Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have conducted a study to determine the carcinogenic potential of ethylene glycol monomethyl ether (EGME), a member of the glycol ether family, as compared to its reactive metabolite 2-methoxy-acetaldehyde (MALD). Since disruption of equilibrium between cell proliferation and cell death is thought to play a key role in multistage carcinogenesis, we investigated, in Syrian hamster embryo (SHE) cells exposed to various doses of EGME and MALD, impairment in apoptosis rate and in ornithine decarboxylase (ODC) metabolism. The activity of this rate-limiting enzyme of polyamine biosynthesis is closely related to cell proliferation and cell transformation. At the end-point, comparative action of the two products on SHE cell morphological transformation frequency was evaluated. One-stage exposure of SHE cells to 2 mM EGME and 200 microM MALD for 5 h did not change basal apoptotic level, whereas 0.16 microM phorbol ester (TPA) decreased it. Using two-stage exposure protocol (1 h xenobiotic followed by 5 h TPA), MALD strongly inhibited apoptosis more than did TPA alone; the parent compound EGME did not have any effect on TPA inhibiting action. Western blotting analysis showed that sequential treatment (MALD/TPA) increased Bcl-2 oncoprotein expression, whereas Bcl-XL and Bax proteins were not changed. The same staged exposure of SHE cells to MALD/TPA strongly induced ODC activity, and the rate was higher than that obtained with TPA alone: this was accompanied by an increase of ODC protein level. This ODC superinduction was not observed with EGME/TPA treatment. In long-term SHE-cell morphological transformation assay, staged exposure to MALD (800 microM or 1 mM for 24 h) followed by TPA applications increased the number of transformed colonies at the seventh day. Such early cooperative events as apoptosis inhibition and ODC superinduction, followed by the increase of SHE-cell transformation frequency, are highly indicative of a carcinogenic potential for the metabolite, MALD.
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PMID:Apoptosis inhibition and ornithine decarboxylase superinduction as early epigenetic events in morphological transformation of Syrian hamster embryo cells exposed to 2-methoxyacetaldehyde, a metabolite of 2-methoxyethanol. 1022 Dec 78

Antisense oligodeoxynucleotides (ASOs) prevent expression of proteins by binding to specific regions of mRNA. This report investigates a potential lipid-based delivery system for ASO. A hydrophobic complex was recovered following addition of cationic lipids to ASOs in a Bligh and Dyer monophase [chloroform/methanol/water (1:2.1:1, v/v/v)]. The addition of monovalent cationic lipids (dioleyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dioleoyltrimethylammonium propane), resulted in > 95% recovery of the ASOs from the organic phase when ASO phosphate charge was neutralized. Cholesteryldimethylaminoethylcarbamate mediated efficient extraction at a charge ratio (+/-) > 5.2. ASOs could not be extracted into the organic phase by the polyvalent lipids, dioctadecylamidoglycyl spermine and 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propaminium trifluoroacetate, even at a charge ratio (+/-) > 5. Dioleoylphosphatidylethanolamine, but not dioleoylphosphatidylcholine, prevented formation and destabilized the hydrophobic complexes. The characterization of the hydrophobic complex led to the development of lipid-ASO particles containing dioleyldimethylammonium chloride, dioleoylphosphatidylethanolamine and poly(ethylene glycol)-conjugated phosphatidylethanolamine (LAPs). When FITC-labeled ASOs in LAPs were added to B-cell lymphoma cells (DoHH2) in vitro, cell-associated ASO decreased as poly(ethylene glycol)-conjugated phosphatidylethanolamine incorporation increased. Western Blot analysis demonstrated that no significant downregulation of Bcl-2 protein was observed when using LAPs. The results suggest that the use of stabilized PEG-conjugated lipids may be detrimental for cationic lipid-based ASO delivery.
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PMID:A lipid-based delivery system for antisense oligonucleotides derived from a hydrophobic complex. 1268 66

A novel transferrin receptor (TfR)-targeted liposomal formulation was synthesized and evaluated for the delivery of a phosphorothioate antisense oligodeoxyribonucleotide (ODN) (G3139, oblimerson sodium, or Genasense) to Bcl-2 in K562 leukemia cells. Liposomes composed of DC-Chol/egg PC/PEG-DSPE (25:73.5:1.5, mol/mol/mol) were loaded with G3139 with high efficiency (70-80%). To prepare targeted liposomes, transferrin was first coupled to PEG-DSPE and then incorporated into the bilayer by post-insertion. The liposomes had a mean diameter of 100 to 150 nm and exhibited colloidal stability for up to 8 weeks. Uptake of Tf-conjugated G3139-containing liposomes in TfR positive K562 cells was found to be more efficient than that of the non-targeted control formulation and could be blocked by excess free Tf. Treatment with Tf-conjugated liposomes resulted in Bcl-2 protein downregulation in K562 cells that was approximately 2-fold greater than with non-targeted liposomes (p<0.05) and 10-fold greater than with free G3139. Treatment with 2 microM G3139 in Tf-conjugated liposomes resulted in >80% reduction in Bcl-2 transcript. In addition, Tf-conjugated liposomal G3139-sensitized K562 cells to daunorubicin, lowering IC50 from 1.8 microM to 0.18 microM. In conclusion, Tf-conjugated liposomes are effective delivery vehicles for G3139 antisense oligos in TfR positive K562 cells and warrant further investigation as an in vivo oligo delivery vehicle.
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PMID:Efficient delivery of a Bcl-2-specific antisense oligodeoxyribonucleotide (G3139) via transferrin receptor-targeted liposomes. 1656 96

Terminal prostate cancer is refractory to conventional anticancer treatments because of frequent overexpression of antiapoptotic proteins Bcl-2 and/or Bcl-x(L). Adenovirus-mediated delivery of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a secreted cytokine having cancer-selective apoptosis-inducing properties, profoundly inhibits prostate cancer cell growth. However, forced overexpression of Bcl-2 or Bcl-x(L) renders prostate cancer cells resistant to Ad.mda-7. We constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV generates large quantities of MDA-7/IL-24 as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal prostate epithelial cells and parental and Bcl-2- or Bcl-x(L)-overexpressing prostate cancer cells confirmed cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 (CTV) into xenografts derived from DU-145-Bcl-x(L) cells in athymic nude mice completely eradicated not only primary tumors but also distant tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for advanced prostate cancer patients with metastatic disease.
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PMID:Eradication of therapy-resistant human prostate tumors using a cancer terminator virus. 1754 25

Transient focal ischemia caused by middle cerebral artery occlusion (MCAo) produces apoptotic cell death in the penumbra area. Bcl-2 is a protooncogene that plays a major antiapoptotic role, at the cellular level, by counteracting the activation of apoptosis effectors, that is, caspases. It has been suggested that nitroglycerin (NTG), a nitric oxide donor, reduces ischemia/reperfusion-induced brain damage via the inhibition of caspase activity and NMDA receptor. In this chapter, we evaluated the protective effects of NTG against cerebral damage caused by transient (2h) MCAo (tMCAo) focusing our interest on the potential effects on Bcl-2 expression. Male Wistar rats were administered intraperitoneally (i.p.) with NTG (10mg/kg) or vehicle (PEG, 1ml/kg) 20min before the induction of MCAo by intraluminal silicon-coated filament (0.37-mm diameter). Cerebral infarct volume was measured 22h after reperfusion, while cortical Bcl-2 expression was evaluated at the end of 2-h MCAo (without reperfusion) and at 5h of reperfusion. The results show significant reduction of the infarct volume in rats preinjected with NTG, as compared to the vehicle group. After 2h of occlusion, no significant difference was seen in Bcl-2 expression in the ipsilateral and contralateral cortex of either experimental groups (NTG and vehicle). However, 5h after reperfusion, a significant increase of Bcl-2 expression was detected in the damaged cortex of control rats, probably reflecting a compensatory response aiming at counteracting the cell death process; this increase was absent in the NTG-treated rats. These data, while confirming the neuroprotective effect of NTG in an in vivo ischemia/reperfusion model, seem to suggest that the drug may act by downsizing the complex chain of events underlying apoptosis activation and consequent activation of antiapoptotic responses.
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PMID:Neuroprotective effect of nitroglycerin in a rodent model of ischemic stroke: evaluation of Bcl-2 expression. 1767 76

Curcumin, a major pigment of turmeric, is a natural antioxidant possessing a variety of pharmacological activities and therapeutic properties. But its mechanisms are unknown. In our previous study, we found that a 2-h exposure to curcumin induced DNA damage to both the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) in HepG2 cells and that mtDNA damage was more extensive than nDNA damage. Therefore, experiments were initiated to evaluate the role of mtDNA damage in curcumin-induced apoptosis. The results demonstrated that HepG2 cells challenged with curcumin for 1 h showed a transient elevation of the mitochondrial membrane potential (DeltaPsim), followed by cytochrome c release into the cytosol and disruption of DeltaPsim after 6 h exposure to curcumin. Apoptosis was detected by Hoechst 33342 and annexin V/PI assay after 10 h treatment. Interestingly, the expression of Bcl-2 remained unchanged. A resistance to apoptosis for the corresponding rho0 counterparts confirmed a critical dependency for mitochondria during the induction of apoptosis in HepG2 cells mediated by curcumin. The effects of PEG-SOD in protecting against curcumin-induced cytotoxicity suggest that curcumin-induced cytotoxicity is directly dependent on superoxide anion O2- production. These data suggest that mitochondrial hyperpolarization is a prerequisite for curcumin-induced apoptosis and that mtDNA damage is the initial event triggering a chain of events leading to apoptosis in HepG2 cells.
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PMID:Curcumin induces apoptosis through mitochondrial hyperpolarization and mtDNA damage in human hepatoma G2 cells. 1769 41

The objective of this study was to investigate whether PEGylated conjugated linoleic acid (PCLA), as compared with conjugated linoleic acid (CLA) alone, displays anti-cancer properties in MCF-7 breast cancer cells. To generate PCLA, CLA was simply coupled to poly(ethylene glycol) (PEG) at the melting state of PEG without a solvent or a catalyst. The coupling reaction generated an ester linkage between the carboxyl group of CLA and hydroxyl one of PEG. The half-life of the generated PCLA was 52h at pH 7.4 at 37 degrees C, indicating that PCLA potentially acts as a pro-drug. Apoptosis of MCF-7 breast cancer cells treated with PCLA showed a dose response to PCLA concentration during treatment. In addition, pro-apoptotic proteins such as Bax were up-regulated, whereas anti-apoptotic proteins, such as Bcl-2, were down-regulated by treatment with both CLA and PCLA. The tumor suppressor gene p53 was significantly up-regulated by treatment with increasing concentrations of PCLA, suggesting that PCLA-induced apoptosis is regulated by a p53-mediated signaling pathway. Overall, the anti-cancer effects of PCLA on MCF-7 breast cancer cells may have therapeutic significance.
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PMID:PEGylated conjugated linoleic acid stimulation of apoptosis via a p53-mediated signaling pathway in MCF-7 breast cancer cells. 1857 37

In this study, cationic nanoparticles self-assembled from the amphiphilic copolymer poly(N-methyldietheneamine sebacate)-co-[(cholesteryl oxocarbonylamido ethyl) methyl bis(ethylene) ammonium bromide] sebacate) (P(MDS-co-CES) were synthesized and used to deliver Bcl-2 targeted siRNA into HepG2, HeLa and MDA-MB-231 cell lines, and downregulate Bcl-2 mRNA expression levels. Confocal microscopic studies show that the nanoparticles were able to complex with siRNA and deliver it inside the cells efficiently, but siRNA was easily dissociated from the complexes in the cytoplasm for its biological functions. Bcl-2 mRNA expression levels as low as 10% were achieved after treatment with nanoparticle/siRNA complexes. The downregulation efficiency of Bcl-2 mRNA level was similar to that mediated by Lipofectamine but higher than that induced by PEI. PEG was also conjugated to siRNA via a cleavable disulfide bond, and nanoparticle/siRNA-PEG complexes showed no significant protein adsorption as compared with 26 and 17% for blank nanoparticles and nanoparticle/siRNA complexes, respectively. The presence of serum caused slight aggregation of nanoparticle/siRNA or nanoparticle/siRNA-PEG complexes. However, the size of the complexes was still below 250 nm after being incubated in PBS containing 10% serum for 4 h. On the other hand, PEGylated siRNA delivered by the nanoparticles downregulated Bcl-2 mRNA expression level in the cells as efficiently as unmodified siRNA. Bcl-2 protein was also downregulated efficiently by nanoparticle/siRNA complexes in all cell lines tested. The downregulation of Bcl-2 mRNA or Bcl-2 protein did not show significant cell death in the tested siRNA and polymer concentration range. However, the delivery of siRNA sensitized HeLa cells to paclitaxel treatment, yielding significant improvement over the untreated cells (p<0.05). These cationic nanoparticles may be potentially employed to downregulate Bcl-2 expression and sensitize cancer cells to anticancer drugs for more efficient chemotherapy.
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PMID:Efficient delivery of Bcl-2-targeted siRNA using cationic polymer nanoparticles: downregulating mRNA expression level and sensitizing cancer cells to anticancer drug. 1907 31

Epigallocatechin-3-gallate (EGCG), a catechin polyphenols component, is the main ingredient of green tea extract. It has been reported that EGCG is a potent antioxidant and beneficial in oxidative stress-related diseases, but others and our previous study showed that EGCG has pro-oxidant effects at high concentration. Thus, in this study, we tried to examine the possible pathway of EGCG-induced cell death in cultures of rat hippocampal neurons. Our results showed that EGCG caused a rapid elevation of intracellular free calcium levels ([Ca(2+)](i)) in a dose-dependent way. Exposure to EGCG dose- and time-dependently increased the production of reactive oxygen species (ROS) and reduced mitochondrial membrane potential (Deltapsi(m)) as well as the Bcl-2/Bax expression ratio. Importantly, acetoxymethyl ester of 5,5'-dimethyl-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid, and vitamin E could attenuate EGCG-induced apoptotic responses, including ROS generation, mitochondrial dysfunction, and finally partially prevented EGCG-induced cell death. Furthermore, treatment of hippocampal neurons with EGCG resulted in an elevation of caspase-3 and caspase-9 activities with no significant accompaniment of lactate dehydrogenase release, which provided further evidence that apoptosis was the dominant mode of EGCG-induced cell death in cultures of hippocampal neurons. Taken together, these findings indicated that EGCG induced hippocampal neuron death through the mitochondrion-dependent pathway.
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PMID:Epigallocatechin-3-gallate induced primary cultures of rat hippocampal neurons death linked to calcium overload and oxidative stress. 1922 18

A multi-inlet microfluidic hydrodynamic focusing (MF) system to prepare lipopolyplex (LP) containing Bcl-2 antisense deoxyoligonucleotide (ODN) was developed and evaluated. The lipopolyplex nanoparticles consist of ODN:protamine:lipids (1:0.3:12.5wt/wt ratio) and the lipids included DC-Chol:egg PC:PEG-DSPE (40:58:2mol/mol%). Using K562 human erythroleukemia cells, which contain an abundance of Bcl-2 and overexpression of transferrin receptors (TfR), and G3139 (oblimerson sodium or Genasense(TM)) as a model cell line and drug, respectively, the Bcl-2 down-regulation at the mRNA and protein levels as well as cellular uptake and apoptosis was compared between the conventional bulk mixing (BM) method and the MF method. The lipopolyplex size and surface charge were characterized by dynamic light scattering (DLS) and zeta potential (zeta) measurement, respectively, while the ODN encapsulation efficiency was determined by gel electrophoresis. Cryogenic transmission electron microscopy (Cryo-TEM) was used to determine the morphology of LPs. Our results demonstrated that MF produced LP nanoparticles had similar structures but smaller size and size distribution compared to BM LP nanoparticles. MF LP nanoparticles had higher level of Bcl-2 antisense uptake and showed more efficient down-regulation of Bcl-2 protein level than BM LP nanoparticles.
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PMID:Delivery of antisense oligodeoxyribonucleotide lipopolyplex nanoparticles assembled by microfluidic hydrodynamic focusing. 1971 52


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