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)

Since hepatocellular carcinoma remains a major challenging clinical problem in many parts of the world including Eastern Asia and Southern Africa, it is imperative to develop more effective chemopreventive and chemotherapy agents. Herein, we present an investigation regarding the anticancer potential of luteolin, a natural flavonoid, and the mechanism of its action in human hepatoma HepG2 cells. Using DNA fragmentation assay and nuclear staining assay, it showed that luteolin induced apoptosis of HepG2 cells. Luteolin induced the cytosolic release of cytochrome c and activated CPP32. We found that Bax and Bak translocated to mitochondria apparently, whereas Fas ligand (FasL) was unchanged after a treatment with luteolin for 3 h. In addition, it showed that c-Jun NH2-terminal kinase (JNK) was activated after the treatment of luteolin for 3-12 h. Further investigation showed that a specific JNK inhibitor, SP600125, reduced the activation of CPP 32, the mitochondrial translocation of Bax, as well as the cytosolic release of cytochrome c that induced by luteolin. Finally, the apoptosis induced by luteolin was suppressed by a pretreatment with SP600125 via evaluating annexin V-FITC binding assay. These data suggest that luteolin induced apoptosis via mechanisms involving mitochondria translocation of Bax/Bak and activation of JNK.
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PMID:Induction apoptosis of luteolin in human hepatoma HepG2 cells involving mitochondria translocation of Bax/Bak and activation of JNK. 1571 Jan 73

In a previous study, we showed that G3139, an antisense phosphorothioate oligonucleotide that down-regulates the expression of Bcl-2 protein, did not cause chemosensitization of 518A2 melanoma cells. In this work, we show that G3139, and the 2-base mismatch, G4126, can initiate apoptosis in this and other melanoma cell lines as shown by increased cell surface Annexin V expression, typical nuclear phenotypic changes as assessed by 4',6-diamidino-2-phenylindole staining, activation of caspase-3 (but not caspase-8) and Bid, appearance of DEVDase (but not IETDase) activity, and cleavage of poly(ADP-ribose)-polymerase 1. Depolarization of the mitochondrial membrane occurs as a relatively late event. All of these processes seem to be substantially, but perhaps not totally, Bcl-2 independent as shown by experiments employing an anti-Bcl-2 small interfering RNA, which as shown previously down-regulated Bcl-2 protein expression but did not produce apoptosis or chemosensitization in melanoma cells. In fact, these G3139-induced molecular events were not dramatically altered in cells that forcibly overexpressed high levels of Bcl-2 protein. Addition of irreversible caspase inhibitors (e.g., the pan-caspase inhibitor zVAD-fmk) to G3139-treated cells almost completely blocked cytotoxicity. Examination of the time course of the appearance of caspase-3 and cleaved poly(ADP-ribose)-polymerase 1 showed that this could be correlated with the release of cytochrome c from the mitochondria, an event that begins only approximately 4 hours after the end of the oligonucleotide/LipofectAMINE 2000 5-hour transfection period. Thus, both G3139 and cytotoxic chemotherapy activate the intrinsic pathway of apoptosis in these cells, although Bcl-2 expression does not seem to contribute strongly to chemoresistance. These findings suggest that the attainment of G3139-induced chemosensitization in these cells will be difficult.
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PMID:Phosphorothioate oligodeoxynucleotides and G3139 induce apoptosis in 518A2 melanoma cells. 1571 1

Prostate cancer is the second leading cause of cancer deaths among men in the United States. Studies show that people with diets rich in tomato-based foods have reduced risks of cancer, viz., prostate cancer. This is attributed, in part, to lycopene, the most abundant carotenoid in tomatoes. Thus, we studied the effect of lycopene at physiologically attainable concentrations on apoptosis, cellular proliferation, and necrosis in LNCaP human prostate cancer cells. Cells at 37 degrees C and >80% confluency were treated with media alone (0.32% tetrahydrofuran vehicle) or with increasing concentrations (0.3-3.0 microM) of lycopene overnight. After washing monolayers, analyses by high-performance liquid chromatography (HPLC) showed that cellular accumulation of lycopene was 5.5 +/- 0.8, 14.0 +/- 3.2, and 36.7 +/- 12.3 pmole/10(6) cells for 0.3, 1.0, and 3.0 muM, respectively, and not detected in control cells. Lycopene did not alter cellular proliferation because bromodeoxyuridine (BrdU) incorporation and cell numbers were identical among groups. However, results of a 3[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay showed that mitochondrial function decreased 61%-83% with increasing concentrations of lycopene (P < 0.001). Cytotoxicity and necrosis did not contribute to this effect because lactate dehydrogenase (LDH) release (1.5%-1.8%) and trypan blue exclusion (89%-93%) were similar. Subsequently, we demonstrated that increasing concentrations of lycopene significantly (P < 0.05) reduced mitochondrial transmembrane potential, induced the release of mitochondrial cytochrome c, and increased annexin V binding, confirming induction of apoptosis. Thus, lycopene at physiologically relevant concentrations did not affect cellular proliferation or promote necrosis but clearly altered mitochondrial function and induced apoptosis in LNCaP human prostate cancer cells.
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PMID:Physiologically attainable concentrations of lycopene induce mitochondrial apoptosis in LNCaP human prostate cancer cells. 1573 20

Farnesyltransferase inhibitors (FTIs) are currently under investigation for leukemia treatment. We evaluated the FTI manumycin A (manumycin) in two myeloid leukemia cell lines (U937 and HL-60). Manumycin induced nitric oxide production and apoptosis of the leukemia cells. Nitric oxide or other reactive oxygen species may induce oxidative DNA damage, and the number of apurinic sites increased after manumycin treatment, which was reversed by concurrent treatment with N-acetyl-L-cysteine. Since repair of DNA damage is important to cell survival, we hypothesized that methoxyamine, an inhibitor of base-excision repair, would enhance the antineoplastic effect of manumycin. The combination of manumycin and methoxyamine resulted in enhanced apoptosis by six criteria increased annexin V binding, release of mitochondrial cytochrome c into the cytosol, activation of caspase-9, activation of caspase-3, specific cleavage of poly-adenosyl ribose polymerase, and increase in the sub-G1 cell cycle fraction. The drug combination enhanced inhibition on the soft agar clonogenic assay and on the formazan dye cell viability assay. The effects of manumycin or manumycin plus methoxyamine on apoptosis were blocked by N-acetyl-L-cysteine, and partially by nitric oxide synthase inhibitors or scavenger of peroxide. We conclude that methoxyamine enhances manumycin-induced apoptosis in myeloid leukemia cells.
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PMID:Enhancement of manumycin A-induced apoptosis by methoxyamine in myeloid leukemia cells. 1574 47

Tocotrienols and tocopherols represent the 2 subgroups within the vitamin E family of compounds, but tocotrienols display significantly greater apoptotic activity against a variety of cancer cell types. However, the exact mechanism mediating tocotrienol-induced apoptosis is not understood. Studies were conducted to determine the effects of tocotrienols on mitochondrial-stress-mediated apoptotic signaling in neoplastic +SA mammary epithelial cells grown in vitro. Exposure for 24 h to 0-20 micromol/L gamma-tocotrienol resulted in a dose-responsive increase in +SA cells undergoing apoptosis, as determined by flow cytometric analysis of Annexin V staining. However, tocotrienol-induced apoptosis was not associated with a disruption or loss of mitochondrial membrane potential, or the release of mitochondrial cytochrome c into the cytoplasm, as determined by JC-1 flow cytometric staining and ELISA assay, respectively. Interestingly, apoptotic +SA cells showed a paradoxical decrease in mitochondrial levels of pro-apoptotic proteins Bid, Bax, and Bad, and a corresponding increase in mitochondrial levels of anti-apoptotic proteins, Bcl-2 and Bcl-xL, suggesting that mitochondrial membrane stability and integrity might actually be enhanced for a limited period of time following acute tocotrienol exposure. In summary, these findings clearly demonstrate that tocotrienol-induced apoptosis occurs independently of mitochondrial stress apoptotic signaling in neoplastic +SA mammary epithelial cells.
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PMID:Tocotrienol-induced cytotoxicity is unrelated to mitochondrial stress apoptotic signaling in neoplastic mammary epithelial cells. 1574 70

Bovine lactoferricin (LfcinB) is a cationic, amphipathic peptide that is cytotoxic for human and rodent cancer cells. However, the mechanism by which LfcinB causes the death of cancer cells is not well understood. Here, we show that in vitro treatment with LfcinB rapidly induced apoptosis in several different human leukemia and carcinoma cell lines as determined by DNA fragmentation assays and phosphatidylserine headgroup inversion detected by Annexin V binding to the surface of cancer cells. Importantly, LfcinB treatment did not adversely affect the viability of untransformed human lymphocytes, fibroblasts, or endothelial cells. Studies with different LfcinB-derived peptide fragments revealed that the cytotoxic activity of LfcinB resided within the amino acid sequence FKCRRWQWRM. Treatment of Jurkat T leukemia cells with LfcinB resulted in the production of reactive oxygen species followed by caspase-2-induced dissipation of mitochondrial transmembrane potential and subsequent activation of caspase-9 and caspase-3. Selective inhibitors of caspase-2 (Z-VDVAD-FMK), caspase-9 (Z-LEHD-FMK), and caspase-3 (Z-DEVD-FMK) protected both leukemia and carcinoma cells from LfcinB-induced apoptosis. Conversely, a caspase-8 inhibitor (Z-IETD-FMK) had no effect, which argued against a role for caspase-8 and was consistent with the finding that death receptors were not involved in LfcinB-induced apoptosis. Furthermore, Jurkat T leukemia cells that overexpressed Bcl-2 were less sensitive to LfcinB-induced apoptosis, which was characterized by mitochondrial swelling and the release of cytochrome c from mitochondria into the cytosolic compartment. We conclude that LfcinB kills cancer cells by triggering the mitochondrial pathway of apoptosis at least in part through the generation of reactive oxygen species.
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PMID:Bovine lactoferricin selectively induces apoptosis in human leukemia and carcinoma cell lines. 1582 35

Liver cirrhosis is often preceded by overt signs of hepatitis, including parenchymal cell inflammation and infiltration of polymorphonuclear (PMN) leukocytes. Activated PMNs release both reactive oxygen species and reactive halogen species, including hypochlorous acid (HOCl), which are known to be significantly cytotoxic due to their oxidizing potential. Because the role of mitochondria in the hepatotoxicity attributed to HOCl has not been elucidated, we investigated the effects of HOCl on mitochondrial function in the human hepatoma HepG2 cell line, human fetal liver cells, and isolated rat liver mitochondria. We show here that HOCl induced mitochondrial dysfunction, and apoptosis was dependent on the induction of the mitochondrial permeability transition (MPT), because HOCl induced mitochondrial swelling and collapse of the mitochondrial membrane potential with the concomitant release of cytochrome c. These biochemical events were inhibited by the classical MPT inhibitor cyclosporin A (CSA). Cell death induced by HOCl exhibited several classical hallmarks of apoptosis, including annexin V labeling, caspase activation, chromatin condensation, and cell body shrinkage. The induction of apoptosis by HOCl was further supported by the finding that CSA and caspase inhibitors prevented cell death. For the first time, these results show that HOCl activates the MPT, which leads to the induction of apoptosis and provides a novel insight into the mechanisms of HOCl-mediated cell death at sites of chronic inflammation.
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PMID:Hypochlorous acid-mediated mitochondrial dysfunction and apoptosis in human hepatoma HepG2 and human fetal liver cells: role of mitochondrial permeability transition. 1591 86

Sapphyrins are pentapyrrolic, metal-free, expanded porphyrins. In the present study, the activity of sapphyrins as anticancer agents in hematopoietic-derived tumor cells was explored. It was found that a dihydroxylated water-soluble sapphyrin derivative (PCI-2000) is a potent inducer of apoptosis in a wide variety of tumor cell lines including lymphoma (Ramos, DHL-4, and HF-1), leukemia (Jurkat and HL-60), and myeloma (8226/S, 1-310, C2E3, and 1-414). PCI-2000 triggers an apoptotic pathway in these tumor cells as shown by release of cytochrome c from mitochondria; activation of caspases 9, 8, and 3; cleavage of the caspase substrate poly(ADP-ribose) polymerase; and Annexin V binding. Apoptosis can be partially inhibited by overexpression of the antiapoptotic protein Bcl-2 or treatment with benzyloxycarbonyl-valine-alanine-aspartic acid-fluoromethylketone, a cell-permeable caspase inhibitor. Both PCI-2000 and PCI-2010, a tetrahydroxy bis-carbamate derivative of PCI-2000, result in increased levels of phosphorylated p38 mitogen-activated protein kinase. Inhibition of p38 mitogen-activated protein kinase phosphorylation resulted in a synergistic increase of PCI-2000 cytotoxicity. PCI-2010 showed less toxicity in mice than PCI-2000 and was active in slowing the growth of Ramos and HL-60 tumor xenografts in nude mice. These results provide preclinical rationale for the further study of sapphyrins for potential use in the treatment of hematopoietic-derived tumors.
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PMID:Sapphyrins induce apoptosis in hematopoietic tumor-derived cell lines and show in vivo antitumor activity. 1595 54

When nitric oxide (NO) is produced at micromolar concentrations, as during inflammation, exposure to surrounding cells is potentially cytotoxic. The NO-dependent signaling pathways that initiate cell death are thought to involve the tumor suppressor protein p53, but the degree to which this factor contributes to NO-induced cell death is less clear. Various reports either confirm or negate a role for p53 depending on the cell type and NO donor used. In this study, we have used several pairs of cell lines whose only differences are the presence or absence of p53, and we have treated these cell lines with the same NO donor, spermineNONOate (SPER/NO). Treatment with SPER/NO induced such apoptotic markers as DNA fragmentation, nuclear condensation, poly(ADP-ribose) polymerase cleavage, cytochrome c release, and Annexin V staining. p53 was required for at least 50% of SPER/NO-induced apoptotic cell death in human lymphoblastoid cells and for almost all in primary and E1A-tranformed mouse embryonic fibroblasts, which highlights the possible importance of DNA damage for apoptotic signaling in fibroblasts. In contrast, p53 did not play a significant role in NO-induced necrosis. NO treatment also induced the phosphorylation of p53 at Ser15; pretreatment with phosphoinositide-3 kinase (PI3K) family inhibitors, wortmannin, LY294002, and caffeine, blocked such phosphorylation, but the p38 mitogen-activated protein kinase inhibitor, SB203580, did not. Pretreatment with the PI3K family inhibitors also led to a switch from NO-induced apoptosis to necrosis, which implicates a PI3K-related kinase such as ataxia telangiectasia mutated (ATM) or ATR (ATM and Rad3 related) in p53-dependent NO-induced apoptosis.
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PMID:Nitric oxide-induced apoptosis in lymphoblastoid and fibroblast cells dependent on the phosphorylation and activation of p53. 1602 10

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


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