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)

Many anticancer agents are known to induce apoptosis in cultured cells, but human solid tumor cells are often resistant to apoptosis induction. Human pancreatic adenocarcinoma AsPC-1 cells were found to be resistant to apoptosis. So, we screened microbial culture filtrates and synthetic chemicals for their ability to induce apoptosis in AsPC-1 cells. Polyoxypeptin A was isolated from a Streptomyces culture broth as a potent inducer of apoptosis. Its cyclic hexadepsipeptide structure contains a simple but hitherto unreported amino acid, (2S,3R)-3-hydroxy-3-methylproline. Polyoxypeptin A induced early cell death, apoptotic morphology, and internucleosomal DNA fragmentation in AsPC-1 cells at low concentrations. Polyoxypeptin A can induce caspase 3 activation in human T cell leukemia Jurkat cells but not in AsPC-1 cells. The mechanism of apoptosis in AsPC-1 cells has not been elucidated yet. Less toxic derivatives of polyoxypeptin A are being prepared. A macrocyclic lactam called BE-14106 was also isolated from Streptomyces as an inducer of apoptosis in AsPC-1 cells. Histidine-pyridine-histidine-3 (HPH-3) is an oxygen-activating ligand derived from the structure of bleomycin, and it also induced apoptosis in AsPC-1 cells. Induction of apoptosis by HPH-3 was inhibited by zinc and copper ions, indicating that chelation with ferrous ion is responsible for induction of apoptosis, as is chelation by bleomycin to cleave DNA. Bleomycin A2 and its portion having no DNA-binding region, glycopeptide-3(GP-3), did not induce apoptosis in AsPC-1 cells. Thus, among the actions of bleomycin-related compounds, the induction of apoptosis is a unique characteristic of HPH-3.
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PMID:Screening for inducers of apoptosis in apoptosis-resistant human carcinoma cells. 1047 Mar 71

Calcium overload is suggested to play a fundamental role in the process of rod apoptosis in chemical-induced and inherited retinal degenerations. However, this hypothesis has not been tested directly. We developed an in vitro model utilizing isolated rat retinas to determine the mechanisms underlying Ca(2+)- and/or Pb(2+)-induced retinal degeneration. Confocal microscopy, histological, and biochemical studies established that the elevated [Ca(2+)] and/or [Pb(2+)] were localized to photoreceptors and produced rod-selective apoptosis. Ca(2+) and/or Pb(2+) induced mitochondrial depolarization, swelling, and cytochrome c release. Subsequently caspase-9 and caspase-3 were sequentially activated. Caspase-7 and caspase-8 were not activated. The effects of Ca(2+) and Pb(2+) were additive and blocked completely by the mitochondrial permeability transition pore (PTP) inhibitor cyclosporin A, whereas the calcineurin inhibitor FK506 had no effect. The caspase inhibitors carbobenzoxy-Leu-Glu-His-Asp-CH(2)F and carbobenzoxy-Asp-Glu-Val-Asp-CH(2)F, but not carbobenzoxy-Ile-Glu-Thr-Asp-CH(2)F, differentially blocked post-mitochondrial events. The levels of reduced and oxidized glutathione and pyridine nucleotides in rods were unchanged. Our results demonstrate that rod mitochondria are the target site for Ca(2+) and Pb(2+). Moreover, they suggest that Ca(2+) and Pb(2+) bind to the internal metal (Me(2+)) binding site of the PTP and subsequently open the PTP, which initiates the cytochrome c-caspase cascade of apoptosis in rods.
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PMID:Lead and calcium produce rod photoreceptor cell apoptosis by opening the mitochondrial permeability transition pore. 1076 53

Opening of a high-conductance pore in the mitochondrial inner membrane induces onset of the mitochondrial permeability transition (mPT). Cyclosporin A and trifluoperazine inhibit this pore and block necrotic cell death in oxidative stress, Ca2+ ionophore toxicity, Reye-related drug toxicity, pH-dependent ischaemia/reperfusion injury and other models of cell injury. Confocal fluorescence microscopy directly visualizes the increased mitochondrial membrane permeability of the mPT from the movement of calcein from the cytosol into the matrix space. Pyridine nucleotide oxidation, increased mitochondrial Ca2+ and mitochondrial generation of reactive oxygen species (ROS) all contribute to the onset of the mPT in situ. Confocal microscopy also shows directly that the mPT is a critical link in apoptotic signalling by tumour necrosis factor-alpha at a point downstream of caspase 8 and upstream of caspase 3. Cyclosporin A blocks this mPT, preventing release of pro-apoptotic cytochrome c from mitochondria and subsequent apoptotic cell killing. Progression to necrosis or apoptosis after the mPT depends on the availability of ATP, which blocks necrosis but promotes the apoptotic programme. Given the pathophysiological importance of the mPT, development of agents to modulate the mPT represents an important new goal for pharmaceutical drug discovery.
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PMID:Confocal microscopy of the mitochondrial permeability transition in necrotic and apoptotic cell death. 1098 68

We examined the effects of ZNC-2381 (1-(4-aminophenyl)methyl-3-(3-nitrophenyl)-1,3-dihydroimidazo[4,5-b] pyridine-2-one), a new oral hepatoprotective agent, on hepatocellular caspase-3 activity and apoptosis induced by anti-mouse Fas antibody (anti-Fas ab) in mice. Oral ZNC-2381, administered at doses of 10, 30 and 100 mg/kg 1 h before inducing hepatic injury with anti-Fas ab, dose-dependently inhibited the increase in serum alanine aminotransferase (s-ALT) activity 8 h after injection of anti-Fas ab. Increases in DNA fragmentation (nucleosome assay) and caspase-3 activity in the liver 2 h after injection of anti-Fas ab were also inhibited by ZNC-2381 in a dose-dependent manner. As shown by histopathological examination, ZNC-2381 dose-dependently inhibited the appearance of TUNEL-positive apoptotic cells in the liver. Moreover, in studies in vitro, ZNC-2381 (1- 100 micromol/l) concentration-dependently inhibited increases in DNA fragmentation and caspase-3 activity caused by anti-Fas ab in isolated mouse hepatocytes. N- Acetyl-Asp-Glu-Val-Asp aldehyde (Ac-DEVD-cho), a caspase-3-specific inhibitor, inhibited hepatocellular apoptosis caused by anti-Fas ab both in vivo and in vitro, as well as the increase in s-ALT activity in vivo. These results demonstrate that orally administered ZNC-2381 inhibits hepatocellular apoptosis induced by anti-Fas ab and presents the progression of hepatic injury. We propose that the mechanism of action of ZNC-2381 may involve blockade of the signal transduction pathway (caspase-3) of apoptosis mediated by anti-Fas ab.
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PMID:Effects of a novel hepatoprotective drug, ZNC-2381, on fas-induced hepatocellular caspase-3 activity and apoptosis in mice. 1117 76

We examined the effect of 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (ibudilast), which has been clinically used for bronchial asthma and cerebrovascular disorders, on cell viability induced in a model of reperfusion injury. Ibudilast at 10 - 100 microM significantly attenuated the H(2)O(2)-induced decrease in cell viability. Ibudilast inhibited the H(2)O(2)-induced cytochrome c release, caspase-3 activation, DNA ladder formation and nuclear condensation, suggesting its anti-apoptotic effect. Phosphodiesterase inhibitors such as theophylline, pentoxyfylline, vinpocetine, dipyridamole and zaprinast, which increased the guanosine-3',5'-cyclic monophosphate (cyclic GMP) level, and dibutyryl cyclic GMP attenuated the H(2)O(2)-induced injury in astrocytes. Ibudilast increased the cyclic GMP level in astrocytes. The cyclic GMP-dependent protein kinase inhibitor KT5823 blocked the protective effects of ibudilast and dipyridamole on the H(2)O(2)-induced decrease in cell viability, while the cyclic AMP-dependent protein kinase inhibitor KT5720, the cyclic AMP antagonist Rp-cyclic AMPS, the mitogen-activated protein/extracellular signal-regulated kinase inhibitor PD98059 and the leukotriene D(4) antagonist LY 171883 did not. KT5823 also blocked the effect of ibudilast on the H(2)O(2)-induced cytochrome c release and caspase-3-like protease activation. These findings suggest that ibudilast prevents the H(2)O(2)-induced delayed apoptosis of astrocytes via a cyclic GMP, but not cyclic AMP, signalling pathway.
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PMID:Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model. 1145 57

Toxic reactive oxygen species (ROS) such as hydrogen peroxide, nitric oxide, superoxide, and the hydroxyl radical are generated in a variety of neuropathological conditions and cause significant DNA damage. We determined the effects of 3-aminobenzamide (AB), an inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), on cell death in differentiated PC12 cells, a model of sympathetic neurons, after H(2) O(2) injury. Exposure to 0.5 mm H(2) O(2) resulted in a significant decrease in intracellular NAD(H), NADP(H), and ATP levels. This injury resulted in the death of 90% of the cells with significant necrosis early (2 h) after injury and increased apoptosis (12-24 h after injury), as measured by PS exposure and the presence of cytoplasmic oligonucleosomal fragments. Treatment with 2.5 mm AB restored pyridine nucleotide and ATP levels and ameliorated cell death (65% versus 90%) by decreasing the extent of both necrosis and apoptosis. Interestingly, we observed that H(2) O(2) -induced injury caused a delayed cell death exhibiting features of apoptosis but in which caspase-3 like activity was absent. Moreover, pretreatment with AB restored caspase-3-like activity. Our results suggest that apoptosis and necrosis are both triggered by PARP overactivation, and that maintenance of cellular energy levels after injury by inhibiting PARP shifts cell death from necrosis to apoptosis.
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PMID:Poly(ADP-ribose) polymerase inhibition prevents both apoptotic-like delayed neuronal death and necrosis after H(2)O(2) injury. 1209 61

The effect of xymedone, a non-glucoside analog of pyridine nucleosides, on the apoptosis of human CD4+ T cells of the Jurkat line was studied by laser flow cytometry method. Xymedone decreased the membrane expression of phosphatidylserine and suppressed the increase in permeability of the cytoplasmic membrane, thus inhibiting the onset of a degradation stage of the apoptotic cascade. Possible mechanisms of the antiapoptogenic effect of xymedone within the framework of a (cytochrome C/caspase 3)-dependent signal pathway of the apoptosis are discussed.
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PMID:[Xymedon decreases phosphatidylserine membrane expression induced by proapoptogenic deficit of serum growth factors in Jurkat T-cells]. 1222 95

In the present study, we outlined the part of the molecule mediating the prominent pro-apoptotic effect of the Michael adduct of ascorbic acid with p-chloro-nitrostyrene, a new synthetic phosphatase inhibitor. The nitrostyrene (NS) moiety was identified as the structure essential for apoptosis induction. NS and its ascorbic acid adducts displayed LC(50) values of 10-25 microM with no significant reduction of potency in okadaic acid resistant cells overexpressing the MDR1 P-glycoprotein. Induction of apoptosis by NS derivatives and the protein phosphatase 2A inhibitor cantharidic acid was proven by the analysis of caspase-3 activation and subsequent fragmentation of DNA. Further structure activity analysis revealed the necessity of the nitro group at the beta-position of the side chain. The pro-apoptotic potential of adducts of NS with pyrimidine- or pyridine-derivatives varied between NS and a progressive reduction in potency up to a nearly complete loss of cytotoxicity. Substitutions at the benzene core of NS suggested a prominent enhancement of toxicity only by substitutions at the 2- or 3-position. Heterocyclic aromatics can substitute for the benzene ring of NS albeit with a 2-3-fold reduced potency. In conclusion, nitrostyrene was identified as the core structure mediating the pro-apoptotic effect of a new synthetic phosphatase inhibitor. Further studies defined a nitrovinyl side chain attached to an aromatic ring as the pharmacophore structure of a new group of pro-apoptotic agents. These observations present the basis for the development of a new group of anticancer drugs.
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PMID:Structure activity analysis of the pro-apoptotic, antitumor effect of nitrostyrene adducts and related compounds. 1256 88

Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. Since P(1) aspartic acid is a required element of recognition for this enzyme, a library of capped aspartyl aldehydes was synthesized using solid-phase chemistry. The 5-bromonicotinamide derivative of the aspartic acid aldehyde was identified to be an inhibitor of caspase-3. Substitution at the 5-position of the pyridine ring and conversion of the aldehyde to ketones led to a series of potent inhibitors of caspase-3.
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PMID:Nicotinyl aspartyl ketones as inhibitors of caspase-3. 1279 21

The protein kinase family represents an enormous opportunity for drug development. However, the current limitation in structural diversity of kinase inhibitors has complicated efforts to identify effective treatments of diseases that involve protein kinase signaling pathways. We have identified a new structural class of protein serine/threonine kinase inhibitors comprising an aminoimidazo[1,2-a]pyridine nucleus. In this report, we describe the first successful use of this class of aza-heterocycles to generate potent inhibitors of cyclin-dependent kinases that compete with ATP for binding to a catalytic subunit of the protein. Co-crystal structures of CDK2 in complex with lead compounds reveal a unique mode of binding. Using this knowledge, a structure-based design approach directed this chemical scaffold toward generating potent and selective CDK2 inhibitors, which selectively inhibited the CDK2-dependent phosphorylation of Rb and induced caspase-3-dependent apoptosis in HCT 116 tumor cells. The discovery of this new class of ATP-site-directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis for a new medicinal chemistry tool to be used in the search for effective treatments of cancer and other diseases that involve protein kinase signaling pathways.
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PMID:The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo[1,2-a]pyridines. 1474 70


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