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)

To investigate the mechanistic basis for the biological properties of anthocyanins, two aglycone anthocyanins [delphinidin (DY) and cyanidin (CY)] were used to examine their effects on cell cycle progression and on induction of apoptosis in human cancer cells (uterine carcinoma and colon adenocarcinoma cells) and in normal human fibroblasts. These compounds differ in the number and position of hydroxyl groups on the beta ring in the molecular structure. Cellular uptake of anthocyanins was confirmed by HPLC analysis and no metabolites were detected. The clonogenic assay showed that CY induces a dose-dependent growth inhibitory effect only in fibroblasts. This effect was confirmed by flow cytometric analysis, showing a significant reduction of cells in S phase. In contrast, DP inhibited cell growth in normal and tumour cell lines. This event is accompanied in fibroblasts by an accumulation of cells in the S phase suggesting a block in the transition from S to G2 phase. On the other hand, in tumour cell lines we observed a reduction of cells in G1 phase, paralleled by the appearance of a fraction of cells with a hypodiploid DNA content, thus demonstrating an apoptotic effect by DP. The occurrence of apoptosis induced by DP was confirmed by morphological and biochemical features, including nuclear condensation and fragmentation, annexin V staining, DNA laddering and poly(ADP-ribose) polymerase-1-proteolysis. Furthermore, the mitochondrial membrane potential of apoptotic cells after treatment with DP was significantly lost. The different effects exerted by DP as compared with CY suggest that the presence of the three hydroxyl groups on the beta ring in the molecular structure of DP may be important for its greater biological activity.
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PMID:Anthocyanins induce cell cycle perturbations and apoptosis in different human cell lines. 1501 60

We reported that 50% of cisplatin-induced apoptosis in primary cultures of rabbit renal proximal tubule cells (RPTC) proceeded via caspase-independent mechanisms. This study determined whether caspase-independent apoptosis, using multiple and diverse endpoints, could be produced by toxicants other than cisplatin and in cell models other than RPTC. Cisplatin, staurosporine, vincristine, and A23187 induced RPTC apoptosis after 24 h as indicated by 2- to 2.5-fold increases in annexin V and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining, and 2- to 10-fold increases in cell shrinkage. All toxicants induced 8- to 50-fold increases in caspase-3 activities, which were completely inhibited by the pan caspase inhibitor ZVAD-fmk. However, ZVAD-fmk only decreased cisplatin- and staurosporine-induced annexin V staining and cell shrinkage 30 to 50%, staurosporine-induced TUNEL staining 30%, and did not affect vincristine- or A23187-induced RPTC apoptosis. All toxicants tested induced apoptotic RPTC nuclear morphology. However, similar to its effect on annexin V and TUNEL staining, ZVAD-fmk only partially inhibited toxicant-induced apoptotic nuclear morphology. Cisplatin and staurosporine also induced annexin V staining in the human epithelial cancer cell lines Caki-1 (kidney carcinoma), A549 (lung carcinoma), A172 (glioblastoma), and murine lymphocytic leukemia L1210 cells. Pretreatment with ZVAD-fmk inhibited cisplatin-induced annexin V staining in Caki-1, A172, and A549 cells but had no affect in L1210 cells. Pretreatment with ZVAD-fmk did not decrease staurosporine-induced annexin V staining in Caki-1, A549, L1210, and A172 cells. These results suggest that a significant fraction of apoptosis induced by diverse toxicants in renal epithelial cells and in four different cancer cell lines is caspase-independent.
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PMID:Identification of caspase-independent apoptosis in epithelial and cancer cells. 1502 82

Incorporation of bromodeoxyuridine (BrdU) during DNA replication is frequently used for cell cycle analysis. The flow cytometric BrdU/Hoechst quenching technique is conducive to high-resolution assessment of cell cycle kinetics, but requires continuous BrdU treatment, which may have cytostatic or cytotoxic effects. Here, we have examined the impact of BrdU on the proliferation of BT474 and SK-BR-3 breast cancer cell lines and compared the observed effects with cell proliferation of RT4 and J82 bladder carcinoma cells, previously described to be sensitive and insensitive to BrdU, respectively. Both uni- and bi-parametric DNA measurements were performed to identify BrdU-induced alterations in the S-phase fraction and in cell cycle progression. An annexinV/propidium iodide (PI) assay was used to identify potential induction of apoptosis by BrdU. Proliferative activity in BT474, SK-BR-3, and RT4 cultures was reduced in different cell cycle phases due to continuous treatment with 60, 5.0, and 3.5 micro m BrdU. This effect, which was not found in J82 cultures, was dependent on exposure time (96 versus 48 h) and was also dose-dependent for RT4 and SK-BR-3. BrdU application does not induce apoptosis or necrosis as revealed with the annexin V/PI assay. We concluded that continuous BrdU treatment did not affect cell viability, but essentially alters cell cycle progression in three out of four cell lines tested. Cell-type specific validation of the feasibility of the powerful BrdU/Hoechst quenching technique is required and recommended.
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PMID:Exposure to continuous bromodeoxyuridine (BrdU) differentially affects cell cycle progression of human breast and bladder cancer cell lines. 1503 May 53

Anti-tumor associated antigen (TAA).CD3.CD28 trispecific antibody(TsAb) is able to provide two signals for fully and continuously activation of T lymphocytes and recruit them around tumor cells, presenting an attractive concept in tumor immunotherapy. Here, a new single chain trispecific antibody (scTsAb), named CEA-scTsAb, was constructed by fusion of anti-CEA (Carcinoma Embryonic Antigen) single chain antibody (scFv), anti-CD3 scFv and anti-CD28 VH, spaced by polypeptide interlinkers taken from the fragment of constant region (FC) of human IgG and human serum albumin (HSA). It was expressed in Escherichia coli at low temperature (30 degrees C) with up to 50% of the antibody being present in soluble form. After one step of DEAE anion chromatography, the soluble product was sufficiently pure for further in vitro activity assays. First, it was proved that CEA-scTsAb could recognize three antigens (CEA, CD28 and Jurkat cell membrane antigen) specifically and could distinguish antigen positive cells from antigen negative cells in vitro. Then fresh PBMC (peripheral blood mononuclear cells), without being pre-treated by co-stimulatory reagents, such as IL-2 or CD28 mAb, were used as effector cells to test their ability to mediate tumor specific cytolysis of CEA-positive tumor cells, SW1116. It was found by photomicrography that T lymphocytes were attracted to SW1116 cells in the presence of CEA-scTsAb, which resulted in effective cytolysis of tumor cells. As shown by MTT assay, the efficacy of tumor specific cytolysis mediated by CEA-scTsAb related to both the quantity and activation of PBMC. At an effector cells/target cells ratio (E/T) of 5, it was proved by dual-color FACS with propidium iodide (PI) and FITC-annexin V that both necrosis and apoptosis of tumor cells were causes of tumor specific cytolysis. In summary, a new single chain trispecific (CEA x CD3 x CD28) antibody was constructed and characterized carefully in this paper and was found to possess functions: (i) to activate T lymphocytes independently of additional co-stimulatory signal, (ii) to attract activated T lymphocytes around CEA-positive tumor cells, (iii) to attack CEA-positive tumor cells with recruited T lymphocytes. Because it recognizes a widely distributed tumor antigen (CEA), with moderate molecular weight (about 75 kDa) and a simple production procedure, and is able to mediate a high level of tumor specific cytolysis without any additional co-stimulating reagents, CEA-scTsAb is very promising for the task of immunotherapy in future.
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PMID:A new recombinant single chain trispecific antibody recruits T lymphocytes to kill CEA (carcinoma embryonic antigen) positive tumor cells in vitro efficiently. 1511 82

Epidemiological studies and clinical observations suggest that nonsteroidal anti-inflammatory drugs and certain selective cyclooxygenase (COX)-2 inhibitors may reduce the relative risk of clinically evident prostate cancer. This prompted us to investigate the chemopreventive potential of celecoxib, a selective COX-2 inhibitor, against prostate carcinogenesis in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Similar to prostate cancer in humans, prostate malignancies in TRAMP mice progress from precursor intraepithelial lesions, to invasive carcinoma that metastasizes to lymph nodes, liver, lungs, and occasionally to bone. The basal enzyme activity and protein expression of COX-2 is significantly higher (>4-fold) in the dorsolateral prostate of TRAMP mice up to 24 weeks of age compared with their nontransgenic littermates. Eight-week-old TRAMP mice were randomly divided and fed either control diet (AIN 76A) or a custom prepared AIN 76A diet containing 1500-ppm celecoxib ad libitum for 24 weeks, a dosage that would compare with the normal recommended dose for the treatment of human disease. Studies from two independent experiments, each consisting of 10 mice on test, showed that the cumulative incidence of prostate cancer development at 32 weeks of age in animals fed with AIN 76A diet was 100% (20 of 20) as observed by tumor palpation, whereas 65% (13 of 20), 35% (7 of 20), and 20% (4 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, and liver. Celecoxib supplementation to TRAMP mice from 8-32 weeks of age exhibited significant reduction in tumor development (5 of 20) with no signs of metastasis. Celecoxib feeding resulted in a significant decrease in prostate (56%; P < 0.0003) and genitourinary weight (48%; P < 0.008). Sequential magnetic resonance imaging analysis of celecoxib-fed mice documented lower prostate volume compared with the AIN 76A-fed group. Histopathological examination of celecoxib-fed animals showed reduced proliferation, and down-modulation of COX-2 and prostaglandin E2 levels in the dorsolateral prostate and plasma, respectively. These results correlated with retention of antimetastasis markers, viz E-cadherin, and alpha- and beta-catenin, along with a significant decrease in vascular endothelial growth factor protein expression. Celecoxib supplementation also resulted in enhanced in vivo apoptosis in the prostate as monitored by several techniques including a recently perfected technique of 99mTc-labeled annexin V in live animals followed by phosphor imaging. One striking observation in an additional study was that celecoxib feeding to mice with established tumors (16 weeks of age) significantly improved their overall survival (P = 0.014), compared with AIN 76A-fed group. Our findings suggest that celecoxib may be useful in chemoprevention of prostate cancer.
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PMID:Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model. 1512 78

Protein patterns in six samples from primary vaginal cancers, in five from normal vaginal tissue and in five primary cervical cancers, were analysed using two-dimensional polyacrylamide gel electrophoresis (2-DE). Protein expression profile was evaluated by computer-assisted image analysis (PDQUEST) and proteins were subsequently identified using matrix-assisted laser desorption/ionisation mass spectrometry. The aim was to analyse the protein expression profiles using the hierarchical clustering method in vaginal carcinoma and to compare them with the protein pattern in cervical carcinoma in order to find a helpful tool for correct classification and for increased biomedical knowledge. Protein expression data of a distinct set of 33 protein spots were differentially expressed. These differences were statistically significant (Mann-Whitney signed-Ranked Test, P<0.05) between normal tissue, vaginal and cervical cancer. Furthermore, protein profiles of pairs of primary vaginal and cervical cancers were found to be very similar. Some of the protein spots that have so far been identified include Tropomyosin 1, cytokeratin 5, 15 and 17, Apolipoprotein A1, Annexin V, Glutathione-S-transferase. Others are the stress-related proteins, calreticulin, HSP 27 and HSP 70. We conclude that cluster analysis of proteomics data allows accurate discrimination between normal vaginal mucosa, primary vaginal and primary cervical cancer. However, vaginal and cervical carcinomas also appear to be relatively homogeneous in their gene expression, indicating similar carcinogenic pathways. There might, further, be a possibility to identify tumour-specific markers among the proteins that are differentially expressed. The results from this study have to be confirmed by more comprehensive studies in the future.
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PMID:Protein expression patterns in primary carcinoma of the vagina. 1519 89

Cellular calcium has been implicated in induction of apoptosis. We have shown that 1,25(OH)(2)D(3)-induced apoptosis is associated with a sustained increase in concentration of intracellular Ca(2+) ([Ca(2+)](i)) resulting from depletion of the endoplasmic reticulum (ER) Ca(2+) stores and activation of the voltage-insensitive Ca(2+) entry pathway [1,25-Dihydroxyvitamin D(3), intracellular Ca(2+) and apoptosis in breast cancer cells, in: A.W. Norman, R. Bouillon, M. Thomasset (Eds.), Vitamin D: Chemistry, Biology and Clinical Applications of the Steroid Hormone, University of California, Riverside, 1997, pp. 473-474; Vitamin D and intracellular calcium, in: P. Quinn, V. Kagan (Eds.), Subcellular Biochemistry: Fat-Soluble Vitamins, Plenum Press, New York, 1998, pp. 271-297; 1,25-Dihydroxyvitamin D(3) and calcium signaling, in: A.W. Norman, R. Bouillon, M. Thomasset (Eds.), Vitamin D Endocrine System: Structural, Biological, Genetic and Clinical Aspects, University of California, Riverside, 2000, pp. 715-718; 1,25-Dihydroxyvitamin D(3) triggers calcium-mediated apoptosis in breast cancer cells, in: A.W. Norman, R. Bouillon, M. Thomasset (Eds.), Vitamin D Endocrine System: Structural, Biological, Genetic and Clinical Aspects, University of California, Riverside, 2000, pp. 399-402; Endocrine 9 (1998) 321]. This study was undertaken to investigate mechanism of 1,25(OH)(2)D(3)-induced apoptosis in breast cancer cells and compare effects of the hormone on Ca(2+) and apoptosis in cancer and normal human mammary epithelial cells. The treatment of MCF-7 breast cancer cells with 1,25(OH)(2)D(3) induced a sustained increase in [Ca(2+)](i) and activated the Ca(2+)-dependent proapoptotic proteases, micro-calpain and caspase-12, as evaluated with antibodies to active (cleaved) forms of the enzymes and the calpain substrate. The selective inhibition of Ca(2+) binding sites of micro-calpain decreased apoptotic indices in the 1,25(OH)(2)D(3)-treated cells. 1,25(OH)(2)D(3) did not induce apoptosis in normal human mammary epithelial cells (HMECs), as evaluated by DNA fragmentation (TUNEL), loss of the plasma membrane asymmetry (Annexin V assay) and morphological criteria. In these cells, 1,25(OH)(2)D(3) triggered a transient Ca(2+) response, which was not accompanied by the calpain and caspase activation. HMEC, but not MCF-7 cells expressed the Ca(2+) binding protein calbindin-D(28k) and buffered Ca(2+) increases induced by a Ca(2+) ionophore ionomycin. In conclusion, we have identified the novel apoptotic pathway in breast carcinoma cells treated with 1,25(OH)(2)D(3): increase in [Ca(2+)](i) -->micro-calpain activation --> caspase-12 activation --> apoptosis. Our findings also imply that differences of Ca(2+) regulatory mechanisms in breast cancer versus normal mammary epithelial cells underlay resistance of normal cells and susceptibility of cancer cells to 1,25(OH)(2)D(3)-induced Ca(2+)-mediated apoptosis.
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PMID:Calcium as a mediator of 1,25-dihydroxyvitamin D3-induced apoptosis. 1522 13

S100 proteins belong to the EF-hand Ca2+-binding protein family and are involved in the regulation of a variety of cellular processes. Individual S100 proteins are expressed in cell- and tissue-specific manners, and functional deterioration of S100 proteins leads to a number of human diseases, including cancer. We previously demonstrated that S100C/A11 was translocated to nuclei and inhibited DNA synthesis in human keratinocytes when exposed to high Ca2+. In the present study we examined the effects of synthetic partial peptides of S100C/A11 on human carcinoma cell lines. Only an N-terminal peptide with 19 amino acid residues (MAK19) showed cytotoxicity to the cell lines in dose- and time-dependent manners when introduced into cells by flanking the HIV-TAT protein transduction domain (TAT-MAK19). Pulse field electrophoresis revealed that DNA of the treated cells was partially degradated. Annexin V, a marker of cellular apoptosis, was detected in the cells treated with TAT-MAK19 by immunostaining and flow cytometry. The induction of apoptotic cell death was apparently independent of p53, p21WAF1/CIP1, and caspase activity, but treatment with TAT-MAK19 resulted in partial translocation of apoptosis-inducing factor (AIF) from the cytoplasm to nuclei. These results indicate that MAK19 induces apoptosis in human cell lines and may therefore lead to the establishment of a new molecular target for the treatment of human cancer.
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PMID:Introduction of an N-terminal peptide of S100C/A11 into human cells induces apoptotic cell death. 1524

Screening of synthetic retinoids for activity against prostate carcinoma cell lines has identified antagonists of retinoic acid receptors (RARs) as potent growth inhibitors (Hammond et al, 2001, Br J Cancer 85, 453-462). Here we report that 5 days of exposure to a high-affinity pan-RAR antagonist (AGN194310) abolished growth of prostate carcinoma cells from 14 out of 14 patients, with half-maximal inhibition between 200 and 800 nM. It had similar effects (at approximately 250 nM) on the prostate carcinoma lines LNCaP, DU-145 and PC-3. AGN194310 inhibited the growth of normal prostate epithelium cells less potently, by 50% at approximately 1 microM. The growth of tumour cells was also inhibited more than that of normal cells when RARbeta together with RARgamma, but not RARalpha alone, were antagonised. Treatment of LNCaP cells with AGN194310 arrested them in G1 of cell cycle within 12 h, with an accompanying rise in the level of p21(waf1). The cells underwent apoptosis within 3 days, as indicated by mitochondrial depolarisation, Annexin V binding and DNA fragmentation. Apoptosis was caspase-independent: caspases were neither cleaved nor activated, and DNA fragmentation was unaffected by the pan-caspase inhibitor Z-VAD-FMK. The ability of AGN 194310 to induce apoptosis of prostate cancer cells and its differential effect on malignant and normal prostate epithelial cells suggests that this compound may be useful in the treatment of prostate cancer.
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PMID:An antagonist of retinoic acid receptors more effectively inhibits growth of human prostate cancer cells than normal prostate epithelium. 1526 11

Exposure to environmental radiation and the application of new clinical modalities, such as radioimmunotherapy, have heightened the need to understand cellular responses to low dose and low-dose rate ionizing radiation. Many tumor cell lines have been observed to exhibit a hypersensitivity to radiation doses <50 cGy, which manifests as a significant deviation from the clonogenic survival response predicted by a linear-quadratic fit to higher doses. However, the underlying processes for this phenomenon remain unclear. Using a gel microdrop/flow cytometry assay to monitor single cell proliferation at early times postirradiation, we examined the response of human A549 lung carcinoma, T98G glioma, and MCF7 breast carcinoma cell lines exposed to gamma radiation doses from 0 to 200 cGy delivered at 0.18 and 22 cGy/min. The A549 and T98G cells, but not MCF7 cells, showed the marked hypersensitivity at doses <50 cGy. To further characterize the low-dose hypersensitivity, we examined the influence of low-dose radiation on cell cycle status and apoptosis by assays for active caspase-3 and phosphatidylserine translocation (Annexin V binding). We observed that caspase-3 activation and Annexin V binding mirrored the proliferation curves for the cell lines. Furthermore, the low-dose hypersensitivity and Annexin V binding to irradiated A549 and T98G cells were eliminated by treating the cells with pifithrin, an inhibitor of p53. When p53-inactive cell lines (2800T skin fibroblasts and HCT116 colorectal carcinoma cells) were examined for similar patterns, we found that there was no hyperradiosensitivity and apoptosis was not detectable by Annexin V or caspase-3 assays. Our data therefore suggest that low-dose hypersensitivity is associated with p53-dependent apoptosis.
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PMID:Low-dose radiation hypersensitivity is associated with p53-dependent apoptosis. 1549 30


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