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)

p8 is a small-stress protein involved in several cellular functions including apoptosis. To identify its putative partners, we screened a HeLa cDNA library by using the two-hybrid technique and found that p8 binds the antiapoptotic protein prothymosin alpha (ProTalpha). Fluorescence spectroscopy, circular dichroism, and NMR spectroscopy showed that p8 and ProTalpha formed a complex. Binding resulted in important changes in the secondary and tertiary structures of the proteins. Because p8 and ProTalpha form a complex, they could act in concert to regulate the apoptotic cascade. We induced apoptosis in HeLa cells by staurosporine treatment and monitored the effects of knocking down p8 and/or ProTalpha or overexpressing p8 and/or ProTalpha on caspase 3/7 and 9 activities and on cell death. Transfecting ProTalpha or p8 small interfering RNAs increased the activities of both caspases and the number of apoptotic nuclei. However, transfecting both small interfering RNAs resulted in no further increase. Overexpressing p8 or ProTalpha did not alter caspase activities, whereas overexpressing both resulted in a significant reduction of caspase activities. These results strongly suggest that the antiapoptotic response of HeLa cells upon staurosporine treatment requires expression of both p8 and ProTalpha.
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PMID:Regulation of apoptosis by the p8/prothymosin alpha complex. 1647 4

Isocostunolide is a sesquiterpene lactone isolated from the roots of Inula helenium. Its chemical structure was determined by NMR and FAB-MS spectra. No biological activities of this compound have yet been reported. In this study, we found isocostunolide could effectively induce cytotoxicity in three cancer cell lines (A2058, HT-29, and HepG2), with an IC(50) of 3.2, 5.0, and 2.0 micro g/mL, respectively. DNA flow cytometric analysis indicated that isocostunolide actively induced apoptosis of cancer cells accompanied by a marked loss of G0/G1 phase cells. To address the mechanism of the apoptotic effect of isocostunolide, we analyzed the induction of apoptosis-related proteins in A2058. The levels of pro-caspase-8, Bid, pro-caspase-3, and poly(ADP-ribose) polymerase (PARP) decreased. However, the level of Fas was increased markedly in a dose-dependent manner. Furthermore, this compound markedly induced a depolarization of mitochondrial membranes to facilitate cytochrome c release into cytosol. The findings suggest that isocostunolide may activate a mitochondria-mediated apoptosis pathway. To address this, we found that isocostunolide-induced loss of mitochondrial membrane potential occurred via modulation of the Bcl-2 family proteins. The production of intracellular reactive oxygen species (ROS) in A2058 was not elicited. In summary, for the first time, we have isolated and characterized isocostunolide from I. helenium. This compound induces apoptosis through a mitochondria-dependent pathway in A2058 cells.
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PMID:Isocostunolide, a sesquiterpene lactone, induces mitochondrial membrane depolarization and caspase-dependent apoptosis in human melanoma cells. 1669 6

3Alpha-acetyl-11-keto-alpha-boswellic acid (3alpha-acetoxy-11-oxo-olean-12-en-24-oic acid, 1) was synthesized by a radical-type reaction using bromine and 3alpha-acetyl-alpha-boswellic acid isolated from the oleo-gum-resin of Boswellia carterii. 1D and 2D NMR (COSY, HMBC, ROESY) at 500 MHz were used for shift assignments and structure verification. The compound investigated is present in a herbal preparation extracted from Boswellia serrata oleo-gum-resin, it inhibits the growth of chemotherapy-resistant human PC-3 prostate cancer cells in vitro and induces apoptosis as shown by activation of caspase 3 and the induction of DNA fragmentation. In addition, compound 1 is active IN VIVO as shown by inhibition of proliferation and induction of apoptosis in PC-3 prostate cancer cells xenotransplanted onto the chick chorioallantoic membrane.
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PMID:Characterization of 3alpha-acetyl-11-keto-alpha-boswellic acid, a pentacyclic triterpenoid inducing apoptosis in vitro and in vivo. 1702 3

The metabolic changes that occur as a function of time in MG-63 osteosarcoma three-dimensional tumor spheroids undergoing radiation-induced apoptosis were studied using high-resolution proton nuclear magnetic resonance ((1)H-NMR) spectroscopy. Specifically, the (1)H-NMR spectra of MG-63 spheroids collected at 24, 48 and 72 h after exposure to 5 Gy of ionizing radiation were compared to the spectra of their respective controls. Small spheroids (about 50-80 microm in diameter) with no hypoxic center were used. Apoptosis was verified by both staining of spheroid DNA with the Hoechst 33258 dye and determination of caspase 3 enzyme activity at the three times examined. The results demonstrate that, as the percentage of apoptosis rises with time after exposure to ionizing radiation, the metabolic changes that take place in MG-63 spheroids follow very precise temporal dynamics. In particular, significant time-related increases in both CH(2) and CH(3) mobile lipids, considered by many authors as markers of apoptosis, were observed. In addition, temporal variations were also observed in choline-containing metabolites, reduced glutathione (GSH), glutamine/glutamate, taurine, alanine, creatine/phosphocreatine and lactate. These data show that in addition to CH(2) and CH(3) lipids, other metabolites can also be extremely useful in a deeper understanding of the temporal dynamics of radiation-induced apoptosis. This comprehension is particularly important in spheroids, a cell model of great complexity that resembles in vivo tumors much more closely than monolayer cultures. Ultimately, it is hoped that such studies can help to evaluate the outcome of radiotherapy protocols more accurately.
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PMID:Temporal dynamics of 1H-NMR-visible metabolites during radiation-induced apoptosis in MG-63 human osteosarcoma spheroids. 1706 11

Vascular aging is characterized by decreased nitric oxide (NO) bioavailability, oxidative stress, and enhanced apoptotic cell death. We hypothesized that interspecies comparative assessment of vascular function among rodents with disparate longevity may offer insight into the mechanisms determining successful vascular aging. We focused on four rodents that show approximately an order of magnitude range in maximum longevity (ML). The naked mole rat (NMR; Heterocephalus glaber) is the longest-living rodent known (ML > 28 yr), Damara mole rats (DMRs, Cryptomys damarensis; ML approximately 16 yr) and guinea pigs (GPs, Cavia porcellus; ML approximately 6 yr) have intermediate longevity, whereas laboratory mice are short living (ML approximately 3.5 yr). We compared interspecies differences in endothelial function, O(2)(-)* and H(2)O(2) production, and resistance to apoptotic stimuli in blood vessels. Sensitivity to acetylcholine-induced, NO-mediated relaxation was smaller in carotid arteries from NMRs, GPs, and DMRs than in mouse vessels. Measurements of production of O(2)(-)* (lucigenin chemiluminescence and ethidium bromide fluorescence) and H(2)O(2) (dichlorofluorescein fluorescence) showed that free radical production in vascular endothelial and smooth muscle cells is comparable in vessels of the three longer-living species and in arteries of shorter-living mice. In mouse arteries, H(2)O(2) (from 10(-6) to 10(-3) mol/l) and heat exposure (42 degrees C for 15-45 min) enhanced apoptotic cell death, as indicated by an increased DNA fragmentation rate and increased caspase 3/7 activity. In NMR vessels, only the highest doses of H(2)O(2) enhanced apoptotic cell death, whereas heat exposure did not increase DNA fragmentation rate. Interspecies comparison showed there is a negative correlation between H(2)O(2)-induced apoptotic cell death and ML. Thus endothelial vasodilator function and vascular production of reactive oxygen species do not correlate with maximal lifespan, whereas increased lifespan potential is associated with an increased vascular resistance to proapoptotic stimuli.
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PMID:Comparison of endothelial function, O2-* and H2O2 production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice. 1709 Jul 84

The new sodium bis(1,2,4-triazol-1-yl)acetate ligand, Na[HC(CO(2))(tz)(2)], has been prepared in methanol solution by using 1,2,4-triazole, dibromoacetic acid, and NaOH. Treatment of the [Cu(CH(3)CN)(4)][PF(6)] acceptor with Na[HC(CO(2))(tz)(2)] or Na[HC(CO(2))[(pz(Me2))(2)] in the presence of the tris(hydroxymethyl)phosphine coligand in methanol/acetonitrile solutions produced unprecedented mononuclear copper(I) complexes of the [L(n)]Cu[P(CH(2)OH)(3)](2) (L(1), 2; L(2), 3) [(CH(3)CN)(2)Cu(P(CH(2)OH)(3))(2)]PF(6), 4. These compounds have been characterized by elemental analyses, FTIR, ESI-MS, and multinuclear (1H and 31P) NMR spectral data. The new copper(I) complexes were tested for their cytotoxic properties against a panel of several human tumor cell lines. The results reported here indicate that all the complexes showed in vitro antitumor activity similar or better than that of cisplatin, the most used metal-based antitumor drug. In particular, [HC(CO(2))(pz(Me2))(2)]Cu[P(CH(2)OH)(3)](2), 3 showed IC(50) values markedly lower than the reference compound against all tumor cell lines. Chemosensitivity tests performed on cisplatin sensitive and resistant cell lines have demonstrated that all these Cu(I) complexes were able to overcome cisplatin resistance, supporting the hypothesis of a different mechanism of action compared to that exhibited by the reference drug. Flow cytometric analysis on 2008 human ovarian carcinoma cells revealed that complex 3, chosen as the best candidate, induced a marked enlargement of both cell size and granularity, and a significant increase in the fraction of G2/M cells that, differently from cisplatin, was not accompanied by the appearance of a relevant sub-G1 fraction. Besides, no evidence of caspase-3 activation was detected in cells treated with complex 3. We hypothesize that the cytotoxic activity of the new copper(I) complex may be correlated to its ability to trigger paraptosis, a nonapoptotic mechanism of cell death.
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PMID:Synthesis, characterization, and in vitro antitumor properties of tris(hydroxymethyl)phosphine copper(I) complexes containing the new bis(1,2,4-triazol-1-yl)acetate ligand. 1714 61

The effects of naturally-occuring polyphenols, resveratrol and quercetin, on cell viability and apoptosis were studied in Namalwa B-cell lymphoma line. Apoptotic cells were identified using DNA flow cytometric analysis and 1H NMR spectroscopy. The effects of the agents on the cell cycle kinetics and activation of caspase-3 were examined. Both resveratrol and quercetin induced apoptosis in Namalwa cells as demonstrated by the increased number of hypodiploid cells, elevated level of mobile lipid domains and caspase-3 activation. Treatment with 40 microM of resveratrol for 48 h resulted in time-dependent cell-cycle arrest at G0/G1. In contrast, upon quercetin treatment Namalwa cells accumulated in G2/M. Obtained results suggest that resveratrol and quercetin induced caspase-dependent apoptosis in human malignant lymphoid cells in vitro. These findings provide a rationale for further studies of in vivo effects of those polyphenols.
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PMID:[Apoptosis of human malignant lymphoid NAMALWA cells induced by resveratrol and quercetin]. 1723 28

Novel trinuclear complexes C23H31N6O6CuSn2Cl5 [1], C23H31N6O6CuZr2Cl5 [2], C23H31N6O6ZnSn2Cl5 [3], and C23H31N6O6ZnZr2Cl5 [4] were synthesized and characterized by spectroscopic (IR, 1H, 13C, 2D COSY, and 119Sn NMR, EPR, UV-vis, ESI-MS) and analytical methods. In complexes 1-4, the geometry of copper and zinc metal ions were described as square-based pyramidal with l-tryptophan coordinated to copper/zinc via carboxylate group while Sn/Zr was present in the hexacoordinate environment. The interaction of 1 and 2 with calf thymus DNA in Tris buffer was studied by electronic absorption titration, luminescence titration, cyclic voltammetry, circular dichroism, and viscometric measurements. The emission quenching of these complexes by [Fe(CN)6]4- depressed greatly when bound to DNA. Observed changes in the circular dichoric spectra of DNA in presence of 1 and 2 support the strong binding of complexes with DNA. The relative specific viscosity of DNA bound to 1 and 2 decreased, indicating that the complexes bind to DNA via covalent binding. The results reveal that the extent of DNA binding of 1 was greater than that of 2. To evaluate the mechanistic pathway of DNA inhibition, counting experiments and MTT assay were employed to assess the induction of apoptosis by 1. Western blot analysis of whole cell lysates and mitochondrial fractions with Bcl-2 and p-53 family proteins and caspase-3 colorimetry assay were also carried out on a human neuroblastoma cell line SY5Y.
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PMID:DNA binding studies of novel Copper(II) complexes containing L-tryptophan as chiral auxiliary: in vitro antitumor activity of Cu-Sn2 complex in human neuroblastoma cells. 1737 49

In this study, biologically active compounds were isolated from Protaetia brevitarsis larva (PBL) by dichloromethane extraction. The dichloromethane extract from PBL was highly cytotoxic to various cancer cells. From a silica gel column chromatograpy of this extract, we obtained four fractions (F-2, F-4, F-5 and F-7) having apoptosis-inducing activity. These fractions induced DNA ladder and caspase-3 activation during apoptosis in colon 26 tumor cells. In 1H and 13C NMR and mass spectral analysis of the fraction F-2 showing the highest apoptosis-inducing activity, we found that the fraction was composed of three free fatty acids such as palmitic acid, (Z)-9-octadecenoic acid and octadecenoic acid. These results indicate that the dichloromethane extract of PBL includes anticancer components composed of at least three fatty acids, and apoptosis-inducing activity of the extract was mediated by caspase-3 activation in tumor cells.
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PMID:Isolation of fatty acids with anticancer activity from Protaetia brevitarsis larva. 1742 44

Fucoidan from Cladosiphon okamuranus and its sulfate derivatives were prepared. Sulfate contents of native and oversulfated fucoidan were estimated to be 13.5% and 32.8%, respectively. The results of (1)H NMR suggest that 2,4-di-O-sulfo-, 2-mono-O-sulfo- and 4-mono-O-sulfo-l-fucopyranose were involved in oversulfated fucoidan and 4-mono-O-sulfo-l-fucopyranose was involved in native fucoidan. The oversulfated fucoidan reduced the proliferation of U937 cells in a dose-dependent manner, but the activity of native fucoidan was weak. The sulfate content and substituting position of sulfate group might be important factors of anti-proliferative activity in U937 cells. To examine whether the anti-proliferative activity of oversulfated fucoidan was caused by induction of apoptosis, apoptosis assay, caspase-3 activity assay and Western blotting analysis were performed. These results indicated that the oversulfated fucoidan induced apoptosis via caspase-3 and -7 activation-dependent pathway.
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PMID:Anti-proliferative activity of oversulfated fucoidan from commercially cultured Cladosiphon okamuranus TOKIDA in U937 cells. 1743 32


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