Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-small cell lung cancer (NSCLC) is a common and often fatal malignancy, diagnosed at an advanced stage in more than half of the cases. Chemo-resistance remains a major problem in the treatment of NSCLC patients with conventional chemotherapeutic agents. Therefore main research efforts are focused on the development of novel targeted agents. In this review we provide an overview on the use of TNF-related apoptosis-inducing ligand (TRAIL) receptor targeting agents in NSCLC models and in early clinical studies. Different TRAIL receptor targeting agents are available which have been tested in NSCLC models and some were tested in the clinic. The efficacy of these drugs as single agents in NSCLC models is discussed as well as different mechanisms of resistance that are found in NSCLC cell lines. In order to maximize sensitivity to TRAIL receptor targeting drugs, combined use with other drugs is of interest. The current status of tested combinations of TRAIL receptor targeting agents with other therapeutics, such as classical cytotoxics, Bcl-2 family targeting agents, proteasome inhibitors, EGFR inhibitors, histone deacetylase inhibitors and COX-2 inhibitors as well as their mechanisms in preclinical studies are discussed. Clinical studies on TRAIL targeted therapies in which NSCLC patients were included are discussed and future perspectives are considered.
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PMID:TRAIL receptor targeting therapies for non-small cell lung cancer: current status and perspectives. 2003 2

The phytochemical resveratrol has recently gained attention for its protection against metabolic disease and for extension of life span, which have been linked to its metabolic effects and SIRT1 activation in fat cells. However, little is known about the effect of resveratrol on fat cell apoptosis. Here, we identify a novel, SIRT1-independent mechanism by which resveratrol regulates fat cell numbers. We demonstrate for the first time that resveratrol enhances TNF-related apoptosis-inducing ligand (TRAIL)- or CD95-induced apoptosis of human preadipocytes in a highly synergistic manner (EC(50) at 72 h: resveratrol, >300 microM; TRAIL, >100 ng/ml; combination: 30 microM resveratrol and 10 ng/ml TRAIL, combination index 0.4). Similar results in primary human preadipocytes prepared from subcutaneous white adipose tissue and mature human adipocytes underline the relevance to human physiology. Mechanistic studies reveal that resveratrol inhibits PI3K-driven phosphorylation of Akt, leading to increased Bax activation, loss of mitochondrial membrane potential, cytochrome c release, and caspase-dependent apoptosis. The synergistic interaction of resveratrol and TRAIL depends on the intrinsic apoptosis pathway and caspases, since Bcl-2 overexpression and the caspase inhibitor zVAD.fmk inhibit apoptosis, whereas knockdown of SIRT1 by RNA interference has no effect. The discovery of this novel activity of resveratrol significantly advances the knowledge of fat tissue regulation by resveratrol and has important implications for its use in metabolic and age-related diseases.
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PMID:Identification of a novel proapoptotic function of resveratrol in fat cells: SIRT1-independent sensitization to TRAIL-induced apoptosis. 2009 79

Defects in apoptosis are observed in many cancer cell types and contribute in a relevant way to tumorigenesis. Apoptosis is a complex and well-regulated cell death program that plays a key role in the control of cell homeostasis, particularly at the level of the hematopoietic system. Apoptosis can be initiated through two different mechanisms involving either activation of the death receptors (extrinsic pathway) or activation of a mitochondrial apoptotic process (intrinsic pathway). Among the various death receptors a peculiar role is played by TNF-related apoptosis-inducing ligand (TRAIL)-receptors (TRAIL-Rs) and their ligand TRAIL. TRAIL recently received considerable interest for its potent anti-tumor killing activity, sparing normal cells. Here, we will review the expression and the abnormalities of TRAIL/TRAIL-R system in hematologic malignancies. The large majority of primary hematologic tumors are resistant to TRAIL-mediated apoptosis, basically due to the activation of anti-apoptotic signaling pathway (such as NF-kappaB), overexpression of anti-apoptotic proteins (such as FLIP, Bcl-2, XIAP) or expression of TRAIL decoy receptors or reduced TRAIL-R1/-R2 expression. Strategies have been developed to bypass this TRAIL resistance and are based on the combination of TRAIL with chemotherapy or radiotherapy, or with proteasome or histone deacetylase or NF-kappaB inhibitors. The agents used in combination with TRAIL either enhance TRAIL-R1/-R2 expression or decrease expression of anti-apoptotic proteins (c-FLIP, XIAP, Bcl-2). Many of these combinatorial therapies hold promise for future developments in treatment of hematologic malignancies.
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PMID:TRAIL/TRAIL-R in hematologic malignancies. 2033 67

TNF-related apoptosis-inducing ligand (TRAIL) shows promise as a cancer treatment, but acquired tumor resistance to TRAIL is a roadblock. Here we investigated whether nimbolide, a limonoid, could sensitize human colon cancer cells to TRAIL. As indicated by assays that measure esterase activity, sub-G(1) fractions, mitochondrial activity, and activation of caspases, nimbolide potentiated the effect of TRAIL. This limonoid also enhanced expression of death receptors (DRs) DR5 and DR4 in cancer cells. Gene silencing of the receptors reduced the effect of limonoid on TRAIL-induced apoptosis. Using pharmacological inhibitors, we found that activation of ERK and p38 MAPK was required for DR up-regulation by nimbolide. Gene silencing of ERK abolished the enhancement of TRAIL-induced apoptosis. Moreover, our studies indicate that the limonoid induced reactive oxygen species production, which was required for ERK activation, up-regulation of DRs, and sensitization to TRAIL; these effects were mimicked by H(2)O(2). In addition, nimbolide down-regulated cell survival proteins, including I-FLICE, cIAP-1, cIAP-2, Bcl-2, Bcl-xL, survivin, and X-linked inhibitor of apoptosis protein, and up-regulated the pro-apoptotic proteins p53 and Bax. Interestingly, p53 and Bax up-regulation by nimbolide was required for sensitization to TRAIL but not for DR up-regulation. Overall, our results indicate that nimbolide can sensitize colon cancer cells to TRAIL-induced apoptosis through three distinct mechanisms: reactive oxygen species- and ERK-mediated up-regulation of DR5 and DR4, down-regulation of cell survival proteins, and up-regulation of p53 and Bax.
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PMID:Nimbolide sensitizes human colon cancer cells to TRAIL through reactive oxygen species- and ERK-dependent up-regulation of death receptors, p53, and Bax. 2749 66

The BH3-only proteins of the Bcl-2 family are known to mediate mitochondrial dysfunction during apoptosis. However, the identity of the critical BH3-only proteins and the mechanism of their action following treatment by diverse apoptotic stimuli remain to be fully resolved. We therefore used RNAi to screen the entire Bcl-2 family for their involvement in three major apoptotic pathways in HeLa cells. We found that Bcl-xL and Mcl-1 are major inhibitors of apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL), endoplasmic reticulum (ER) stress, and proteasome inhibition. Among the 10 BH3-only proteins, Bid and Noxa were found to be critically involved in TRAIL-induced apoptosis, in which Noxa participates by constitutively binding to Mcl-1. Bim and Noxa were found to be necessary for ER stress-induced apoptosis, in which Noxa assisted Bim function by sequestering Mcl-1 and binding to Bcl-xL. As a critical BH3-only protein, Noxa was strongly upregulated and became associated with both Mcl-1 and Bcl-xL during apoptosis induced by proteasome inhibition. In addition, we found that Noxa became 'Mcl-1 free' following treatment by ER stress and proteasome inhibition, but not after TRAIL treatment. These results defined the critical Bcl-2 network during apoptosis and suggested that Noxa participated in triggering mitochondrial dysfunction in multiple apoptotic pathways through distinct mechanisms.
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PMID:Selective involvement of BH3-only proteins and differential targets of Noxa in diverse apoptotic pathways. 2111 47

Acetaminophen (N-acetyl-para-aminophenol (APAP), paracetamol) is a commonly used analgesic and antipyretic agent. Although considered safe at therapeutic doses, accidental or intentional overdose causes acute liver failure characterized by centrilobular hepatic necrosis with high morbidity and mortality. Although many molecular aspects of APAP-induced cell death have been described, no conclusive mechanism has been proposed. We recently identified TNF-related apoptosis-inducing ligand (TRAIL) and c-Jun kinase (JNK)-dependent activation of the pro-apoptotic Bcl-2 homolog Bim as an important apoptosis amplification pathway in hepatocytes. In this study, we, thus, investigated the role of TRAIL, c-JNK and Bim in APAP-induced liver damage. Our results demonstrate that TRAIL strongly synergizes with APAP in inducing cell death in hepatocyte-like cells lines and primary hepatocyte. Furthermore, we found that APAP strongly induces the expression of Bim in a c-JNK-dependent manner. Consequently, TRAIL- or Bim-deficient mice were substantially protected from APAP-induced liver damage. This study identifies the TRAIL-JNK-Bim axis as a novel target in the treatment of APAP-induced liver damage and substantiates its general role in hepatocyte death.
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PMID:Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage. 2165 29

Glutathione-S-transferase of the Pi class (GSTP1) is frequently overexpressed in a variety of solid tumors and has been identified as a potential therapeutic target for cancer therapy. GSTP1 is a phase II detoxification enzyme and conjugates the tripeptide glutathione to endogenous metabolites and xenobiotics, thereby limiting the efficacy of antitumor chemotherapeutic treatments. In addition, GSTP1 regulates cellular stress responses and apoptosis by sequestering and inactivating c-Jun N-terminal kinase (JNK). Thiazolides are a novel class of antibiotics for the treatment of intestinal pathogens with no apparent side effects on the host cells and tissue. Here we show that thiazolides induce a GSTP1-dependent and glutathione-enhanced cell death in colorectal tumor cell lines. Downregulation of GSTP1 reduced the apoptotic activity of thiazolides, whereas overexpression enhanced it. Thiazolide treatment caused strong Jun kinase activation and Jun kinase-dependent apoptosis. As a critical downstream target of Jun kinase we identified the pro-apoptotic Bcl-2 homolog Bim. Thiazolides induced Bim expression and activation in a JNK-dependent manner. Downregulation of Bim in turn significantly blocked thiazolide-induced apoptosis. Whereas low concentrations of thiazolides failed to induce apoptosis directly, they potently sensitized colon cancer cells to TNF-related apoptosis-inducing ligand- and chemotherapeutic drug-induced cell death. Although GSTP1 overexpression generally limits chemotherapy and thus antitumor treatment, our study identifies GSTP1 as Achilles' heel and thiazolides as novel interesting apoptosis sensitizer for the treatment of colorectal tumors.
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PMID:Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase-Bim axis and reveals glutathione-S-transferase P1 as Achilles' heel. 2215 36

Cystic echinococcosis (hydatidosis) is a zoonotic helminthic disease of human and other intermediated hosts wherein infection is caused by the larval stages of tapeworm Echinococcus granulosus. Growth of the larval stage is formed throughout the internal organs, the liver and lung, causing their destruction. Important pathways are unknown about suppression and survival of cysts in human body. In this study, apoptotic bifunctional effects are evaluated in relationship between host and parasite in cystic echinococcosis. Human lymphocytes were treated with hydatid fluid (HF). After 6 h of exposure, caspase-3 activity was measured by fluorometric assay in the HF-treated lymphocytes and control cells. Also, the expression of Bax (as pro-apoptotic protein) and Bcl-2 (an anti-apoptotic protein) mRNA was assessed by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) after 12 h of exposure. For surveying of apoptosis-inducing ligands TNF-related apoptosis-inducing ligand and Fas-L, germinal layer and accompaniment peripheral tissues as healthy control were separated by scalpel from each cyst in sterile condition, then were assess by semiquantitative RT-PCR method in mRNA expression. Both the ratio of Bax/Bcl-2 mRNA expression and caspase-3 activity were higher in the fertile fluid-treated lymphocytes relative to infertile fluid-treated lymphocytes and control group versus the expression level of apoptosis-inducing ligands having a relatively high level in germinal layer of infertile cyst in comparison to fertile cyst and healthy tissue. Apoptosis of germinal layer of fertile cysts is possibly one of the suppression mechanisms in hydatidosis patients, in contrast to lymphocytes apoptosis by modulator of hydatid fluid, one of the hydatid cyst survival mechanisms.
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PMID:The study of apoptotic bifunctional effects in relationship between host and parasite in cystic echinococcosis: a new approach to suppression and survival of hydatid cyst. 2216 69

Stochastic fluctuations in gene expression give rise to cell-to-cell variability in protein levels which can potentially cause variability in cellular phenotype. For TRAIL (TNF-related apoptosis-inducing ligand) variability manifests itself as dramatic differences in the time between ligand exposure and the sudden activation of the effector caspases that kill cells. However, the contribution of individual proteins to phenotypic variability has not been explored in detail. In this paper we use feature-based sensitivity analysis as a means to estimate the impact of variation in key apoptosis regulators on variability in the dynamics of cell death. We use Monte Carlo sampling from measured protein concentration distributions in combination with a previously validated ordinary differential equation model of apoptosis to simulate the dynamics of receptor-mediated apoptosis. We find that variation in the concentrations of some proteins matters much more than variation in others and that precisely which proteins matter depends both on the concentrations of other proteins and on whether correlations in protein levels are taken into account. A prediction from simulation that we confirm experimentally is that variability in fate is sensitive to even small increases in the levels of Bcl-2. We also show that sensitivity to Bcl-2 levels is itself sensitive to the levels of interacting proteins. The contextual dependency is implicit in the mathematical formulation of sensitivity, but our data show that it is also important for biologically relevant parameter values. Our work provides a conceptual and practical means to study and understand the impact of cell-to-cell variability in protein expression levels on cell fate using deterministic models and sampling from parameter distributions.
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PMID:Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis. 2257 May 96

Primary or acquired resistance to current treatment methods remains a major factor in clinical oncology and may be caused by failures in apoptosis programs. TNF-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in several human cancer cell types. However, not all cancer cells are susceptible to TRAIL and mechanisms of resistance and new strategies to enhance sensitivity are an area of intense investigation. Therefore, we investigated whether TRAIL resistance is due to Bcl-2 levels. In this study, we generated an adenoviral vector, Ad5.TRAIL/siBcl2, that permitted co-expression of shRNA against Bcl-2 and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapeutic gene from a cytomegalovirus promoter. Infection with Ad5.TRAIL/siBcl2 resulted in significant cytotoxicity in non-small cell lung cancer (NSCLC) cells in vitro. In contrast, it had no effect on a normal lung cell line, WI-38. Impressively, treatment of the established NSCLC tumor model with Ad5.TRAIL/siBcl2 resulted in significant tumor regression, compared with other adenoviruses. This potent antitumor activity induced by Ad5.TRAIL/siBcl2 was due to strong inhibition of Bcl-2 and high expression of TRAIL. Thus, this study may provide a framework for future clinical applications of Ad5.TRAIL/siBcl2 in lung tumor gene therapy.
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PMID:Adenovirus-mediated TRAIL expression and downregulation of Bcl-2 expression suppresses non-small cell lung cancer growth in vitro and in vivo. 2261 33


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