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)

Reactive oxygen species are known to be potentially dangerous, but are also needed for signal-transduction pathways. Tumor cells have relatively low amounts of superoxide dismutase (SOD), which quenches superoxide anion (O2(-*)), and as a result of a higher level of aerobic metabolism, higher concentrations of O2(-*) , compared to normal cells. But this may not be true of all tumor cells. Some tumor cells have relatively higher amounts of vitamin E, a potent anti-oxidant, and a higher level of anaerobic metabolism, resulting in a balance that is tilted more towards higher anti-oxidant capacity. In both instances of higher aerobic and anaerobic metabolism methods designed to augment free radical generation in tumor cells can cause their death. It is suggested that free radicals and lipid peroxides suppress the expression of Bcl-2, activate caspases and shorten telomere, and thus inducing apoptosis of tumor cells. Ionizing radiation, anthracyclines, bleomycin and cytokines produce free radicals and thus are useful as anti-cancer agents. But they also produce many side-effects. 2-methoxyoestradiol and polyunsaturated fatty acids (PUFAs) inhibit SODs and cause an increase of O2(-*) in tumor cells leading to their death. In addition, PUFAs (especially gamma-linolenic acid), 2-methoxyoestradiol and thalidomide may possess anti-angiogenic activity. This suggests that free radicals can suppress angiogenesis. Limited clinical studies done with gamma-linolenic acid showed that it can regress human brain gliomas without any significant side-effects. Thus, PUFAs, thalidomide and 2-methoxyoestradiol or their derivatives may offer a new radical approach to the treatment of cancer.
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PMID:A radical approach to cancer. 1195 Oct 81

Nitric oxide (NO) mediates apoptosis induction in fibroblasts with constitutive src or induced ras oncogene expression, whereas nontransformed parental cells and revertants are not affected. This direct link between the transformed phenotype and sensitivity to NO-mediated apoptosis induction seems to be based on the recently described extracellular superoxide anion generation by transformed cells, as NO-mediated apoptosis induction in transformed cells is inhibited by extracellular superoxide dismutase (SOD), by SOD mimetics and by apocynin, an inhibitor of NADPH oxidase. Furthermore, nonresponsive nontransformed cells can be rendered sensitive for NO-mediated apoptosis induction when they are supplemented with xanthine oxidase/xanthine as an extracellular source for superoxide anions. As superoxide anions and NO readily interact in a diffusion-controlled reaction to generate peroxynitrite, peroxynitrite seems to be the responsible apoptosis inducer in NO-mediated apoptosis induction. In line with this conclusion, NO-mediated apoptosis induction in superoxide anion-generating transformed cells is inhibited by the peroxynitrite scavengers ebselen and FeTPPS. Moreover, direct application of peroxynitrite induces apoptosis both in transformed and nontransformed cells, indicating that peroxynitrite is no selective apoptosis inducer per se, but that selective apoptosis induction in transformed cells by NO is achieved through selective peroxynitrite generation. The interaction of NO with target cell derived superoxide anions represents a novel concept for selective apoptosis induction in transformed cells. This mechanism may be the basis for selective apoptosis induction by natural antitumor systems (like macrophages, natural killer cells, granulocytes) that utilize NO for antitumor action. Apoptosis induction mediated by NO involves mitochondrial depolarization and is blocked by Bcl-2 overexpression.
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PMID:Nitric oxide mediates apoptosis induction selectively in transformed fibroblasts compared to nontransformed fibroblasts. 1208 14

Humic acid (HA) has been implicated as an etiologic factor in the vasculopathy of Blackfoot disease. In this study, the ability of HA to induce apoptosis was studied in cultured human umbilical vein endothelial cells. Treatment of endothelial cells with a variety of concentrations of HA (50-200 microg/ml) resulted in dose- and time-dependent sequences of events marked by apoptosis as shown by loss of cell viability, chromatin condensation, and internucleosomal DNA fragmentation. Antioxidants (superoxide dismutase, vitamin C, and vitamin E) and Ca(2+) chelator (BAPTA) effectively suppressed HA-induced DNA fragmentation (apoptosis). Further studies have shown that HA induced dramatic Ca(2+)-dependent caspase activation (2, 3, 6, 8, and 9). In contrast, negligible caspase-1 activation was observed. The increase in HA-induced apoptosis correlated with a reduction in Bcl-2, a potent cell death inhibitor, and an increase in Bax protein levels, which heterodimerizes with and thereby inhibits Bcl-2. Both of the antioxidants vitamin C and vitamin E prevented the dysregulation of Bcl-2 and Bax in HA-treated endothelial cells. Furthermore, the increase in p53 protein levels correlated with an increase in HA-induced apoptosis. We concluded that both Ca(2+) and oxidative stress were mediators of apoptosis caused by HA and the induction of apoptotic cell death on endothelial cells may be important to the etiology of HA-induced vascular disorder of Blackfoot disease.
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PMID:Humic acid induces apoptosis in human endothelial cells. 1212 61

There have been very few investigations as to whether mitochondrial-mediated apoptosis in vivo is the underlying mechanism of doxorubicin cardiotoxicity. Moreover, no investigations have been conducted to determine whether there are adaptive responses after doxorubicin treatment. We administered a single dose of doxorubicin (20 mg/kg) to male rats and isolated intact mitochondria from their hearts 4 days later. Apoptosis, as determined by the amount of cytosolic mononucleosomal and oligonucleosomal DNA fragments (180 bp or multiples), was significantly increased after doxorubicin treatment. In contrast, Troponin-T, a cardiac-specific marker for necrotic damage, was unaltered 4 days after doxorubicin treatment. Cytosolic cytochrome c increased 2-fold in the doxorubicin-treated rats and was significantly correlated (r = 0.88; P < 0.01) with the increase in caspase-3 activity observed. Moreover, the level of bleomyocin-detectable iron in serum was significantly increased and may have contributed to the increase in oxidative stress, which was indicated by an increase in cytosolic 8-iso prostaglandin F(2alpha). Cytosolic copper zinc superoxide dismutase activity also increased significantly further supporting the notion that doxorubicin increases superoxide radical production. In addition to adaptations to antioxidant defenses, other adaptive mechanisms occurred in the mitochondria such as an increase in the respiratory P/O ratio and an increase in the Bcl-2:Bax ratio. These findings demonstrate that doxorubicin induces oxidative stress and mitochondrial-mediated apoptosis, as well as adaptive responses by the mitochondria to protect cardiac myocytes in vivo.
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PMID:Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. 1218 13

In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT.
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PMID:Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. 1220 Jan 98

Human neuroblastoma cells, SH-SY5Y, contain relatively low levels of thioredoxin (Trx); thus, they serve favorably as a model for studying oxidative stress-induced apoptosis (Andoh, T., Chock, P. B., and Chiueh, C. C. (2001) J. Biol. Chem. 277, 9655-9660). When these neurotrophic cells were subjected to nonlethal 2-h serum deprivation, their neuronal nitric oxide synthase and Trx were up-regulated, and the cells became more tolerant of oxidative stress, indicating that NO may protect cells from serum deprivation-induced apoptosis. Here, the mechanism by which NO exerts its protective effects was investigated. Our results reveal that in SH-SY5Y cells, NO inhibits apoptosis through its ability to activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1 and Trx, which subsequently induces the expression of Bcl-2. Furthermore, active PKG promotes the elevation of c-Jun, phosphorylated MAPK/ERK1/2, and c-Myc, consistent with the notion that PKG enhances the expression of Trx through its c-Myc-, AP-1-, and PEA3-binding motifs. Elevation of Trx and Trx peroxidase-1 and Mn(II)-superoxide dismutase would reduce H(2)O(2) and O(2)(), respectively. Thus, the cytoprotective effect of NO in SH-SY5Y cells appears to proceed via the PKG-mediated pathway, and S-nitrosylation of caspases plays a minimal role.
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PMID:Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. 1241 92

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is an active constituent of Rheum palmatum, and showed inhibitory activity on lipopolysaccharide-induced NO production in our previous study. However, the apoptosis-inducing activity of emodin has remained undefined. Among three structurally related anthraquinones, including emodin, physcion, and chrysophanol, emodin showed the most potent cytotoxic effects on HL-60 cells, accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including an increase in DNA ladder intensity, morphological changes, appearance of apoptotic bodies, and an increase in hypodiploid cells. Emodin at apoptosis-inducing concentrations causes rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity, according to cleavage of caspase 3 substrates poly(ADP-ribose) polymerase and D4-GDI proteins, the appearance of cleaved caspase 3 fragments being detected in emodin- but not physcion- or chrysophanol-treated HL-60 cells. A decrease in the anti-apoptotic protein, Mcl-1, was detected in emodin-treated HL-60 cells, whereas other Bcl-2 family proteins including Bax, Bcl-2, Bcl-XL, and Bad remained unchanged. The caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor, Ac-YVAD-CHO, attenuated emodin-induced DNA ladders, associated with the blockage of PARP and D4-GDI cleavage. Free radical scavenging agents including NAC, catalase, SOD, ALL, DPI, L-NAME and PDTC showed no preventive effect on emodin-induced apoptotic responses, whereas NAC, CAT and PDTC prevented HL-60 cells from ROS (H(2)O(2))-induced apoptosis through inhibition of caspase 3 cascades. Induction of catalase, but not SOD, activity was detected in emodin-treated HL-60 cells by in gel activity assays, and H(2)O(2)-induced intracellular peroxide level was significantly reduced by prior treatment of emodin in HL-60 cells. Our experiments provide evidence that emodin is an effective apoptosis inducer in HL-60 cells through activation of the caspase 3 cascade, but that it is independent of ROS production.
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PMID:Emodin induces apoptosis in human promyeloleukemic HL-60 cells accompanied by activation of caspase 3 cascade but independent of reactive oxygen species production. 1244 60

Neurotoxic properties of L-dopa and dopamine (DA)-related compounds were assessed in human neuroblastoma SH-SY5Y cells with reference to their structural relationship. L-Dopa and its metabolites containing two free hydroxyl residues on their benzene ring showed toxicity in the cell, which was prevented by superoxide dismutase (SOD) and reduced glutathione (GSH), but not by catalase. Furthermore, a synthetic derivative of DA, 3-hydroxy-4-methoxyphenethylamine (HMPE) containing methoxy residue at position 4 in the benzene ring, exerted partial cytotoxicity, which was not prevented by SOD, GSH or catalase. However, the metabolites containing methoxy residue at position 3 failed to show a toxic effect in the SH-SY5Y cells. Moreover, DA induced apoptotic cell death, which was observed by nuclear and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and measurement of caspase-3 activity; this compound up-regulated apoptotic factor p53 while down-regulating anti-apoptotic factor Bcl-2. In the cell-free in vitro electron spin resonance (ESR) spectrometry, DA possessing two hydroxyl groups showed generation of DA-semiquinone radicals, which were markedly prevented by addition of SOD or GSH but not by catalase. On the other hand, methylation of one of the hydroxyl residues on the benzene ring of DA converted DA to an unoxidizable compound (3-MT or HMPE), and caused it to lose the property to produce semiquinone radicals. It has been previously reported that SOD acting as a superoxide:semiquinone oxidoreductase prevents quinone formation, and that reduced GSH through forming a complex with DA-quinone prevents quinone binding to the thiol group of the intact protein. Therefore, the present results suggest that DA and its metabolites containing two hydroxyl residues exert cytotoxicity mainly due to generation of highly reactive quinones.
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PMID:Apoptosis-inducing neurotoxicity of dopamine and its metabolites via reactive quinone generation in neuroblastoma cells. 1249 14

The developing central nervous system is extremely sensitive to ethanol, with well-defined temporal periods of vulnerability. Many brain regions are particularly susceptible to ethanol during the early neonatal period, corresponding to the human third trimester, which represents a dynamic period of growth and differentiation. For this study, neonatal rats were acutely exposed to ethanol or control conditions at a neonatal age when the developing striatum has been shown to be vulnerable to ethanol (postnatal day 3 [P3]), and at a later age (P14), when this developing region is relatively ethanol-resistant. We then analyzed basal levels of neurotrophic factors (NTFs), and ethanol-mediated changes in NTFs, apoptosis-related proteins, antioxidants, and reactive oxygen species (ROS) generation, which may underlie this differential temporal vulnerability. Sequential analyses were made following ethanol exposure on these two postnatal days, with assessments of NTFs nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4); apoptosis-related proteins Bcl-2, Bcl-xl, Bax, Akt and c-jun N-terminal kinase (JNK); antioxidants superoxide dismutase, glutathione reductase and catalase; and ROS. The results indicated that basal levels of BDNF, and to some degree NGF, were greater at the older age, and that ethanol exposure at the earlier age elicited considerably more pro-apoptotic and fewer pro-survival changes than those produced at the later age. Thus, differential temporal vulnerability to ethanol in this CNS region appears to be related to differences in both differential levels of protective substances (e.g. NTFs), and differential cellular responsiveness which favors apoptosis at the most sensitive age and survival at the resistant age.
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PMID:Effects of ethanol on neurotrophic factors, apoptosis-related proteins, endogenous antioxidants, and reactive oxygen species in neonatal striatum: relationship to periods of vulnerability. 1258 29

The evidence for a role of apoptosis in the neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and in the more acute conditions of cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI) is reviewed with regard to potential intervention by means of small antiapoptotic molecules. In addition, the available animal models for these diseases are discussed with respect to their relevance for testing small antiapoptotic molecules in the context of what is known about the apoptotic pathways involved in the diseases and the models. The principal issues related to pharmacotherapy by apoptosis inhibition, i.e., functionality of rescued neurons and potential interference with physiologically occurring apoptosis, are pointed out. Finally, the properties of a number of small antiapoptotic molecules currently under clinical investigation are summarized. It is concluded that the evidence for a role of apoptosis at present is more convincing for PD and ALS than for AD. In PD, damage to dopaminergic neurons may occur through oxidative stress and/or mitochondrial impairment and culminate in activation of an apoptotic, presumably p53-dependent cascade; some neurons experiencing energy failure may not be able to complete apoptosis, end up in necrosis and give rise to inflammatory processes. These events are reasonably well reflected in some of the PD animal models, notably those involving 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone. In sporadic ALS, an involvement of pathways involving p53 and Bcl-2 family members appears possible if not likely, but is not established. The issue is important for the development of antiapoptotic compounds for the treatment of this disease because of differential involvement of p53 in different mutant superoxide dismutase (SOD) mice. Most debated is the role of apoptosis in AD; this implies that little is known about potentially involved pathways. Moreover, there is a lack of suitable animal models for compound evaluation. Apoptosis or related phenomena are likely involved in secondary cell death in cerebral ischemia, TBI, and SCI. Most of the pertinent information comes from animal experiments, which have provided some evidence for prevention of cell death by antiapoptotic treatments, but little for functional benefit. Much remains to be done in this area to explore the potential of antiapoptotic drugs. There is a small number of antiapoptotic compounds in clinical development. With some of them, evidence for maintenance of functionality of the rescued neurons has been obtained in some animal models, and the fact that they made it to phase II studies in patients suggests that interference with physiological apoptosis is not an obligatory problem. The prospect that small antiapoptotic molecules will have an impact on the therapy of neurodegenerative diseases, and perhaps also of ischemia and trauma, is therefore judged cautiously positively.
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PMID:Prospects for antiapoptotic drug therapy of neurodegenerative diseases. 1265 69


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