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

Colorectal carcinoma is a human malignant tumor, which is very resistant to currently available methods of treatment. Therefore, developing an effective agent with anti-colorectal carcinoma activity is important. In the present study, 8 structurally related flavones including flavone, 3-OH flavone, 5-OH flavone, 7-OH flavone, quercetin, kaempferol, quercetin, and morin were used to study their effects on colorectal carcinoma cells (HT29, COLO205, COLO320-HSR). Results of MTT assay indicated that flavone shows the most potent cytoxic effect among them on these three cell types. The cytotoxicity induced by flavone is mediated by inducing the occurrence of apoptosis characterized by the appearance of DNA ladders, apoptotic bodies and hypodiploid cells. Activation of caspase 3 protein procession and enzyme activity with inducing cleavage of caspase 3 substrates PARP was identified in flavone-treated cells, and an inhibitory peptide Ac-DEVD-FMK for caspase 3, but not Ac-YVAD-FMK for caspase 1, attenuates the cytotoxic effect of flavone in COLO205 and HT29 cells. Elevation of p21 but no p53 protein was observed in flavone-treated cells. Increasing intracellular peroxide level was detected in flavone-treated cells by DCHF-DA assay, and antioxidants such as tiron, catalase, SOD, PDTC, but not DPI, suppress flavone-induced cytotoxic effect. In vivo anti-tumor study indicates that flavone exhibits ability to inhibit tumor formation elicited by s.c. injection of COLO205 cells in nude mice, and apoptotic cells and an increase in p21, but not p53, protein were observed in tumor tissues derived from flavone-treated group. Additionally, flavone induced apoptosis in primary colon carcinoma cells COLO205-X with appearance of DNA ladders, caspase 3 protein procession, PARP protein cleavage, and an increase in p21 (not p53) protein. These data provide evidence to suggest that flavone is an effective agent to induce apoptosis in colorectal carcinoma cells in vitro and in vivo; activation of caspase 3, ROS production, and increasing p21 protein are involved.
 ...
PMID:Flavone inhibition of tumor growth via apoptosis in vitro and in vivo. 1528 67

Sesamin and sesamolin were tested for their ability to protect BV-2 microglia from hypoxia-induced cell death. These antioxidants dose-dependently reduced hypoxia-induced lactate dehydrogenase (LDH) release and dichlorofluorescein (DCF)-sensitive reactive oxygen species (ROS) production. Their effects on signaling pathway mitogen-activated protein kinases (MAPKs) and caspase-3 in hypoxia-induced cell death were further examined. Extracellular signal-regulated protein kinases (ERK1/2), c-jun NH(2)-terminal kinase (JNK), and p38 MAPKs were activated during hypoxia. The sesamin or sesamolin reduced caspase-3 and MAPK activation correlated well with diminished LDH release in BV-2 cells under hypoxia. Furthermore, they preserved superoxide dismutase (SOD) and catalase activities in BV-2 cells under hypoxia. Taken together, these results indicate that the mechanism of sesame antioxidants involves inhibition of MAPK pathways and apoptosis through scavenging of ROS in hypoxia-stressed BV-2 cells.
 ...
PMID:Protective effects of sesamin and sesamolin on murine BV-2 microglia cell line under hypoxia. 1530 87

Ketoconazole (KTZ) has been used as a second-line agent in hormone-refractory cancer therapy. Since transition metal complexes including those of Ru(III), show important anticancer activity with limited toxicity, we investigated the potential antitumor efficacy of Ru(II) complexed to KTZ or clotrimazole (CTZ) compared to Ru(II) alone or uncomplexed azoles. RuCl2(KTZ)2 exerted greater apoptosis- associated caspase-3 activation than RuCl2(CTZ)2, KTZ, CTZ or RuCl2(MeCN)4 against several human tumor cell monolayers. PARP cleavage and a decrease in S+G2 cells were evident after RuCl2(KTZ)2 treatment in genetically matched C8161 melanoma monolayers with unequal p53 functional status. Release of mitochondrial cytochrome c and Mn-SOD suggest mitochondria as a target of RuCl2(KTZ)2. Treatment of WM164 melanoma monolayers with 25 microM of cisplatin or RuCl2(KTZ)2 showed that the latter is more effective than cisplatin at inducing PARP fragmentation and proapoptotic Bak expression. Such results suggest that these Ru(II) and Pt(II) metal complexes are unequally effective and act through alternative signaling pathways. In studies with multicellular spheroids, which frequently are more resistant to cytotoxic anticancer drugs than monolayers, those from wt p53 C8161 melanoma underwent PARP fragmentation in response to RuCl2(KTZ)2. In contrast, spheroids of mut p53 A431 carcinoma overexpressing EGF receptor were resistant to either RuCl2(KTZ)2 or anti-EGF receptor C225 MAb. However, joint treatment with both agents restored growth arrest and apoptosis in these spheroids. In contrast to the antitumor action of cisplatin, which is known to be hampered by p53 dysfunction, we show that RuCl2(KTZ)2 is active irrespective of p53 functional status against several adherent tumor cells and synergizes with anti-EGF receptor C225 MAb to kill tumor spheroids resistant to either agent.
 ...
PMID:Tumor apoptosis induced by ruthenium(II)-ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor. 1538 61

Pycnogenol (PYC), a patented combination of bioflavonoids extracted from the bark of French maritime pine (Pinus maritima), inhibits apoptosis and necrosis of developing neurons exposed acutely to ethanol (EtOH). The present study shows that the protective mechanisms of PYC in EtOH-exposed postnatal day 9 cerebellar granule cells (P9 CGCs) include (1) reduction of reactive oxygen species (ROS) production; (2) counteraction of suppressed copper/zinc superoxide dismutase (Cu/Zn SOD) and glutathione peroxidase/reductase (GSH-Px/GSSG-R) system activities; (3) upregulation of Cu/Zn SOD protein expression; (4) mitigation of the EtOH-mediated exacerbation of catalase (CAT) activity; and, (5) specific binding and inhibition of active caspase-3. These results indicate that the mechanisms by which PYC antagonizes EtOH-induced oxidative stress include oxidant scavenging and modulation of endogenous, cellular proteins. Using findings from the present and previous studies, a model delineating the mechanisms of EtOH effects on the system of antioxidant enzymes in developing CGCs is presented.
 ...
PMID:Protective mechanisms of pycnogenol in ethanol-insulted cerebellar granule cells. 1538 91

The identification of the pathogenic mechanism of selective motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) may lead to the development of new therapies to halt or slow the disease course. A novel, MN-specific, Fas-mediated programmed cell death (PCD) pathway has been reported in MNs which involves the activation of p38 MAP kinase (phospho-p38) and neuronal nitric oxide synthase (nNOS). PCD was found to be exacerbated in MNs expressing ALS-linked superoxide dismutase (SOD) mutations. Because this MN-specific pathway was investigated in vitro, we performed an in vivo study to evaluate its potential involvement in MN loss in the lumbar region of spinal cord of mutant SOD transgenic (G93A) mice. Compared to nontransgenic littermates, we found significant increases in the numbers of immunopositive ventral horn MNs of G93A mice as young as 60 days of age for several constituents of this putative PCD pathway, including phospho-p38, nNOS, phospho-ASK1 MAP kinase kinase, and active caspase-3. This study provides in vivo evidence of an MN-specific PCD pathway that may be a pathogenic mechanism of ALS and may be activated very early in the disease process, well before clinical symptoms are evident (200 days). These findings suggest that early diagnosis and therapeutic intervention may be critical for the successful treatment of the disease. These enzymes may provide new markers for earlier diagnosis of ALS and new molecular targets for therapeutic intervention.
 ...
PMID:Activation of programmed cell death markers in ventral horn motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in a transgenic mouse model. 1549 59

Several properties of pancreatic beta-cells in type 2 diabetes (T2D) were studied by using islets isolated from T2D subjects. Moreover, because metformin has protective effects on nondiabetic beta-cells exposed to high glucose or free fatty acid levels, we investigated its direct action on T2D islet cells. Diabetic islets were characterized by reduced insulin content, decreased amount of mature insulin granules, impaired glucose-induced insulin secretion, reduced insulin mRNA expression, and increased apoptosis with enhanced caspase-3 and -8 activity. These alterations were associated with increased oxidative stress, as shown by higher nitrotyrosine concentrations, increased expression of protein kinase C-beta2 and nicotinamide adenine dinucleotide phosphate reduced-oxidase, and changes in mRNA expression of manganese- superoxide dismutase, Cu/Zn-superoxide dismutase, catalase, and glutathione peroxidase. Twenty-four-hour incubation of T2D islets with metformin was associated with increased insulin content, increased number and density of mature insulin granules, improved glucose-induced insulin release, and increased insulin mRNA expression. Moreover, apoptosis was reduced, with concomitant decrease of caspase-3 and -8 activity. These changes were accompanied by reduction or normalization of several markers of oxidative stress. Thus, T2D islets have several functional and survival defects, which can be ameliorated by metformin; the beneficial effects of the drug are mediated, at least in part, by a reduction of oxidative stress.
 ...
PMID:Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. 1553 8

Hyperhomocysteinemia is believed to induce endothelial dysfunction and promote atherosclerosis; however, the pathogenic mechanism has not been clearly elucidated. In this study, we examined the molecular mechanism by which homocysteine (HCy) causes endothelial cell apoptosis and by which nitric oxide (NO) affects HCy-induced apoptosis. Our data demonstrated that HCy caused caspase-dependent apoptosis in cultured human umbilical vein endothelial cells, as determined by cell viability, nuclear condensation, and caspase-3 activation and activity. These apoptotic characteristics were correlated with reactive oxygen species (ROS) production, lipid peroxidation, p53 and Noxa expression, and mitochondrial cytochrome c release following HCy treatment. HCy also induced p53 and Noxa expression and apoptosis in endothelial cells from wild type mice but not in the p53-deficient cells. The NO donor S-nitroso-N-acetylpenicillamine, adenoviral transfer of inducible NO synthase gene, and antioxidants (alpha-tocopherol and superoxide dismutase plus catalase) but not oxidized SNAP, 8-Br-cGMP, nitrite, and nitrate, suppressed ROS production, p53-dependent Noxa expression, and apoptosis induced by HCy. The cytotoxic effect of HCy was decreased by small interfering RNA-mediated suppression of Noxa expression, indicating that Noxa up-regulation plays an important role in HCy-induced endothelial cell apoptosis. Overexpression of inducible NO synthase increased the formation of S-nitroso-HCy, which was inhibited by the NO synthase inhibitor N-monomethyl-l-arginine. Moreover, S-nitroso-HCy did not increase ROS generation, p53-dependent Noxa expression, and apoptosis. These results suggest that up-regulation of p53-dependent Noxa expression may play an important role in the pathogenesis of atherosclerosis induced by HCy and that an increase in vascular NO production may prevent HCy-induced endothelial dysfunction by S-nitrosylation.
 ...
PMID:Nitric oxide inhibition of homocysteine-induced human endothelial cell apoptosis by down-regulation of p53-dependent Noxa expression through the formation of S-nitrosohomocysteine. 1556 2

1, 6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl]diamantine (DPD), a new cytostatic and differentiation inducing agent, was found to inhibit the growth of several cancer cell lines in the National Cancer Institute (NCI) Anticancer Drug Screen system. Previously, we demonstrated that DPD inhibited the growth of human colon cancer cell lines both in vitro and in vivo. In this study, we examined the anticancer effects of DPD on two human leukemia cells lines. DPD exerted growth inhibitory activities in vitro against two human leukemia cell lines, the promyeloid line HL-60 and the lymphoblastic line Molt-3. The in vivo effect of tumor growth suppression by DPD was also observed in mouse xenografts. No acute toxicity was observed after an intra-peritoneal challenge of DPD in "severe combined immune-deficiency" (SCID) mice twice a week. The in vitro study showed HL-60 was more sensitive to DPD than Molt-3 through induction of G(0)/G(1) cell-cycle arrest with the appearance of a hypodiploid DNA fraction. The increased superoxide (O(2)(-)), dissipation of the mitochondrial membrane potential, activation of caspase 3, and increase in annexin V binding were evident before apoptosis in DPD-treated cells. The superoxide dismutase 1 (SOD1) mRNA expression was also decreased in DPD-treated HL-60 and Molt-3 cells. Thus, it appeared that inhibition of SOD might be the major cause for the production of cellular superoxide with concomitant decrease of H(2)O(2) in DPD-treated cells. Addition of antioxidant can reduce DPD-induced mitochondrial damage, caspase activation, and annexin V binding in HL-60 cells. The results suggest that the cellular generation of O(2)(-) plays a role in initiating and coordinating DPD-mediated growth arrest and apoptosis of HL-60 cells. Importantly, addition of arsenic trioxide, a compound capable of reactive oxygen species (ROS) generation, significantly enhanced the in vitro activity of DPD. These results suggest that DPD appears to be a potential new modality in human leukemia therapy.
 ...
PMID:Effects of 1, 6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl]diamantane (DPD), a reactive oxygen species and apoptosis inducing agent, on human leukemia cells in vitro and in vivo. 1558 71

Evidence from human amyotrophic lateral sclerosis (ALS) patients and ALS-linked Cu/Zn superoxide dismutase (Cu/Zn-SOD) transgenic mice bearing the mutation of glycine to alanine at position 93 (G93A) suggests that the pro-apoptotic protein prostate apoptosis response-4 (Par-4) might be a critical link in the chain of events leading to motor neuron degeneration. We now report that Par-4 is enriched in synaptosomes and post-synaptic density from the ventral horn of the spinal cord. Levels of Par-4 in synaptic compartments increased significantly during rapid and slow declining stages of muscle strength in hSOD1 G93A mutant mice. In the pre-muscle weakness stage, hSOD1 G93A mutation sensitized synaptosomes from the ventral horn of the spinal cord to increased levels of Par-4 expression following excitotoxic and apoptotic insults. In ventral spinal synaptosomes, Par-4-mediated production of pro-apoptotic cytosolic factor(s) was significantly enhanced by the hSOD1 G93A mutation. RNA interference (RNAi) knockdown of Par-4 inhibited mitochondrial dysfunction and caspase-3 activation induced by G93A mutation in synaptosomes from the ventral horn of the spinal cord, and protected spinal motor neurons from apoptosis. These results identify the synapse as a crucial cellular site for the cell death promoting actions of Par-4 in motor neurons, and suggest that targeted inhibition of Par-4 by RNAi may prove to be a neuroprotective strategy for motor neuron degeneration.
 ...
PMID:RNAi knockdown of Par-4 inhibits neurosynaptic degeneration in ALS-linked mice. 1560 96

Yuk-Hap-Tang (YHT) induces cell death in human cervical carcinoma HeLa cells. Caspase-3, -6 and -9 were markedly activated in HeLa cells treated with YHT. The preferred substrate for caspase-3 cysteine protease, PARP, was cleaved to its 85-kDa cleavage product. YHT increased the amount of the anti-apoptotic protein, Bcl-2, and the pro-apoptotic protein, Bax. Although p53 has been reported to accumulate in cancer cells in response to anticancer agents, the p53 expression level was not changed in HeLa cells treated with YHT. Manganese (Mn)-TBAP, a mitochondria-specific SOD mimetic agent and NAC/GSH (N-acetyl cysteine/ reduced glutathione) reduced the YHT-induced cytotoxicity and decreased the number of the YHT-induced apoptotic cells. Furthermore, YHT reduced the expression of Mn-SOD protein and its activity in HeLa cells. The data demonstrate that YHT induces the apoptosis of human cervical carcinoma HeLa cells by intervening Mn-SOD.
 ...
PMID:Yuk-Hap-Tang induces apoptosis by intervening mn-SOD in human cervical carcinoma HeLa cells. 1567 94


<< Previous 1 2 3 4 5 6 7 8 9 10