the differentiation-associated keratin 20, and the calcium-binding protein annexin V. Proteins that were differentially regulated in only some of the cultured tumors included alpha-enolase, triosphosphate isomerase, members of the 14-3-3 family, hnRNPs F and H, PGDH, hsp (heat-shock protein) 60, BIP, the interleukin-1 receptor antagonist, the nucleolar protein B23, as well as several proteins of yet unknown identity. The suitability of in vitro bladder tumor culture models to study complex biological phenomena such as malignancy and invasion is discussed.
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PMID:Short-term culturing of low-grade superficial bladder transitional cell carcinomas leads to changes in the expression levels of several proteins involved in key cellular activities. 1019 43

Apoptosis of tumor cells and of apparently normal renal cells (ANRC) isolated from the same kidney in 42 untreated patients with renal carcinomas (RC) was evaluated. Thirty five of the investigated tumors were of Grawitz type in different grades of differentiation. The intensity of the apoptotic process was routinely assessed by propidium iodide staining and flow-cytometry analysis. Similar results were obtained in the same cases by using TUNEL assay, by staining with annexin V and by DNA electrophoresis. In 85% of Grawitz carcinomas the proportion of apoptotic tumor cells was quite high, with mean% +/- SD of 57.7+/-27.3, whereas in transitional cell carcinoma of the bladder (TCC), the mean percentage of cells in apoptosis was of 22.3+/-13.9. Unexpectedly, in ANRC displaying normal morphology and normal DNA content (diploidy), the mean% +/- SD of apoptotic cells were found to exceed that of apoptotic tumor cells, 79.2+/-21.6. The percentages of cells expressing Fas receptor and/or Fas ligand varied between large ranges in both tumor and ANRC, thus suggesting that other mechanisms are also involved in the activation of apoptosis. Immunohistochemical studies showed that the intensity of apoptosis correlated well with high p-53 and low bcl-2 expression. The intensity of apoptosis was generally not correlated with the cell proliferation index (S phase fraction), suggesting that in RC apoptosis can be activated in any stage of the cell cycle. Further investigations are necessary to understand the peculiar behaviour of tumor cells as well as of ANRC in renal carcinomas as compared to other types of malignancies.
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PMID:Evaluation of apoptosis of tumor and of apparently normal cells in human renal carcinoma. 1021 1

It is known that steroids can induce cell surface receptor aggregation followed by activation of receptor and nonreceptor tyrosine kinases. It has been shown recently that 17beta-estradiol (E2) can stimulate the Src/p21ras/mitogen-activated protein kinase pathway in breast cancer cells, and this effect is supposed to mediate the E2-induced stimulation of breast cancer cell proliferation, possibly via activation of the c-fos and c-jun early genes or of genes involved in cell cycle control. Here we demonstrate the existence of an alternative mechanism of the cancer-promoting effect of E2. Human breast cancer cells (MCF-7) were exposed to the known proapoptotic agent vitamin E succinate (VES), added alone or together with different concentrations of E2. E2 conjugated with bovine serum albumin (E2-BSA), which cannot cross the plasma membrane of living cells, was also used in some experiments to assess whether E2 acted on the cell surface or at intracellular receptors. Apoptosis was analyzed by fluorescence-activated cell sorting after cell staining with propidium iodide and FITC-labeled annexin V. E2 showed a concentration-dependent stimulatory effect on spontaneous apoptosis but inhibited the VES-induced apoptosis. However, effects produced by the same molar concentrations of E2 were different when the hormone was free and when it was used in the form of the E2-BSA conjugate. The effects of E2 and E2-BSA were sensitive to genistein, a tyrosine kinase inhibitor. These data show that E2 modulates apoptosis of breast cancer cells, probably acting both at the cell surface and inside the cells. Tyrosine phosphorylation is involved in the signaling pathways mediating this E2 effect.
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PMID:Estradiol modulates breast cancer cell apoptosis: a novel nongenomic steroid action relevant to carcinogenesis. 1032 69

Programmed cell death, apoptosis, is an inducible, organized, energy requiring form of demise that results in the disappearance of a cell without the induction of an inflammatory response. Apoptotic cell death is strikingly different than necrotic death, which is disorderly, does not require energy and results in local inflammation, usually secondary to sudden release of intracellular contents. Apoptosis is induced when cells undergo severe injury to their nucleus, as occurs following exposure to gamma or X-radiation, or mitcochondria, as occurs in a variety of viral illnesses. Apoptosis can also be induced by external signals, such as interaction of fas ligand with fas receptors. Once the cell is committed to apoptosis, the caspase enzyme cascade is activated. An early effect of caspase activation is the rapid expression of phosphatidylserine on the external leaflet of the cell membrane. Membrane bound phosphatidylserine expression serves as a signal to surrounding cells, identifying the expressing cell as undergoing apoptosis. A deficiency or an excess of programmed cell death is an integral component of autoimmune disorders, transplant rejection and cancer. A technique to image programmed cell death would be useful to assist in the development of drugs designed to treat these diseases, and to monitor the effectiveness of therapy. The sudden expression of phosphatidylserine on the cell membrane is a target that could be used for this purpose. A 35 kD physiologic protein, Annexin V lipocortin, binds with nanomolar affinity to membrane bound phosphatidylserine. Annexin V has been radiolabeled with Technetium-99m by direct coupling to free sulfhydryl groups, and through the hydrazinonicatinamide and N2S2 linking agents. The biodistribution of the agents labeled with each of the methods is slightly different. In all cases the radiopharmaceutical binds to cells undergoing apoptosis in vitro, and permits imaging of the process in experimental animals.
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PMID:Dying a thousand deaths. Radionuclide imaging of apoptosis. 1042 13

The induction of apoptosis in T cells is one of several mechanisms by which tumors escape immune recognition. We have investigated whether tumors induce apoptosis in dendritic cells (DC) by co-culture of murine or human DC with different tumor cell lines for 4-48 h. Analysis of DC morphological features, JAM assay, TUNEL, caspase-3-like and transglutaminase activity, Annexin V binding, and DNA fragmentation assays revealed a time- and dose-dependent induction of apoptosis in DC by tumor-derived factors. This finding is both effector and target specific. The mechanism of tumor-induced DC apoptosis involved regulation of Bcl-2 and Bax expression. Double staining of both murine and human tumor tissues confirmed that tumor-associated DC undergo apoptotic death in vivo. DC isolated from tumor tissue showed significantly higher levels of apoptosis as determined by TUNEL assay when compared with DC isolated from spleen. These findings demonstrate that tumors induce apoptosis in DC and suggest a new mechanism of tumor escape from immune recognition. DC protection from apoptosis will lead to improvement of DC-based immunotherapies for cancer and other immune diseases.
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PMID:Tumor's other immune targets: dendritic cells. 1044 78

HeLa X human skin fibroblast hybrid cells have been developed into a model for radiation-induced neoplastic transformation of human cells. Previous studies indicate that the appearance of neoplastically transformed foci in this system is delayed for several population doublings after irradiation and appears to involve the loss of putative tumor suppressor loci on fibroblast chromosomes 11 and 14. We now show that after treatment with 7 Gy of X-rays, transformed foci initiation correlates with delayed apoptosis initiated in the progeny of the irradiated cells after 10-12 cell divisions and with reduced plating efficiency (delayed death). The cells develop classic apoptotic morphology, positive terminal deoxynucleotidyl transferase-mediated nick end labeling and phosphatidylserine (annexin V) staining, and cleavage of poly(ADP-ribose) polymerase. In addition, a delayed induction of the p53 protein and the proapoptotic Bax protein is evident over a week after radiation exposure. We propose that a delayed build-up of mitosis-dependent genomic DNA damage or a loss of genetic material over time (10-12 cell divisions postirradiation) has two relevant outcomes: (a) cell death due to the delayed induction of a p53-dependent apoptosis; and (b) neoplastic transformation of a minor subset of survivors that has lost fibroblast chromosomes 11 and 14 (tumor suppressor loci for this system) and has either evaded apoptosis or not acquired enough genetic damage to induce apoptosis. It is postulated that both phenomena result from X-ray-induced, translesion-mediated genomic instability.
Cancer Res 1999 Aug 15
PMID:Delayed apoptotic responses associated with radiation-induced neoplastic transformation of human hybrid cells. 1046 94


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