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)

Arsenic trioxide (ATO) induces apoptosis in a range of solid tumors and leukemia cells, and has been clinically applied for the treatment of acute promyelocytic leukemia with confirmed efficacy. Acute megakaryocytic leukemia (AMKL) is an aggressive malignancy with poor prognosis, if bone marrow transplantation is not possible. In this study, we applied flow cytometry, Western blot analysis and microarray techniques to investigate the effects of ATO on apoptosis and the cell division cycle of AMKL cell lines CHRF-288-11 and MEG-01. Our data demonstrated that ATO is a potent agent against AMKL as indicated by apoptotic markers, Annexin V and caspase-3. ATO activated the intrinsic (mitochondrial) pathway of apoptosis, which involved disrupting mitochondrial membrane potential, increased Bax/Bcl-2 ratio and caspase-9 activation, as well as the extrinsic (death receptor) pathway mediated by Fas and caspase-8 activation. We provided the first evidence that ATO stimulated expressions of CD137 mRNA and protein, which might be relevant to the extrinsic mechanism. ATO induced delays of cell cycle progression at S phase and arrest at G2/M phase of AMKL cells, but caspase-3 expression appeared not to be phase-specific. The multiple-signaling mechanism of ATO warrants it a potential agent to incorporate in the treatment regimen of AMKL.
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PMID:Arsenic trioxide mediates intrinsic and extrinsic pathways of apoptosis and cell cycle arrest in acute megakaryocytic leukemia. 1601 Apr 37

Therapeutic radiation and subsequent detection of tumor cell death has been performed mainly in vitro systems, making it difficult to accurately characterize the mechanisms of tumor cell death after radiosurgery. To better characterize what occurs to glioma cells after radiation therapy, we developed a rat model using the 9L gliosarcoma cell line implanted reproducibly to the caudate nucleus in rats. After 1 Gy radiation, 9L tumors in vivo induced mainly necrosis (determined by trypan blue exclusion) of 10 - 74 % at 6 - 72 hours post-radiation. This is in contrast to a previous in vitro study which demonstrated that 18 Gy of radiation induces considerably less cell death as determined by trypan blue exclusion (approximately 20 - 25 % at 6 - 72 hours post-radiation). However, significant amounts of apoptosis were detected as early as 6 hours after radiation. Apoptosis determination was by annexin V (marker of early apoptosis) and propidium iodide (marker of membrane stability) staining followed by flow cytometry detection. When caspase 3 and caspase 8 enzymatic activities (mediators of apoptosis) were measured from freshly explanted tumor cells, peak activity was found 6 hours after 1 Gy radiation (p < 0.01). Taken together, these data indicate the presence of apoptosis early after radiation therapy (1 Gy) which progressed to necrosis in a unique in vivo model of gliosarcoma that may prove useful in determining new therapeutic approaches to radiation therapy and tumor cell biology.
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PMID:Gliosarcoma cell death after radiosurgery in a rat model. 1601 90

Phenylethyl isothiocyanate (PEITC) is a well recognized potential chemopreventive compound against human cancers. In this study, the molecular mechanism of PEITC-induced apoptosis was examined with two antioxidants (N-acetyl-cysteine and vitamin E) and a caspase-3 inhibitor (z-DEVD-fmk). Results demonstrated that PEITC significantly induced human hepatoma PLC/PRF/5 (CD95-negative) cells undergoing apoptosis. Treatment with 0 approximately 10 microM PEITC-triggered cell apoptosis as revealed by the externalization of annexin V-targeted phosphatidylserine and the subsequent appearance of sub-G1 population. Results also displayed that PEITC-induced apoptosis involves the up-regulation of p53 and Bax protein, down-regulation of the XIAP, Bcl-2, Bcl-(XL) and Mcl-1 proteins, cleavage of Bid, and the release of cytochrome c and Smac/Diablo, which were accompanied by the activation of caspases -9, -3 and -8. PEITC-induced the generation of reactive oxygen species and the decrease of mitochondrial membrane potential (Deltapsim) in a time-dependent pattern. N-acetyl-cysteine and vitamin E at 100 microM, and z-DEVD-fmk at 50 microM markedly blocked PEITC-induced apoptosis, which was demonstrated by a decline in the reactive oxygen species generation and the release of the cytochrome c and Smac/Diablo from mitochondria to the cytosol. N-acetyl-cysteine, vitamin E and z-DEVD-fmk also prevented the PEITC in inducing the loss of Deltapsim. They also affected the activity of XIAP and Bax proteins. Taken together, these studies suggest that PEITC is an apoptotic inducer that acts on the mitochondria and the feedback amplification loop of caspase-8/Bid pathways in PLC/PRF/5 cells.
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PMID:Effects of antioxidants and caspase-3 inhibitor on the phenylethyl isothiocyanate-induced apoptotic signaling pathways in human PLC/PRF/5 cells. 1605 26

The cytotoxic effect of several diorganotin(IV) and triorganotin(IV)-meso-tetra(4-sulfonatophenyl)porphine derivatives was tested and only the (Bu(2)Sn)(2)TPPS and the (Bu(3)Sn)(4)TPPS showed cytotoxicity on A375 human melanoma cells. To examine the pathway of (Bu(2)Sn)(2)TPPS or (Bu(3)Sn)(4)TPPS induced A375 cell death, DNA fragmentation analysis, Annexin V binding and PI uptake as well as caspases activation analysis by Western blot were carried out. A375 cells treated exhibited several typical characteristics of apoptosis. Both the (Bu(2)Sn)(2)TPPS and the (Bu(3)Sn)(4)TPPS compounds activate caspase-8 and caspase-9 leading to caspase-3 activation. Thus, we propose that these two porphirin derivatives lead to the apoptosis of human melanoma cells via both death receptor-mediated and mitochondrial apoptotic pathways.
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PMID:Diorganotin(IV) and triorganotin(IV) complexes of meso-tetra(4-sulfonatophenyl)porphine induce apoptosis in A375 human melanoma cells. 1614 Apr 59

Motexafin gadolinium (MGd, Xcytrin) is a tumor-localizing redox mediator that catalyzes the oxidation of intracellular reducing molecules including NADPH, ascorbate, protein and non-protein thiols, generating reactive oxygen species (ROS). MGd localizes to tumors and cooperates with radiation and chemotherapy to kill tumor cells in tissue culture and animal models. In this report, we demonstrate that MGd triggers the mitochondrial apoptotic pathway in the HF-1 lymphoma cell line as determined by loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, activation of caspase-9 prior to caspase-8, cleavage of PARP and annexin V binding. There was minimal effect on MGd-induced apoptosis by the caspase inhibitor z-VAD-fmk, even though caspase-3 activity (as measured by DEVD-cleavage) was completely inhibited. However, MGd-induced apoptosis was reduced to baseline levels by the more potent caspase inhibitor Q-VD-OPh, demonstrating that MGd-induced apoptosis is indeed caspase-dependent. Apoptosis induced by dexamethasone, doxorubicin and etoposide (mediated through the mitochondrial pathway) was also more sensitive to inhibition by Q-VD-OPh than z-VAD-fmk. Our results demonstrating differential sensitivity of drug-induced apoptosis to caspase inhibitors suggest that the term "caspase-independent apoptosis" cannot be solely defined as apoptosis that is not inhibited by z-VAD-fmk as has been utilized in some published studies.
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PMID:Motexafin gadolinium induces mitochondrially-mediated caspase-dependent apoptosis. 1615 46

Apoptosis and autophagy are closely interconnected types of programmed cell death. In the present study, mouse C2C12 muscle cells were starved in Earle's Balanced Salt Solution or treated with TNF-alpha and cycloheximide to induce autophagy and apoptosis, respectively. The majority of starved C2C12 cells underwent autophagy, as shown by LC3 processing, formation of autophagic vesicles and bulk degradation of long-lived proteins. However, some cells showed features of apoptosis including caspase-3 cleavage, chromatin condensation, DNA fragmentation and annexin V labeling. Caspase-3 cleavage was also induced in culture medium without serum, suggesting that serum withdrawal rather than amino acid deprivation triggered apoptosis. Starvation eliminated multiple pro-apoptotic proteins, but upregulated caspase-8, and rendered starved C2C12 cells much more susceptible to TNF-alpha/cycloheximide-induced apoptosis than non-starved cells. Our data suggest that amino acid deprivation of C2C12 cells induces a complex form of cell death with hallmarks of both apoptosis and autophagy.
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PMID:Amino acid deprivation induces both apoptosis and autophagy in murine C2C12 muscle cells. 1615 57

Statins are lipid-lowering agents with pleiotropic effects. We investigated the apoptotic effects of fluvastatin on peripheral CD4+ T cells from healthy subjects. Fluvastatin induced apoptosis in resting CD4+ T cells but not in CD4+ T cells strongly activated with a high concentration of PMA plus ionomycin (PMA/I) analyzed with annexin V and propidium iodide staining. However, CD4+ T cells activated with a low concentration of PMA/I or with anti-CD3 antibodies were apoptotic after treatment with fluvastatin. Activities of caspases-8, -9, and -3 were increased in resting CD4+ T cells treated with fluvastatin (10 microM). In strongly activated CD4+ T cells, fluvastatin inhibited the activation of caspase-8 induced by PMA/I and increased caspase-9 activity. The caspase-3 activity did not differ between untreated and fluvastatin-treated strongly activated CD4+ T cells. Treatment with fluvastatin (10 microM) enhanced cytochrome c release and increased the Bax/Bcl-2 ratio in both resting and strongly activated CD4+ T cells. Although the in vitro concentration of fluvastatin used in this study is higher than in vivo, other factors may sensitize apoptotic cell death of CD4+ T cells in vivo. In conclusion, fluvastatin induces apoptosis in resting T cells but not in strongly activated T cells, a difference that might be due to the interaction between caspase-8 and caspase-9.
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PMID:Effect of fluvastatin on apoptosis in human CD4+ T cells. 1622 33

Rhabdomyolysis is a severe adverse effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). This myopathy is strongly enhanced by the combination with statins and fibrates, another hypolipidaemic agent. We have evaluated the initial step of statin-induced apoptosis by the detection of membrane flip-flop using flow cytometric analysis. L6 rat myoblasts were treated with various statins (atorvastatin (3 microM), cerivastatin (3 microM), fluvastatin (3 microM), pravastatin (3 mM), or simvastatin (3 microM)) for 2, 4 or 6 h followed by reacting with FITC-conjugated annexin V for the detection of initial apoptosis signal (flip-flop). Various statin-treated myoblasts were significantly stained with FITC-annexin V at 6 h, whereas they were not detected at 2 h. Moreover, immunoblot analysis indicated that when the cells were treated with cerivastatin (3 microM), membrane-associated Ras protein was activated and detached until 6 h, resulting in cell death through the consequent activation of caspase-8. On the other hand, since cytosolic Ras activation did not activate, there is still an unknown mechanism in statin-related Ras depletion. In conclusion, statin-induced apoptosis in muscular tissue was directly initiated by the farnesyl-anchored Ras protein depletion from cell membrane with subsequent apoptosis.
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PMID:Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein. 1625 81

We hypothesized that inhibition of the FAS-mediated apoptosis pathway by FLICE-like inhibitory protein (c-FLIP) may contribute to oncogenesis in ALK+ anaplastic large-cell lymphoma (ALCL). Treatment with increasing concentrations of CH-11 (CD95/FAS agonistic antibody) had no effect on cell viability of 2 ALK+ ALCL cell lines, Karpas 299 and SU-DHL1, each expressing high levels of c-FLIP. However, inhibition of endogenous c-FLIP expression by specific c-FLIP siRNA in Karpas 299 and SU-DHL1 cells treated with CH-11 resulted in FAS-mediated cell death associated with increased annexin V binding, apoptotic morphology, and cleavage of caspase-8. In 26 ALK+ ALCL tumors, assessed for expression of DISC-associated proteins, CD95/FAS and c-FLIP were commonly expressed, in 23 (92%) of 25 and 21 (91%) of 23 tumors, respectively. By contrast, CD95L/FASL was expressed in only 3 (12%) of 26 ALCL tumors, although it was strongly expressed by surrounding small reactive lymphocytes. Our findings suggest that overexpression of c-FLIP protects ALK+ ALCL cells from death-receptor-induced apoptosis and may contribute to ALCL pathogenesis.
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PMID:c-FLIP confers resistance to FAS-mediated apoptosis in anaplastic large-cell lymphoma. 1630 56

Trichosanthis kirilowii MAXIM has been used as a folk remedy to treat diabetes, leukemia, and breast cancer. In the present study, the apoptotic mechanism of the methylene chloride fraction of Trichosanthis Fructus (MCTF) was investigated in human leukemic U937 cells. MCTF exhibited antiproliferative effectsagainst U937 cells (IC50=ca. 8 microg/ml). Apoptotic bodies were observed in MCTF-treated U937 cells in the TUNEL assay. We also confirmed that MCTF significantly increases annexin V(+)/propidium iodide-cells using FACS analysis. MCTF treatment activated caspase-8, -9 and -3, and led to cleaved poly (ADP-ribose) polymerase and release of cytochrome c into cytosol in a concentration-dependent manner, while MCTF did not affect Bax or Bcl-2 protein levels as shown by Western blot analysis. Taken together, these results indicate that MCTF can induce apoptosis in U937 cells chiefly via a mitochondrial-mediated pathway and suggest that Trichosanthis Fructus can be used in cancer treatment as a chemopreventive agent.
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PMID:The methylene chloride fraction of Trichosanthis Fructus induces apoptosis in U937 cells through the mitochondrial pathway. 1639 3


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