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)

We recently reported that chronic lymphocytic leukemia (CLL) cells synthesize and release vascular endothelial growth factor (VEGF) under normoxic and hypoxic conditions. CLL B cells also express VEGF membrane receptors (VEGF-R1 and VEGF-R2), suggesting that they use VEGF as a survival factor. To assess the mechanism of apoptosis resistance related to VEGF, we determined the impact of VEGF on CLL B cells, and we studied the impact of epigallocatechin-3-gallate (EGCG), a known receptor tyrosine kinase (RTK) inhibitor, on VEGF receptor status and viability of CLL B cells. VEGF165 significantly increased apoptotic resistance of CLL B cells, and immunoblotting revealed that VEGF-R1 and VEGF-R2 are spontaneously phosphorylated on CLL B cells. EGCG significantly increased apoptosis/cell death in 8 of 10 CLL samples measured by annexin V/propidium iodide (PI) staining. The increase in annexin V/PI staining was accompanied by caspase-3 activation and poly-adenosine diphosphate ribose polymerase (PARP) cleavage at low concentrations of EGCG (3 microg/mL). Moreover, EGCG suppressed the proteins B-cell leukemia/lymphoma-2 protein (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP), and myeloid cell leukemia-1 (Mcl-1) in CLL B cells. Finally, EGCG (3-25 microg/mL) suppressed VEGF-R1 and VEGF-R2 phosphorylation, albeit incompletely. Thus, these results suggest that VEGF signaling regulates survival signals in CLL cells and that interruption of this autocrine pathway results in caspase activation and subsequent leukemic cell death.
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PMID:VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia. 1499 3

The discovery of an agent that selectively kills tumor cells and not normal cells is the dream of every cancer researcher. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), first discovered in 1995, was heralded as a selective killer of tumor cells, and its potential is still thought to be high. Almost immediately, broad efforts were made to understand its activity at the molecular level. TRAIL has been shown to interact with the cell surface through five distinct receptors, named death receptor (DR) 4, DR5, decoy receptor (Dc)R1, DcR2, and osteoprotegrin. It activates nuclear factor (NF)-kappaB, c-Jun N-terminal kinases, and apoptosis. The apoptotic signals are mediated through Fas-associated death domain protein (FADD)-mediated recruitment of caspase-8 and caspase-3. Additionally, caspase-8 can cleave Bcl-2 homology domain 3 (BH3)-interfering domain death agonist (Bid), and the cleaved Bid then causes the release of mitochondrial cytochrome c, leading to the activation of pro-caspase-9, which can then activate pro-caspase-3. TRAIL-induced apoptosis is negatively regulated by numerous cellular factors including decoy receptors, cellular FADD-like interleukin 1 beta-converting enzyme (FLICE) interacting protein (cFLIP), cellular inhibitor of apoptosis protein (cIAP), X-linked IAP (XIAP), survivin, and NF-kappaB. Second mitochondria-derived activator of caspases (Smac)?direct IAP binding protein with low pI (DIABLO) mediates proapoptotic signals through inaction of IAP. How the TRAIL-induced apoptosis is downregulated by these factors is discussed in detail in this review. Whether TRAIL selectively kills tumor cells without harming normal cells is also discussed.
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PMID:Regulation of TRAIL-induced apoptosis by ectopic expression of antiapoptotic factors. 1511 Jan 90

Topoisomerases are nuclear enzymes that maintain and modulate DNA structure. Inhibitors of topoisomerases like camptothecin (CPT), etoposide, and others are widely used antitumor drugs that interfere with transcription, induce DNA strand breaks, and trigger apoptosis preferentially in dividing cells. Because transcription inhibitors (actinomycin D, galactosamine, alpha-amanitin) sensitize primary hepatocytes to the cytotoxic action of tumor necrosis factor (TNF), we reasoned whether topoisomerase inhibitors would act similarly. CPT alone was not toxic to primary cultured murine hepatocytes. When incubated with CPT, murine hepatocytes displayed an inhibition of protein synthesis and were thereby rendered sensitive to apoptosis induction by TNF. Apoptosis was characterized by morphology (condensed/fragmented nuclei, membrane blebbing), caspase-3-like protease activity, fragmentation of nuclear DNA, and late cytolysis. Hepatocytes derived from TNF receptor-1 knockout mice were resistant to CPT/TNF-induced apoptosis. CPT treatment completely abrogated the TNF-induced NF-kappa B activation, and mRNA expression of the antiapoptotic factors TNF-receptor associated factor 2, FLICE-inhibitory protein, and X-linked inhibitor of apoptosis protein was also inhibited by CPT. The caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-(OMe)-fluoromethylketone (zVAD-fmk) and benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-chloromethylketone (zDEVD-fmk), as well as depletion of intracellular ATP by fructose prevented CPT/TNF-induced apoptosis. In vivo, CPT treatment sensitized mice to TNF-induced liver damage. In conclusion, the combination of topoisomerase inhibition and TNF blocks survival signaling and elicits a type of hepatocyte death similar to actinomycin D/TNF or galactosamine/TNF. During antitumor treatment with topoisomerase inhibitors, an impaired immune function often results in opportunistic infections, a situation where the systemic presence of TNF might be critical for the hepatotoxicity reported in clinical topoisomerase inhibitor studies.
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PMID:Topoisomerase inhibitor camptothecin sensitizes mouse hepatocytes in vitro and in vivo to TNF-mediated apoptosis. 1512 60

Androgen-insensitive prostate cancer cells are highly resistant to several chemotherapeutic drugs and are characterized by the appearance of apoptosis-resistant cells. In this study, we identified the critical role of X-linked inhibitor of apoptosis protein (XIAP), a potent antiapoptotic factor, in conferring chemotherapy resistance in an androgen-insensitive DU145 human prostate cancer cell line. Results reveal that DU145 cells were highly resistant to cisplatin, but this resistance was overridden when the cells were treated for a prolonged time (>96 hours) with cisplatin (IC(50) = 27.5 to 35.5 micromol/L). A decrease in levels of XIAP and Akt/phospho-Akt and an increase in caspase-3 activity were identified to be key factors in cisplatin sensitivity (40% to 55% decrease in cell viability) at later time points. In contrast, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment caused a 40% to 50% decrease in cell viability within 6 hours (IC(50) = 135 to 145 ng/mL). However, increasing concentrations or prolonged treatment with TRAIL did not change drug potency. A significant increase in caspase-3 activity was observed with TRAIL treatment with no apparent change in XIAP levels. Specific inhibition of XIAP expression using an antisense XIAP phosphorodiamidate morpholino oligomer induced apoptosis and increased caspase-3 activity. Combination of cisplatin with XIAP antisense potentiated cisplatin sensitivity by decreasing the IC(50) from >200 micromol/L with cisplatin alone to 9 to 20 micromol/L and decreasing incubation time required for activity from 96 to 24 hours. Similarly, TRAIL in combination with XIAP antisense phosphorodiamidate morpholino oligomer enhanced TRAIL potency by 12- to 13-fold. In conclusion, abrogation of XIAP expression is essential for therapeutic apoptosis and enhanced chemotherapy sensitization in androgen-refractory prostate cancer cells.
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PMID:X-linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells. 1521 Aug 56

Erythropoietin (EPO) and insulin-like growth factor I (IGF-I) are cytokines that inhibit neuronal apoptosis. However, their maximal antiapoptotic effect, even at high concentrations, is observed only when neurons are pretreated for several hours before insult. Here we show that simultaneous administration of EPO and IGF-I (EPO+IGF-I) eliminates the preincubation period required to prevent N-methyl-D-aspartate (NMDA)-induced apoptosis in cultured rat cerebrocortical neurons. The synergistic effect of EPO+IGF-I was mediated, at least in part, by activation of phosphatidylinositol 3-kinase (PI3-K). EPO+IGF-I synergistically activated Akt (protein kinase B), a downstream target of PI3-K, and prevented dephosphorylation of Akt. Overexpression of a dominant interfering form of Akt (dnAkt) abrogated EPO+IGF-I-mediated neuroprotection. EPO+IGF-I treatment did not prevent initial NMDA-induced caspase-3 activation, which was observed within 6 h of insult; however, EPO+IGF-I-treated neurons survived at least 2 days after NMDA insult. These cytokines prevented neuronal apoptosis downstream of caspase activation by facilitating association between X-linked inhibitor of apoptosis protein, an inhibitor of caspase proteolytic activity, and activated caspase-3. These results imply that EPO+IGF-I exert cooperative actions that afford acute neuroprotection via activation of the PI3-K-Akt pathway.
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PMID:Acute neuroprotective synergy of erythropoietin and insulin-like growth factor I. 1521 Sep 45

In this study we evaluated UCN-01, a small molecule that inhibits protein kinases by interacting with the ATP-binding site, as a potential anti-cancer agent for neuroblastoma. UCN-01 was effective at inducing apoptosis in six neuroblastoma cell lines with diverse cellular and genetic phenotypes. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assays, detection of active caspase-3 and cleaved poly ADP-ribose polymerase (PARP) confirmed that UCN-01 induced apoptosis. Cell cycle analysis determined that the UCN-01 treated cells accumulated in S phase by 16 h. Unlike vinblastine and docetaxel that increased survivin expression, UCN-01 treatment did not increase X-linked inhibitor of apoptosis protein (XIAP) and survivin levels. Analysis of specific phosphoepitopes on chk1/2, Akt, and GSK3beta following UCN-01 treatment determined that there was no significant change in phospho-chk1/2. However, there was decreased immunoreactivity at Ser473 and Thr308 of Akt and Ser9 of GSK3beta by 4 h indicating that the Akt survival pathway and downstream signalling was compromised. Thus, UCN-01 was effective at inducing apoptosis in neuroblastoma cell lines.
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PMID:UCN-01 alters phosphorylation of Akt and GSK3beta and induces apoptosis in six independent human neuroblastoma cell lines. 1525 49

Although inhibition of histone deacetylase has been demonstrated to induce apoptosis of various cancer cells, there is no report on its effect on mast cell demise to date. Here we studied whether a histone deacetylase inhibitor Trichostatin A (TSA) produces apoptosis in p815 mastocytoma cells. TSA prominently increased the amount of acetylated histones, H3, H4, H2A and H2B, in p815 mastocytoma cells. TSA reduced the viability of p815 mastocytoma cells, and many apoptotic manifestations such as generation of DNA fragmentation, activation of caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and increase of DNA hypoploidy proved that the reduction of viability resulted from apoptosis. Whereas TSA treatment increased the expression level of Bad, it decreased the level of Bcl-2, Bcl-xL, and X-linked inhibitor of apoptosis protein. The reduction of mitochondrial membrane potential, the release of cytochrome c and Smac/DIABLO to cytosol, and mitochondrial localization of Bad were also shown. Taken together, TSA induces apoptosis on p815 mastocytoma cells in histone acetylation- and mitochondria-dependent fashion. Our data therefore provide the possibility that TSA could be considered as a novel therapeutic strategy for mastocytoma from its apoptosis-inducing activity.
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PMID:Trichostatin A induces apoptosis of p815 mastocytoma cells in histone acetylation- and mitochondria-dependent fashion. 1549 35

Human epithelial ovarian cancer is the most lethal female cancer. Hormones and growth factors, including the TGF-beta superfamily, have been suggested to play a role in ovarian tumorigenesis. The biological effects of TGF-beta superfamily are mediated by type I and type II serine/threonine kinase receptors and by intracellular Smad proteins. Recently, we have cloned four transcripts of human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. In this study, we have investigated the role of Nodal and ALK7 in four ovarian cancer cell lines, OV2008, C13*, A2780-s, and A2780-cp. Overexpression of Nodal resulted in a significant decrease in the number of metabolically active cells. This effect was mimicked by a constitutively active ALK7 (ALK7-ca) but blocked by dominant negative mutants of ALK7, Smad2, or Smad3. Transient transfection of Nodal and ALK7-ca significantly decreased X-linked inhibitor of apoptosis protein (Xiap) expression, activated both caspase-3 and caspase-9, and increased apoptosis as determined by Hoechst nuclear staining and flow cytometry. In addition, Nodal and ALK7-ca also inhibited cell proliferation as measured by 5-bromo-2'-deoxyuridine (BrdU) assays. Interestingly, the effects of Nodal and ALK7-ca were more potent in chemosensitive A2780-s cells than in its chemoresistant counterpart, A2780-cp cells. These findings demonstrate that Nodal induces apoptosis and inhibits proliferation via ALK7 and Smad2/3 and that the effect of Nodal-ALK7 on apoptosis may be mediated in part by the down-regulation of Xiap and activation of caspase-9 and caspase-3.
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PMID:Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. 1553 7

1. Cinnamaldehyde has been shown to be effective in inducing cell apoptosis in a number of human cancer cells. The aim of the present study was to investigate the effect of vitamin E on the apoptotic signalling mechanism induced by cinnamaldehyde in human hepatoma PLC/PRF/5 cells. 2. Using the XTT assay, cinnamaldehyde exhibited a powerful antiproliferative effect on PLC/PRF/5 cells. Apoptosis was elicited when cells were treated with 1 micromol/L cinnamaldehyde, as characterized by the appearance of phosphatidylserine on the outer surface of the plasma membrane. 3. The apoptotic effect induced by cinnamaldehyde could be further supported by the release of cytochrome c, Smac/Diablo and Omi/HtrA2 from mitochondria to the cytosol and activation of caspase 3. Cinnamaldehyde also upregulated the expression of pro-apoptotic protein (Bax) and down-regulated the levels of anti-apoptotic proteins, such as Bcl-2 and the inhibitor of apoptosis protein family (X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein (cIAP)-1 and cIAP-2). 4. Cinnamaldehyde induces the generation of reactive oxygen species (ROS) in cells. Following the pre-incubation of PLC/PRF/5 cells with anti-oxidants, it was found that 100 micromol/L vitamin E significantly diminished the effect of cinnamaldehyde-induced apoptosis, whereas a lesser effect was seen with on 100 micromol/L N-acetyl-L-cysteine. Vitamin E effectively blocked the release of cytochrome c, Smac/Diablo and Omi/HtrA2 from mitochondria to the cytosol in cells treated with cinnamaldehyde. Vitamin E also markedly suppressed caspase 3 activation. The expression of apoptotic inhibitors (XIAP, cIAP-1, cIAP-2) and anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) proteins was affected by vitamin E pretreatment. 5. Taken together, the results suggest that cinnamaldehyde triggers apoptosis possibly through the mitochondrial pathway. Pretreatment with vitamin E markedly prevented cinnamaldehyde-mediated apoptosis, which was associated with the modulation of XIAP, cIAP-1, cIAP-2, Bcl-2 and Bax protein activity.
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PMID:Effects of vitamin E on the cinnamaldehyde-induced apoptotic mechanism in human PLC/PRF/5 cells. 1556 91

The purpose of the present study is to investigate the role of X-linked inhibitor of apoptosis protein (XIAP) in the regulation of apoptosis induced by cisplatin in human prostate cancer cell line (LNCaP). We examined the effects of cisplatin on cell growth and apoptosis in LNCaP by 2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt (WST-1), flow cytometric analyses, and caspase-3 activity assay. In addition, to clarify the roles of the XIAP, we established clonal cell lines that overexpressed XIAP. The effects of cisplatin on the XIAP expression in the induction of apoptosis in LNCaP were examined by RT-PCR and immunoblot analyses. Although the growth rates were reduced in a dose- and time-dependent manner by cisplatin in LNCaP sublines, the anti-proliferative effects of cisplatin were significantly decreased in XIAP stably overexpressing cell lines. In addition, we found that cisplatin-induced apoptosis following activation of caspase-3, and that the overexpression of XIAP inhibited apoptosis by attenuating caspase-3 activity. Interestingly, treatment of LNCaP cells with 10 and 100 muM cisplatin for 48 h significantly decreased the expression of XIAP at both the protein and mRNA levels in a dose-dependent manner. Furthermore, 10-muM cisplatin treatment of LNCaP decreased XIAP mRNA and protein in a time-dependent manner. These results suggest that cisplatin induces apoptosis by the inhibition of XIAP expression, and that XIAP plays an important role in the regulation of cisplatin-induced apoptosis in LNCaP cells. The ability of cisplatin to down-regulate XIAP may be an important mechanism in chemosensitivity.
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PMID:Cisplatin inhibits the expression of X-linked inhibitor of apoptosis protein in human LNCaP cells. 1561 Aug 60


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