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)

TAS-103 is a DNA intercalating indeno-quinoline derivative that stimulates DNA cleavage by topoisomerases. This synthetic drug has a broad spectrum of antitumor activity against many human solid tumor xenografts and is currently undergoing clinical trials. We investigated the induction of apoptosis in human promyelocytic leukemia cells treated with TAS-103. The treatment of proliferating human leukemia cells for 24 h with various concentrations of the drug induces significant variations in the mitochondrial transmembrane potential (delta(psi)mt) measured by flow cytometry using the fluorochromes 3,3-dihexyloxacarbocyanine iodide, Mitotracker Red, and tetrachloro-tetraethylbenzimidazolcarbocyanine iodide. The collapse of delta(psi)mt is accompanied by a marked decrease of the intracellular pH. Cleavage experiments with the substrates N-acetyl-Asp-Glu-Val-Asp-pNA, poly(ADP-ribose) polymerase, and pro-caspase-3 reveal unambiguously that caspase-3 is a key mediator of the apoptotic pathway induced by TAS-103. Caspase-8 is also cleaved, and the bcl-2 oncoprotein is underexpressed. Drug-induced internucleosomal DNA fragmentation and the externalization of phosphatidylserine residues in the outer leaflet of the plasma membrane were also characterized. The cell cycle perturbations produced by TAS-103 can be connected with the changes in deltapsi(mt). At low concentrations (2-25 nM), the drug induces a marked G2 arrest and concomitantly provokes an increase in the potential of mitochondrial membranes. In contrast, treatment of the HL-60 cells with higher drug concentrations (50 nM to 1 microM) triggers massive apoptosis and a collapse of deltaP(mt) that is a signature for the opening of the mitochondrial permeability transition pores. The discovery of a correlation between the G2 arrest and changes in mitochondrial membrane potential provides an important mechanistic insight into the action of TAS-103.
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PMID:Apoptotic response of HL-60 human leukemia cells to the antitumor drug TAS-103. 1094 13

In the present study, we determined whether a pan caspase inhibitor could prevent or attenuate heat-induced germ cell apoptosis. Groups of five adult (8 wk old) C57BL/6 mice pretreated with vehicle (DMSO) or Quinoline-Val-Asp (Ome)-CH2-O-Ph (Q-VD-OPH), a new generation broad-spectrum caspase inhibitor, were exposed once to local testicular heating (43 degrees C for 15 min) and killed 6 h later. The inhibitor (40 mg/kg body weight) or vehicle was administered intraperitoneally (i.p.) 1 h before local testicular heating. Germ cell apoptosis was detected by TUNEL assay and quantitated as number of apoptotic germ cells per 100 Sertoli cells at stages XI-XII. Compared with controls (16.8 +/- 3.1), mild testicular hyperthermia within 6 h resulted in a marked activation (277.3 +/- 21.6) of germ cell apoptosis, as previously reported by us. Q-VD-OPH at this dose markedly inhibited caspase 3 activation and significantly prevented (by 67.0%) heat-induced germ cell apoptosis. Q-VD-OPH-mediated rescue of germ cells was independent of cytosolic translocation of mitochondrial cytochrome c and DIABLO. Electron microscopy further revealed normal appearance of these rescued cells. Similar protection from heat-induced germ cell apoptosis was also noted after pretreatment with minocycline, a second-generation tetracycline that effectively inhibits cytochrome c release and, in turn, caspase activation. Collectively, the present study emphasizes the role of caspases in heat-induced germ cell apoptosis.
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PMID:Functional role of caspases in heat-induced testicular germ cell apoptosis. 1550 30

Synthesis, biological evaluation, and SAR dependencies for a series of novel 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinoline inhibitors of caspase-3 are described. The inhibitory activity of the synthesized compounds is highly dependent on the nature of 4-substituents on the core scaffold. 4-methyl-and 4-phenyl-substituted derivatives, which were the most active compounds within this series, inhibited caspase-3 with IC50 of 23 and 27 nM, respectively.
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PMID:Synthesis and structure-activity relationship of 4-substituted 2-(2-acetyloxyethyl)-8-(morpholine-4-sulfonyl)pyrrolo[3,4-c]quinoline-1,3-diones as potent caspase-3 inhibitors. 1591 16

From the authors' 650,000 compound collection, they have selected approximately 15,000 potential small-molecule protease inhibitors, which were subjected to high-throughput screening against caspase-3. The screening yielded a series of hits that belong to 11 different scaffolds. Based on the structure of one of the hits, a new class of the small-molecule inhibitors with a double electrophilic warhead, 8-sulfonyl-pyrrolo[3,4-c]quinoline-1,3-diones (SPQ), was synthesized and tested in follow-up mechanistic and anti-apoptosis assays. Mechanistic analysis of a representative compound of this class, CD-001-0011, showed that the compound exhibited a high potency (IC (50)=130 nM), was reversible though noncompetitive, and had a broad selectivity profile to other caspases belonging to groups I to III. The compound was effective in preventing staurosporine induced apoptosis in a few cell lines and retinoic acid-induced apoptosis in zebrafish.
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PMID:Screening for caspase-3 inhibitors: a new class of potent small-molecule inhibitors of caspase-3. 1649 Jul 69

The work described here involved the synthesis and biological evaluation of new heteroaryldiamides and heteroaryldiamines. A new general model in which the structures can be adjusted has been applied in this study. Three different structural units can be distinguished: a central nucleus and two symmetric terminal units. The central element is either an aliphatic chain of varying length and flexibility, piperazine, or a polyamine nucleus. However, the terminal units are pyridine, quinoline, indole, benzene or pyrido[2,3-d]pyrimidine with different substituents. The antitumoural activities of the compounds were evaluated in vitro by examining their cytotoxic effects against human breast, colon, and bladder cancer cell lines. Compounds that showed cytotoxic activity were subjected to both apoptosis and caspase-3 assays. With regard to selectivity, the cytotoxicity was also determined in cell cultures of two nontumoural lines. The most promising compounds are 4c, 5c and 7, which are amino-pyridinium, quinolyl-N-oxide, and pyridyl derivatives, respectively, and these reveal a significant in vitro cytotoxicity in at least two of the three cell lines tested. These compounds induced apoptosis and also produced a rapid dose-dependent increase in the caspase-3 level in HT-29 cells. Other encouraging profiles were found, such as those presented by 1k and 8d, which are cytotoxic and apoptotic but do not provoke an increase in the level of caspase-3, or those presented by 2f, 3c and 4a, which are slightly cytotoxic but do not show any other significant activity. The different types of behaviour of each compound are not necessarily parallel in the three cell lines tested.
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PMID:Synthesis and biological evaluation of heteroaryldiamides and heteroaryldiamines as cytotoxic agents, apoptosis inducers and caspase-3 activators. 1657 81

An ethnobotanical survey of plants used to treat tropical ulcers in Papua New Guinea identified Lunasia amara as possessing anti-Staphylococcus aureus activity. Activity-guided fractionation of the aqueous bark extract resulted in the identification of the quinoline alkaloid lunacridine as the active principle. Lunacridine tends to cyslise at room temperature but the 2'-O-trifluoroacetyl derivative was found to be stable and therefore more suitable for biological assays. The compound exhibited a minimal inhibitory concentration (MIC) of 64 micro g/ml against Staphylococcus aureus NCTC 6571 and activity in the low micromolar range against HeLa and H226 cells; the latter showing signs of caspase-3/7 mediated apoptotic cell death. Experiments with drug resistant strains of Streptococcus pneumoniae suggested topoisomerase as a likely target for the drug in bacteria whilst decatenation assays with human topoisomerase II showed the compound to be a potent inhibitor of this isoform (IC(50)<5 micro M) thus explaining the drug's activity against human cell lines. Both lunacridine and 2'-O-trifluoroacetyl lunacridine exhibited mild DNA intercalation activity giving 50% decrease in ethidium DNA fluorescence at 0.22 and 0.6 mM, respectively, placing the drug amongst the DNA intercalating class of topoisomerase II inhibitors.
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PMID:Lunacridine from Lunasia amara is a DNA intercalating topoisomerase II inhibitor. 1696 12

Nine-day-old harlequin (Hq) mice carrying the hypomorphic apoptosis-inducing factor (AIF)(Hq) mutation expressed 60% less AIF, 18% less respiratory chain complex I and 30% less catalase than their wild-type (Wt) littermates. Compared with Wt, the infarct volume after hypoxia-ischemia (HI) was reduced by 53 and 43% in male (YX(Hq)) and female (X(Hq)X(Hq)) mice, respectively (P<0.001). The Hq mutation did not inhibit HI-induced mitochondrial release of cytochrome c or activation of calpain and caspase-3. The broad-spectrum caspase inhibitor quinoline-Val-Asp(OMe)-CH(2)-PH (Q-VD-OPh) decreased the activation of all detectable caspases after HI, both in Wt and Hq mice. Q-VD-OPh reduced the infarct volume equally in Hq and in Wt mice, and the combination of Hq mutation and Q-VD-OPh treatment showed an additive neuroprotective effect. Oxidative stress leading to nitrosylation and lipid peroxidation was more pronounced in ischemic brain areas from Hq than Wt mice. The antioxidant edaravone decreased oxidative stress in damaged brains, more pronounced in the Hq mice, and further reduced brain injury in Hq but not in Wt mice. Thus, two distinct strategies can enhance the neuroprotection conferred by the Hq mutation, antioxidants, presumably compensating for a defect in AIF-dependent redox detoxification, and caspase inhibitors, presumably interrupting a parallel pathway leading to cellular demise.
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PMID:Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia. 1703 48

Hypoxia-ischaemia in the developing brain results in brain injury with prominent features of apoptosis. In the present study, a third generation dipeptidyl broad-spectrum caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh), was tested in a model of unilateral focal ischaemia with reperfusion in 7-day-old rats. Q-VD-OPh (1 mg/kg, i.p.) reduced cell death, resulting in significant neuroprotection at 48 h of recovery (infarct volume of 12.6 +/- 2.8 vs. 24.3 +/- 2.2%, p = 0.006). The neuroprotective effects observed at 48 h post-ischaemia hold up at 21 days of survival time and attenuate neurological dysfunction. Analysis by gender revealed that females were strongly protected (6.7 +/- 3.3%, p = 0.006), in contrast to males in which there was no significant effect, when Q-VD-OPh was given after clip removal on the left common carotid artery. Immunoblot analysis demonstrated that Q-VD-OPh inhibits caspase 3 cleavage into its p17 active form and caspase 1 up-regulation and cleavage in vivo. Following ischaemia in P7 rats, males and females displayed different time course and pattern of cytochrome c release and active p17 caspase 3 during the first 24 h of recovery. In contrast, no significant difference was observed for caspase 1 expression between genders. These results indicate that ischaemia activates caspases shortly after reperfusion and that the sex of the animal may strongly influences apoptotic pathways in the pathogenesis of neonatal brain injury. The specificity, effectiveness, and reduced toxicity of Q-VD-OPh may determine the potential use of peptide-derived irreversible caspase inhibitors as promising therapeutics.
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PMID:Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for gender. 1716 74

Cisplatin is one of the primary drugs utilized in the treatment of ovarian cancer. However, despite the initial effectiveness of chemotherapy in suppressing this disease, drug resistance almost invariably develops and cures are relatively rare. While it is generally thought that only compounds of the cis geometry express antitumor activity, a number of transplatinum derivates have shown preclinical promise. The current work investigates the influence of transplanaramine (TPA) compounds of structure trans-[Pt (O(2)CR)(2) (L) (L')], (L=NH(3), L'=pyridine, quinoline, isoquinoline; L=L'=pyridine; R=H, CH(3), CH(2)OH, etc.) (with a focus on the contribution of the carboxylate leaving group to drug action) on growth and viability of A2780 human ovarian carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The compounds, as a class, induce cell death through caspase-dependent apoptosis, with activation of both caspase 3 and caspase 9 and concomitant PARP cleavage. The trans-platinum compounds tested show induction of p53 as well as time dependent gammaH2AX induction, consistent with the promotion of DNA lesions. trans-[Pt(O(2)CH)(2)(NH(3))(4-pic)] can be shown to promote significant DNA strand breaks and DNA interstrand cross-linking. The enhanced cytotoxicity of trans-[Pt(O(2)CH)(2)(NH(3))(4-pic)] compared to its isostructural -O(2)CCH(3) and -O(2)CCH(2)OH analogs may be a consequence of its accelerated cellular accumulation, increased hydrolytic activation, interstrand cross-linking and abortive efforts by the cell to repair the cross linked DNA.
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PMID:Promotion of DNA strand breaks, interstrand cross-links and apoptotic cell death in A2780 human ovarian cancer cells by transplatinum planar amine complexes. 1741 17

The present study reports the biological activity of 8-methyl-4-(3-diethylamino-propylamino) pyrimido [4';5';4,5] thieno (2,3-b) quinoline (MDPTQ), a quinoline derivative structurally related to ellipticine and suggests a possible mechanism through which the compound induces apoptosis in carcinoma cell lines. Out of the 8 cell lines used in the study as representatives of different types of cancer, MDPTQ was found to be effective only against leukemia cell lines (HL-60 and K-562) whereas it had no effect on normal human bone marrow cells (BMC) which were used as controls. Fall mitochondrial membrane potential and increased reactive oxygen species (ROS) were mainly responsible for inducing apoptosis in the two cell lines. Cell death was demonstrated by increase in caspase 3 activity as well as phosphatidyl serine exposure. Pre-incubation with N-acetylcysteine (NAC) reduced the increased ROS and caspase 3 activity as well as phosphatidyl serine exposure. MDPTQ also caused cell cycle arrest in these cell lines. The above study for the first time reports the mode of action of a quinoline derivative, which could be a possible future candidate for leukemia therapy. However, there are lot of questions that need to be answered in terms of signalling pathways and its effects on animal models.
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PMID:8-Methyl-4-(3-diethylaminopropylamino) pyrimido [4',5';4,5] thieno (2,3-b) quinoline (MDPTQ), a quinoline derivate that causes ROS-mediated apoptosis in leukemia cell lines. 1755 38


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