Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Impairment of the complex regulatory network of cell death and survival is frequently the reason for therapy resistance of breast cancer cells and a major cause of tumor progression. We established two independent cell lines from a fast growing mouse breast tumor (WAP-SVT/t transgenic animal). Cells from one line (ME-A cells) are sensitive to apoptotic stimuli such as growth factor depletion or treatment with antitumor agents (e.g. doxorubicin). Cells from the second line (ME-C cells), which carry a missense mutation at the p53 codon 242, are very insensitive to apoptotic stimuli. Co-cultivation experiments revealed that the ME-C cells mediate cell death resistance to the ME-A cells. Microarray and Western blot analysis showed that osteopontin (OPN) is selectively overexpressed by the ME-C cells. This glycoprotein is the most abundant protein secreted by the ME-C cells and we obtained strong indications that OPN is the main antiapoptotic factor. However, the OPN containing ME-C cell medium does not alter the expression level of pro- or antiapoptotic genes or known inhibitors of apoptosis (IAPs). Its signaling involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 as the kinase inhibitor PD98059 restores apoptosis but not the Akt inhibitor. In the ME-A cells, mitochondrial cytochrome c release occurs with and without external apoptotic stimuli. OPN containing ME-C cell medium does not prevent the mitochondrial cytochrome c release and caspase-9 processing. In serum starved ME-A cells, the OPN containing ME-C cell medium prevents caspase-3 activation. However, in doxorubicin-treated cells, although apoptosis is blocked, it does not inhibit caspase-3. This indicates that the ME-A cells distinguish between the initial apoptotic stimuli and that the cells possess a further uncharacterized control element acting downstream from caspase-3.
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PMID:Chemotherapy resistance of mouse WAP-SVT/t breast cancer cells is mediated by osteopontin, inhibiting apoptosis downstream of caspase-3. 1716 24

alpha(1)-Acid glycoprotein (AGP, orosomucoid) is a normal constituent of bovine blood. AGP is an immunocalin, a binding protein that can also exert several immunomodulatory functions. In this paper we investigated the effect of bovine alpha(1)-acid glycoprotein (boAGP) on spontaneous and staurosporine-induced apoptosis of blood derived monocytes purified using magnetic cell sorting techniques. Bovine AGP was purified from blood following a chromatographic protocol. The homogeneous protein was used to stimulate the cells as well to raise a polyclonal antibody, that was used throughout all the experiments. When monocytes were incubated with high concentrations of boAGP (0.9 mg/ml), similar to those found in bovine plasma during systemic reaction to inflammation, their spontaneous apoptosis rate was suppressed, as determined by caspase-3/7 enzymatic activity assay. Similar results were obtained when apoptosis was induced by adding staurosporine, a potent protein kinase inhibitor. The apoptosis-modulating activity of boAGP was dependent on its concentration, since physiological concentrations of boAGP (0.3 mg/ml) did not exhibit a statistically significative anti-apoptotic activity. We also investigated whether this apoptosis-modulating activity was dependent on the terminal sialic acid residues exposed on the surface of the protein. Enzymatic treatment with neuraminidase, that cleaves terminal sialic acid residues, completely abolished boAGP's anti-apoptotic activity. These results suggest that the protective effect of AGP is likely mediated by its sialic acid terminal groups.
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PMID:alpha(1)-Acid glycoprotein modulates apoptosis in bovine monocytes. 1732 1

A painful neuropathy is frequently observed in people living with human immunodeficiency virus type 1 (HIV-1). The HIV coat protein, glycoprotein 120 (gp120), implicated in the pathogenesis of neurological disorders associated with HIV, is capable of initiating neurotoxic cascades via an interaction with the CXCR4 and/or CCR5 chemokine receptors, which may underlie the pathogenesis of HIV-associated peripheral neuropathic pain. In order to elucidate the mechanisms underlying HIV-induced painful peripheral neuropathy, we have characterised pathological events in the peripheral and central nervous system following application of HIV-1 gp120 to the rat sciatic nerve. Perineural HIV-1 gp120 treatment induced a persistent mechanical hypersensitivity (44% decrease from baseline), but no alterations in sensitivity to thermal or cold stimuli, and thigmotactic (anxiety-like) behaviour in the open field. The mechanical hypersensitivity was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. Immunohistochemical studies reveal: decreased intraepidermal nerve fibre density, macrophage infiltration into the peripheral nerve at the site of perineural HIV-1 gp120; changes in sensory neuron phenotype including expression of activating transcription factor 3 (ATF3) in 27% of cells, caspase-3 in 25% of cells, neuropeptide Y (NPY) in 12% of cells and galanin in 13% of cells and a spinal gliosis. These novel findings suggest that this model is not only useful for the elucidation of mechanisms underlying HIV-1-related peripheral neuropathy but may prove useful for preclinical assessment of drugs for the treatment of HIV-1 related peripheral neuropathic pain.
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PMID:Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy. 1743 46

This study was carried out to investigate the apoptotic effects of glycine- and proline-rich glycoprotein [Solanum nigrum Linne (SNL) glycoprotein, 150-kDa] isolated from SNL, which has been used as an antipyretic and anticancer agent in Korean herbal medicine. We found that SNL glycoprotein has obviously cytotoxic and apoptotic effects at 80 microg/ml of SNL glycoprotein for 4 h in Hep3B cells (hepatocellular carcinoma cells). In mitochondria-mediated apoptosis pathway, SNL glycoprotein has abilities to stimulate release of mitochondrial cytochrome c, activations of caspase-9 and caspase-3, cleavage of poly(ADP-ribose)polymerase and production of intracellular reactive oxygen species in Hep3B cells. In nuclear factor-kappa B (NF-kappaB)-mediated apoptosis pathway, the results showed that SNL glycoprotein dose-dependently blocked DNA binding activity of NF-kappaB, activity of inducible nitric oxide synthase (iNOS) and production of inducible nitric oxide (NO). Interestingly, pyrrolidine dithiocarbamate (for NF-kappaB inhibitor) and Nomega-nitro-l-arginine methylester hydrochloride (for NO inhibitor) effectively stimulated the caspase-3 activation and induced apoptosis in Hep3B cells. These results indicate that SNL glycoprotein transfers its cell death signal from cytochrome c to caspase 3 by inhibiting NF-kappaB and iNOS activation in Hep3B cells. Here, we speculate that SNL glycoprotein is one of the chemotherapeutic agents to modulate mitochondria-mediated apoptosis signals in Hep3B cells.
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PMID:Cell death signal by glycine- and proline-rich plant glycoprotein is transferred from cytochrome c and nuclear factor kappa B to caspase 3 in Hep3B cells. 1758 35

Apoptotic pathways represent the mechanisms of programmed cell death that counteract initiation and progression of cancer. New therapeutic targets are currently being explored on the basis of our detailed knowledge of the mechanisms and factors involved in apoptosis. In recent years, numerous proteins have been identified, which act as tumour suppressors or as oncoproteins in caspase-independent programmed cell death mechanisms, in which lysosomes are implicated for their lysosomal functions in cancer, mainly attributed to lysosomal proteinases, particularly the cathepsins. If cathepsins are released from the lysosomal lumen into the cytoplasm they initiate a number of processes that may cause either apoptotic or non-apoptotic (necrotic) cell death. The release of cathepsin D into the cytoplasm by vacuolar-type ATPase (V-ATPase) inhibitors produces the characteristic signs of apoptotic cell death, including caspase-3 activation and DNA laddering. For the destabilisation of the lysosomal membrane, two methods are available having therapeutic potential: the formation of reactive oxygen species (ROS) by irradiation or by enzymatic reactions and the lysosomal membrane permeabilisation by lysosomotropic compounds. Findings also suggest that the deregulation of polyamine metabolism or cytotoxic metabolites generated from the oxidative deamination of spermine by amine oxidases in association with lysosomotropic compounds may induce apoptosis. Cross-resistance of cells to cytotoxic actions of a wide variety of natural and synthetic anticancer drugs is the well-known phenomenon called multidrug resistance (MDR), due to glycoprotein P that functions as an ATP-dependent pump. The sensitisation of tumour cells to anticancer drugs by lysosomotropic compounds, and particularly the sensitisation of MDR-resistant cells recommend scrutinizing the potential of lysosomotropic drugs in cancer therapy.
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PMID:Lysosomotropic compounds and spermine enzymatic oxidation products in cancer therapy (review). 1767 72

The cytotoxicity of four triterpenoids, euscaphic acid (1), tormentic acid (2), 2alpha-acetyl tormentic acid (3), and 3beta-acetyl tormentic acid (4), isolated from the roots of Cecropia lyratiloba (Moraceae) by countercurrent chromatography, was evaluated in vitro in sensitive and multidrug resistant leukemia cell lines. A structure/activity relationship analysis of the compounds was performed. Acetylation of compound 2 at C2 increased its activity by a factor of 2 while acetylation at C3 had a smaller effect. Compound 1 induces death by activation of caspase-3, dependent apoptotic pathway. Furthermore, the four triterpenoids were also active toward a multidrug resistant (MDR) leukemia cell line, overexpressing glycoprotein-P (P-gp). These results reveal the potential of the terpenoids as source for the development of new anti-neoplastic and anti-MDR drugs.
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PMID:Natural triterpenoids from Cecropia lyratiloba are cytotoxic to both sensitive and multidrug resistant leukemia cell lines. 1788 44

Previous work has demonstrated that the surface glycoprotein (gp120) of human immunodeficiency virus-1 (HIV-1) can induce damage and apoptosis of neurons both in vitro and in vivo. In this report, we provide evidence that double-stranded RNA-activated protein kinase (PKR), a stress kinase, is involved in HIV/gp120-associated neurodegeneration. In cultures of mixed cortical cells, HIV/gp120 increased the protein level of PKR. Additionally, PKR was phosphorylated in neurons but not glia after exposure to gp120. The use of two independent pharmacological inhibitors of PKR activity abrogated neuronal cell death induced by gp120. Cortical neurons from PKR knock-out mice were significantly protected from neurotoxicity induced by gp120, further validating the pivotal proapoptotic function of PKR. gp120-induced phosphorylated PKR localized prominently to neuronal nuclei; PKR inhibition or the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] abrogated this effect. PKR inactivation also inhibited gp120-induced caspase-3 activation, consistent with its neuroprotective effect. Finally, brain tissue from individuals diagnosed with HIV-associated dementia (HAD), but not HIV infection alone, contained the activated form of PKR, which localized predominantly to neuronal nuclei. Together, these results identify PKR as a critical mediator of gp120 neurotoxicity, suggesting that activation of PKR contributes to the neuronal injury and cell death observed in HAD.
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PMID:Human immunodeficiency virus-1/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons. 1792 46

2-Methoxyestradiol (2ME), a natural derivative of estradiol, is currently evaluated in clinical trials for breast cancer. The current study aims to evaluate the modulatory effects of 2ME on regulation of multidrug resistance (MDR) in doxorubicin (Dox) resistant breast cancer cells (MCF-7/Dox) and its underlying mechanisms. The chemosensitizing effect of 2ME on Dox cytotoxicity is tested by MTT assay. RT(2) Profiler PCR Array was used to identify differentially expressed genes in Dox and/or 2ME treatment groups, based on significance of results 4 genes were selected: MDR1, Bcl2, P53 and Cyclin D1. The expression of these genes was confirmed using western blotting. Lastly, functions of these genes were examined by studying p-glycoprotein (p-gp) function, caspase 3 activity and flowcytometric cell cycle assays respectively. 2ME significantly increased sensitivity of the resistant MCF-7/Dox cells to the cytotoxic effect of Dox by 2.9-folds. The array and western blotting showed that Bcl2 and Cyclin D1 expression were down regulated; P53 expression was not affected while MDR1 was over expressed by combination of 2ME with Dox. 2ME increased p-gp function by 24+/-7.05%, compared to control. Addition of 2ME to Dox increased caspase activity by 27-folds. Combination of 2ME to Dox arrested the cell cycle in G(1) and S phases, compared to Dox. In conclusion, 2ME chemosensitizes resistant breast cancer cells to Dox cytotoxicity by down regulating expression of Bcl2 and Cyclin D1, augmenting caspase 3 activity as well as inducing cell cycle block in G(1) and S phases.
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PMID:2-Methoxyestradiol and multidrug resistance: can 2-methoxyestradiol chemosensitize resistant breast cancer cells? 1822 36

The multi-drug resistance (MDR) could be caused by the over-expression of adenosine triphosphate binding cassette transporters such as p-glycoprotein, thereby resulting in the efflux of anti-cancer drugs from the cells. An anti-resistant stealthy liposomal vincristine plus quinacrine was defined in this study. Human chronic myelogenous leukemia K562 and MDR K562 cells were included for comparisons. Anti-tumor activity studies were performed on female BALB/c nude mice with MDR K562 cell xenografts. Results showed that quinacrine was effective in reversing the resistance in the MDR K562 cells, and enhanced the anti-tumor effect of vincristine in K562 cells. The caspase-9 and -3 activities in the MDR K562 and K562 cells were increased with the dose rise of quinacrine. In the MDR K562 cell xenografts in mice, the anti-resistant tumor effect of the stealthy liposomal vincristine plus quinacrine was evidently observed. The enhanced anti-tumor effects of vincristine by quinacrine in the resistant/non-resistant K562 cells could be because of the direct injury and the potentiating apoptotic effect of vincristine via activating the initiator caspase-9 and subsequently the effector caspase-3, and the long circulatory effect of stealthy liposomes. The stealthy liposomal encapsulation of vincristine plus quinacrine could be a potential therapeutic approach for resistant human leukemia.
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PMID:Enhanced therapeutic effects on the multi-drug resistant human leukemia cells in vitro and xenograft in mice using the stealthy liposomal vincristine plus quinacrine. 1870 53

In this study, we isolated a glycoprotein from the brown alga Hizikia fusiformis (HFGP) and examined whether it could protect against Acetaminophen (AAP)-induced liver injury in vivo and in vitro. AAP, one of the most commonly abused drugs, may cause fatal liver injury. An analysis of the effects of HFGP on AAP toxicity in rats revealed that the serum glutamic pyruvic transaminase level was restored to the control level and glutathione level was also increased by co-treatment with HFGP and AAP. Furthermore, HFGP co-treatment decreased caspase-3/-9 activity. These results indicate that HFGP may inhibit AAP-induced liver injury in Sprague-Dawley rats. Several lines of evidence indicate that oxidative stress plays an important role in AAP-induced liver injury and mitogen-activated protein kinase (MAPK) signaling is involved in the regulation of oxidative stress. Therefore, Western blotting was used to determine which MAPK signaling pathway is involved in the protective effect of HFGP against AAP toxicity in HepG2 cells. We found that ERK activation was involved in the protective effect of HFGP against AAP-induced cell death. Therefore, we propose that MAPK signaling is involved in the protective effect of HFGP against AAP-induced liver injury.
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PMID:Effect of a glycoprotein from Hizikia fusiformis on acetaminophen-induced liver injury. 1880 56


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