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)

Troglitazone, a thiazolidinedione containing compound, was widely used to treat non-insulin dependent-diabetes. Unfortunately, troglitazone was associated with a sporadic liver toxicity that led to a cessation of its use clinically. Here we show that troglitazone induces a rapid and dose-dependent drop of mitochondrial membrane potential in liver HepG2 cells. The decrease in mitochondrial membrane potential induced by 100 microM troglitazone was completed after 5 min and similar in magnitude to that caused by carbonyl cyanide m-chloro phenylhydrazone. The troglitazone-induced loss of mitochondrial membrane potential preceded changes in cell permeability and cell count. In addition, troglitazone-induced a rise of intracellular calcium, subsequent to the drop in mitochondrial membrane potential, which was blocked by EGTA and the Na+/Ca2+ exchange inhibitor bepridil. Finally, application of 100 microM troglitazone for 24h to HepG2 cells resulted in activation of caspase 3. The results of this study shed light on the molecular mechanisms by which troglitazone can cause cytotoxicity.
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PMID:Troglitazone induces a rapid drop of mitochondrial membrane potential in liver HepG2 cells. 1558 58

Amyloid-beta peptide (Abeta) binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, is a cofactor facilitating Abeta-induced cell stress. We hypothesized that ABAD provides a direct link between Abeta and cytotoxicity via mitochondrial oxidant stress. Neurons cultured from transgenic (Tg) mice with targeted overexpression of a mutant form of amyloid precursor protein and ABAD (Tg mAPP/ABAD) displayed spontaneous generation of hydrogen peroxide and superoxide anion, and decreased ATP, as well as subsequent release of cytochrome c from mitochondria and induction of caspase-3-like activity followed by DNA fragmentation and loss of cell viability. Generation of reactive oxygen species (ROS) was associated with dysfunction at the level of mitochondrial complex IV (cytochrome c oxidase, or COX). In neurons cultured from Tg mAPP/ABAD mice, COX activity was selectively decreased, and cyanide, an inhibitor of complex IV, exacerbated leakage of ROS, induction of caspase-3-like activity, and DNA fragmentation. In vivo, Tg mAPP/ABAD mice displayed reduced levels of brain ATP and COX activity, diminished glucose utilization, as well as electrophysiological abnormalities in hippocampal slices compared with Tg mAPP mice. In contrast, neither Tg ABAD mice nor nontransgenic (non-TG) littermates showed similar changes in ATP, COX activity, glucose utilization or electrophysiological properties. Each of the genotypes (Tg ABAD, Tg mAPP and Tg mAPP/ABAD mice, and non-TG littermates) displayed normal reproductive fitness, development and lifespan (1) These findings link ABAD-induced oxidant stress to critical aspects of Alzheimer's disease (AD)-associated cellular dysfunction, suggesting a pivotal role for this enzyme in the pathogenesis of AD.
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PMID:ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. 1566 36

The success of anticancer chemotherapy is often hampered by resistance to apoptosis, which may depend on defects in intracellular cell death pathways. Characterizing the alterations of these pathways is a prerequisite for developing alternative and effective antitumoral strategies. Here, we investigated the susceptibility of a human astrocytoma cell line, ADF, to apoptotic cell death induced by mitochondria-damaging agents. Neither the anticancer agent betulinic acid nor the "mitochondriotropic" poisons 2-deoxy-d-ribose and potassium cyanide induced apoptosis of these cells, despite induction of highly significant mitochondrial depolarization, eventually resulting in necrotic death. Resistance to apoptosis was not due to presence of the multidrug resistance pump or to impaired expression of caspase-8, caspase-9, or "executioner" caspase-3. Cloning of caspase-9 revealed the presence of full-length caspase-9alpha and a short variant (caspase-9beta), which, in other tumors, acts as a dominant negative of the long isoform. All analyzed clones showed a point mutation in the prodomain region that is known to interact with mitochondria-released factors. Thus, in these human astrocytoma cells, mitochondria-damaging agents induce a regulated form of mitochondrial-dependent necrotic cell death (oncosis). Resistance to apoptosis is due to an intrinsic defect of caspase-9, leading to inhibition of enzyme activation and/or impaired interaction with proteins released from depolarized mitochondria. These results may have implications for developing strategies aimed at overcoming tumor resistance to chemotherapy.
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PMID:Resistance of human astrocytoma cells to apoptosis induced by mitochondria-damaging agents: possible implications for anticancer therapy. 1587 6

The effects of reactive oxygen species (ROS) on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in solid cancers have yet to be clearly defined. In this study, we found that the classic uncoupler of oxidative phosphorylation, carbonyl cyanide m-chlorophenylhydrazone (CCCP), induced a reduction in DeltaPsim and generation of ROS. This uncoupling effect enhanced TRAIL-induced apoptosis in TRAIL-resistant human colon carcinoma cell lines (RKO, HT29, and HCT8). Sensitization was inhibited by benzyloxycarbonyl-valine-alanine-aspartate fluoromethylketone, indicating the requirement for caspase activation. CCCP per se did not induce apoptosis or release of proapoptotic factors from mitochondria. Generation of ROS by CCCP was responsible for TRAIL-induced Bax and caspase activation because scavenging ROS completely abrogated apical caspase-8 activation and further downstream events leading to cell death. Overexpression of Bcl-2 did not prevent the initial loss of DeltaPsim and ROS generation following CCCP treatment, but did prevent cell death following TRAIL and CCCP exposure. Uncoupling of mitochondria also facilitated TRAIL-induced release of proapoptotic factors. X-linked inhibitor of apoptosis overexpression abrogated TRAIL-induced apoptosis in the presence of CCCP and decreased initiator procaspase-8 processing, indicating that additional processing of caspase-8 required initiation of a mitochondrial amplification loop via effector caspases. Of interest, depletion of caspase-9 in RKO cells did not protect cells from TRAIL/CCCP-induced apoptosis, indicating that apoptosis occurred via a caspase-9-independent pathway. Data suggest that in the presence of mitochondrial-derived ROS, TRAIL induced mitochondrial release of Smac/DIABLO and inactivation of X-linked inhibitor of apoptosis through caspase-9-independent activation of caspase 3.
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PMID:Reactive oxygen species regulate caspase activation in tumor necrosis factor-related apoptosis-inducing ligand-resistant human colon carcinoma cell lines. 1610 97

Huntington's disease (HD) is caused by mutated huntingtin (htt), a toxic protein ubiquitously expressed in nervous and non-nervous system tissues. Fragmentation of htt by caspases and further accumulation in cells of protein aggregates contribute to cell dysfunction and death. In the attempt to elucidate whether this mechanism depends on patients' genotype, we analysed the pattern of htt fragmentation, the caspase 3, 8 and 9 activities and their variation in lymphoblasts with heterozygous and homozygous CAG mutation and in controls. Cells homozygous for expanded mutation showed greater amount of mutated fragments than heterozygotes and controls, caspase 3, 8 and 9 activities greater in mutated than control cell lines, after cyanide treatment, the caspase 3 and 8 particularly increased in homozygotes. This data offers a biological explanation to the clinical in-patients evidence of mutation homozygosity associated with more severe phenotype.
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PMID:Huntingtin fragmentation and increased caspase 3, 8 and 9 activities in lymphoblasts with heterozygous and homozygous Huntington's disease mutation. 1628 52

Cytotoxicity testing allows determining whether a compound or extract contains significant quantities of biologically harmful chemicals. Cytotoxicity test methods are useful for screening because they serve to separate toxic from nontoxic materials, providing predictive evidence of compound safety. However, a wide range of assays measuring different aspects of cell death is available in the market, but it is difficult to determine which one(s) to use when evaluating a selection of compounds. The objective of this study was to compare different commercially available in vitro assays for cytotoxicity in HepG2 cells according to its sensitivity, reproducibility, simplicity, cost, and speed. The assays evaluated included Alamar Blue for the measurement of mitochondrial activity, ATPlite and ViaLight for the determination of cellular adenosine triphosphate (ATP), ToxiLight as an indicator of cellular necrosis, and Caspase-3 Fluorometric Assay, Apo-ONE Caspase-3/7 Homogeneous Assay, and Caspase-Glo for the determination of caspase-3/7 activity. All assays were performed using 4 compounds of previously reported cytotoxic activity: DMSO, butyric acid, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), and camptothecine. Overall, it was concluded that the best way to evaluate the potential cytotoxicity of a compound is to employ a battery of assays that focus on different aspects of cell death. In this case, the focus has been on ATP levels, cell necrosis, and capsase-3/7 activation. Many other kits are commercially available in the market for these and other aspects of necrosis and/or apoptosis. However, the use of ViaLight Plus, ToxiLight, and Caspase-3 Fluorometric Assay resulted in the most useful combination when working with HepG2 cells.
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PMID:Comparison of in vitro assays of cellular toxicity in the human hepatic cell line HepG2. 1631 2

Near-infrared light via light-emitting diode treatment has documented therapeutic effects on neurons functionally inactivated by tetrodotoxin or methanol intoxication. Light-emitting diode pretreatment also reduced potassium cyanide-induced cell death, but the mode of death via the apoptotic or necrotic pathway was unclear. The current study tested our hypothesis that light-emitting diode rescues neurons from apoptotic cell death. Primary neuronal cultures from postnatal rat visual cortex were pretreated with light-emitting diode for 10 min at a total energy density of 30 J/cm2 before exposing to potassium cyanide for 28 h. With 100 or 300 microM potassium cyanide, neurons died mainly via the apoptotic pathway, as confirmed by electron microscopy, Hoechst 33258, single-stranded DNA, Bax, and active caspase-3. In the presence of caspase inhibitor I, the percentage of apoptotic cells in 300microM potassium cyanide was significantly decreased. Light-emitting diode pretreatment reduced apoptosis from 36% to 17.9% (100 microM potassium cyanide) and from 58.9% to 39.6% (300 microM potassium cyanide), representing a 50.3% and 32.8% reduction, respectively. Light-emitting diode pretreatment significantly decreased the expression of caspase-3 elicited by potassium cyanide. It also reversed the potassium cyanide-induced increased expression of Bax and decreased expression of Bcl-2 to control levels. Moreover, light-emitting diode decreased the intensity of 5-(and -6) chloromethy-2', 7-dichlorodihydrofluorescein diacetate acetyl ester, a marker of reactive oxygen species, in neurons exposed to 300 microM potassium cyanide. These results indicate that light-emitting diode pretreatment partially protects neurons against cyanide-induced caspase-mediated apoptosis, most likely by decreasing reactive oxygen species production, down-regulating pro-apoptotic proteins and activating anti-apoptotic proteins, as well as increasing energy metabolism in neurons as reported previously.
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PMID:Photobiomodulation partially rescues visual cortical neurons from cyanide-induced apoptosis. 1646 35

Our recent study showed that estrogen receptor (ER) beta plays a major role in mediating the salutary effects of 17beta-estradiol (E2) on cardiac function following trauma-hemorrhage (T-H). E2 is known to regulate mitochondrial DNA (mtDNA)-encoded genes including the mitochondrial respiratory complex (MRC) proteins. Depressed MRC activity has been reported to promote the release of cytochrome c from mitochondria and induce apoptosis. We hypothesized that E2 and ERbeta-mediated cardioprotection following T-H is dependent on mtDNA transcription encoding for MRC activity. To test this, male rats underwent T-H (mean BP 40 mm Hg approximately 90 min, then resuscitation). During resuscitation, rats received either ERalpha agonist propylpyrazole triol (PPT; 5 microg/kg), ERbeta agonist diarylpropionitrile (DPN; 5 microg/kg), E2 (50 microg/kg), or vehicle (10% DMSO). Another group of rats received mitochondrial respiratory complex-IV (MRC-IV) inhibitor sodium cyanide (SCN; 6 mg/kg) with or without DPN. The results indicated that 24 h after T-H, cardiac functions were depressed in the vehicle-treated but were normal in the DPN-treated rats. Moreover, E2 or DPN treatment after T-H normalized cardiac mitochondrial ERbeta expression and increased mitochondrial ERbeta DNA-binding activity. This was accompanied by an increase in MRC-IV gene expressions and activity, while MRC-I gene expression remained unchanged. Inhibition of MRC-IV in DPN-treated T-H rats by SCN abolished the DPN-mediated cardioprotection, ATP production, mitochondrial cytochrome c release, caspase-3 cleavage, and apoptosis. Thus, E2 and ERbeta-mediated cardioprotection following T-H appears to be mediated via mitochondrial ERbeta-dependent MRC-IV activity and inhibition of mitochondrial apoptotic signaling pathways.
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PMID:Upregulation of mitochondrial respiratory complex IV by estrogen receptor-beta is critical for inhibiting mitochondrial apoptotic signaling and restoring cardiac functions following trauma-hemorrhage. 1685 1

Prostate cancer is one of the most common non-skin cancers in men. Amygdalin is one of the nitrilosides, natural cyanide-containing substances abundant in the seeds of plants of the prunasin family that have been used to treat cancers and relieve pain. In particular, D-amygdalin (D-mandelonitrile-beta-D-gentiobioside) is known to exhibit selective killing effect on cancer cells. Apoptosis, programmed cell death, is an important mechanism in cancer treatment. In the present study, we prepared the aqueous extract of the amygdalin from Armeniacae semen and investigated whether this extract induces apoptotic cell death in human DU145 and LNCaP prostate cancer cells. In the present results, DU145 and LNCaP cells treated with amygdalin exhibited several morphological characteristics of apoptosis. Treatment with amygdalin increased expression of Bax, a pro-apoptotic protein, decreased expression of Bcl-2, an anti-apoptotic protein, and increased caspase-3 enzyme activity in DU145 and LNCaP prostate cancer cells. Here, we have shown that amygdalin induces apoptotic cell death in human DU145 and LNCaP prostate cancer cells by caspase-3 activation through down-regulation of Bcl-2 and up-regulation of Bax. The present study reveals that amygdalin may offer a valuable option for the treatment of prostate cancers.
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PMID:Amygdalin induces apoptosis through regulation of Bax and Bcl-2 expressions in human DU145 and LNCaP prostate cancer cells. 1688 Jun 11

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder in which excitotoxicity has been implicated as a cause for cell death. To examine neurofilament (NF) aggregate-mediated sensitization of motor neurons to NMDA excitotoxicity, we examined NMDA receptor expression and the impact of NO donors (NOC12 or NOC5) or sodium cyanide (NaCN) on calcium influx and viability in dissociated motor neurons derived from wt and hNFL+/+ (NF aggregate-forming) mice. Alterations in intracellular calcium were assayed using Oregon Green calcium dye and the extent of apoptosis using active caspase-3 immunoreactivity. Although NF aggregate-bearing neurons demonstrated increased intracellular calcium levels and enhanced cell death in response to NMDA receptor activation, this was not associated with increased NMDA receptor expression. The down-regulation of the NMDA receptor using NO donors decreased calcium influx and caspase-3 activation in aggregate-bearing neurons, but had no effect on wt cultures. The converse was observed with NaCN in which intracellular calcium levels increased significantly in wt cultures in association with increased cell death. No effect was observed in aggregate-bearing neurons. These findings suggest that the presence of NF aggregates renders motor neurons more susceptible to NMDA-mediated excitotoxicity, and that this can be reversed by NO.
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PMID:Loss of nitric oxide-mediated down-regulation of NMDA receptors in neurofilament aggregate-bearing motor neurons in vitro: implications for motor neuron disease. 1715 1


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