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)

Thymidine phosphorylase (TP) has chemotactic and angiogenic activities resulting from its enzymatic activity in vitro, and it also promotes tumor growth and inhibits apoptosis in vivo. Recently, we have reported that TP plays an important role in Fas-induced apoptosis. Caspase-8 cleavage, subsequent cytochrome c release, and caspase-3 cleavage were prevented in KB cells transfected with a TP cDNA (KB/TP cells). In this study, treatment with thymidine phosphorylase inhibitor (TPI) or thymidine did not affect cell survival of KB/TP cells during Fas-induced apoptosis. Moreover, treatment with thymine or 2-deoxy-D-ribose (degradation products of thymidine generated by TP) also did not affect cell survival of control transfectant (KB/CV) cells during Fas-induced apoptosis. These findings indicate that TP suppresses Fas-induced apoptotic signal transduction independent of its enzymatic activity.
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PMID:Thymidine phosphorylase suppresses Fas-induced apoptotic signal transduction independent of its enzymatic activity. 1215 Sep 47

Our previous studies conducted in pancreatic cancer models established in nude mice and hamsters revealed that cloned somatostatin receptor subtype 2 (sst2) gene expression induced both antioncogenic and local antitumor bystander effects in vivo. In the present study, in vivo gene transfer of sst2 was investigated in two transplantable models of primary and metastatic pancreatic carcinoma developed in hamsters. LacZ reporter or mouse sst2 genes were expressed by means of two different delivery agents: an adenoviral vector and a synthetic polycationic carrier [linear polyethylenimine (PEI)]. sst2 was injected into either exponentially growing pancreatic primary tumors or hepatic metastases, and then transgene expression and tumor progression were investigated 5-6 days after gene transfer. Molecular mechanisms involved in the inhibition of tumor growth were also analyzed. Both adenovirus- and PEI-mediated in vivo gene transfer in primary pancreatic tumors induced an increase of beta-galactosidase activity and expression of sst2 transgene nRNA (100% and 86% of tumors for adenovirus and PEI vector, respectively). Adenoviral vector-based sst2 gene transfer resulted in significant reduction of pancreatic tumor growth (P < 0.05). Using PEI vector, both pancreatic primary tumor growth and metastatic tumor growth were also significantly slackened as compared with both LacZ-treated and untreated control groups (P < 0.02). Moreover, the proliferative index decreased significantly (P < 0.005), whereas apoptosis increased (P < 0.005) in tumors transferred with sst2 gene. The increase of apoptosis correlated with an activation of the caspase-3 and poly(ADP-ribose) polymerase pathways. We concluded that in both primary and metastatic pancreatic cancer models, the synthetic gene delivery system can achieve in vivo sst2 gene transfer and results in a significant antitumor effect characterized by an increase of apoptosis and an inhibition of cell proliferation. This new strategy of gene therapy allows the restoration of expression of an antioncogenic molecule and could be promising for the treatment of advanced pancreatic cancer.
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PMID:Antitumor effect of in vivo somatostatin receptor subtype 2 gene transfer in primary and metastatic pancreatic cancer models. 1241 37

Previously, we designed a ribozyme that targets the H-ras oncogene at the 12th codon mutation site (Chang et al., 1997). Ribozymes have antisense molecule and site-specific ribonuclease potential. In this study, an adenoviral vector was used to transduce the H-ras ribozyme into laryngeal cancer cells (HEp-2). This served to downregulate the H-ras gene expression in which this ribozyme performed antisense activity due to HEp-2 cells containing wild-type alleles in the 12th H-ras codon. Together, our data demonstrated that the recombinant adenovirus encoding H-ras ribozyme can be broadly regarded as a cytotoxic gene therapy in laryngeal cancer cells regardless of containing wild-type or mutant ras gene. In addition, the mechanism through which the H-ras ribozyme inhibited tumor growth was apoptosis and involved both caspase- and mitochondria-mediated pathways. The activators caspase-8 and -9 as well as the effector caspase-3 in the induction phase of apoptosis and the substrate PARP of caspase-3 in the execution phase were activated 48h following the H-ras ribozyme treatment. Mitochondrial events characterized by the production of superoxide anion and the release of cytochrome c started at 24h. Mitochondrial transmembrane potential loss occurred 48h after the ribozyme treatment. However, Bcl-2 delayed cytochrome c release to the cytosol, but it could not protect the apoptosis effect, suggesting that cytochrome c release from mitochondria may not play a role in H-ras ribozyme-induced apoptosis.
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PMID:Recombinant adenovirus encoding H-ras ribozyme induces apoptosis in laryngeal cancer cells through caspase- and mitochondria-dependent pathways. 1241 27

In an investigation of the antitumor effects of 2-methoxyestradiol (2-ME) in combination with other reactive oxygen generating treatments, 2-ME (0.5 microM) was found to completely inhibit cell proliferation of rat DS-sarcoma cells in vitro, with 71% of cells dying after exposure to 5 microM 2-ME. Concentration-dependent increases in ROS-formation, lipid peroxidation and mitochondrial changes were also observed, and an elevation in caspase-3 activity resulted in DNA fragmentation and apoptosis. Combination of 2-ME with hypoxanthine and xanthine oxidase enhanced in vitro cytotoxicity. In vivo, 2-ME caused a slight inhibition of tumor growth, with no tumors cured. Combination of 2-ME treatment with localized 44 degrees C hyperthermia, respiratory hyperoxia and xanthine oxidase caused a tumor growth delay with 51% of tumors cured. These results suggest that amplifying the levels of reactive oxygen species within tumor tissue with substances such as 2-ME may prove to be a promising strategy for adjuvant treatment of solid tumors.
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PMID:2-Methoxyestradiol enhances reactive oxygen species formation and increases the efficacy of oxygen radical generating tumor treatment. 1243 19

The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) causes cellular transformation and activation of several intracellular signaling events. In this report, we show that BLMP1 (encoded by the LMP1 gene derived from the B95-8 strain of EBV) triggers the expression of inducible nitric oxide synthase (iNOS) in Balb/3T3 fibroblasts. Intriguingly, NLMP1, a natural sequence variant of LMP1 identified in EBV-positive nasopharyngeal carcinoma biopsy, does not similarly induce iNOS expression. BLMP1-induced iNOS in Balb/3T3 cells is active to produce nitric oxide (NO), and NO production can be blocked by several iNOS inhibitors. When subjected to environmental stress, Balb/3T3 cells that produce NO lose viability more rapidly than non NO-producing cells. Blockage of NO generation by iNOS inhibitors enhances the viability of NO-producing cells under stress conditions. The activities of caspase-3 and c-Jun N-terminal kinase, two important regulators mediating stress-induced apoptosis, are significantly potentiated following heat shock treatment of BLMP1-expressing/NO-producing cells, compared to parental and NLMP1-expressing cells. Furthermore, treatment with iNOS inhibitor augmented the cloning efficiency (in culture) and tumor growth (in nude mice) of BLMP1-expressing/NO-producing cells. Collectively, the results demonstrate that BLMP1 induces iNOS expression and NO production in Balb/3T3 cells, which leads to the alteration of cell functions, including sensitivity to environmental stress, capability to colonize independent of anchorage and tumorigenicity in nude mice. Our data additionally implicate that the differential iNOS induction potential of the two LMP1 forms may represent the basis of a functional difference between the two LMP1 proteins.
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PMID:Induction of inducible nitric oxide synthase by Epstein-Barr virus B95-8-derived LMP1 in Balb/3T3 cells promotes stress-induced cell death and impairs LMP1-mediated transformation. 1243 55

We previously found that multiple intraperitoneal administration of magnolol from Magnolia obovata inhibited tumor metastasis and growth in vivo, and that the anti-metastatic effect of magnolol was due to the inhibition of the tumor cell invasion. The purpose of this study was to clarify the inhibitory mechanism of magnolol on the growth of tumor cells, and we expect that magnolol may have the ability to induce apoptosis in tumor cells. In an in vitro proliferation assay, 100 microM of magnolol inhibited the proliferation of B16-BL6, THP-1, BAE and HT-1080 cells, but 30 microM of magnolol did not affected cells proliferation. In addition, 100 microM of magnolol induced apoptotic cell death within 24 h in three tumor cell lines, B16-BL6, THP-1 and HT-1080, not BAE cells, and then up-regulated the activity of caspase-3 and caspase-8. The up-regulation of caspases activity by 100 microM of magnolol was suppressed by the inhibitor of all caspases, z-VAD-fmk. These data suggest that magnolol possesses ability to inhibit tumor growth, and the ability is due to the induction of apoptosis with the activation of caspases.
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PMID:Magnolol has the ability to induce apoptosis in tumor cells. 1249 37

We have previously shown that treatment with (-)-epigallocatechin-3-gallate (EGCG) inhibited vascularity and tumor growth in human colon cancer xenografts in nude mice (Jung et al: Br J Cancer 84, 2001). In this study, we examined whether endothelial cell death by EGCG is mediated by apoptosis and which molecular mechanisms are involved in this process. EGCG was found to suppress cell growth and induce apoptosis largely through mitochondrial depolarization, activation of caspase-3 and cleavage of DNA fragmentation factor-45 in human endothelial ECV 304 cells. The induction of apoptosis by EGCG was confirmed by cleaved and condensed nuclear chromatin and DNA hypoploidy. These results suggest that EGCG may exert at least part of its anticancer effect by inhibiting angiogenesis through inducing endothelial apoptosis.
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PMID:Induction of apoptosis by the green tea flavonol (-)-epigallocatechin-3-gallate in human endothelial ECV 304 cells. 1253 89

2-Methoxyestradiol (2ME2), a natural metabolite of estradiol, is a potent antitumor and antiangiogenic agent. In vitro, 2ME2 inhibits the proliferation of a wide variety of cell lines and primary cultures, and in numerous models in vivo, it has been shown to be an effective inhibitor of tumor growth and angiogenesis. 2ME2 is currently in several Phase I and Phase II clinical trials under the name Panzem. Although various molecular targets have been proposed for this compound, the mechanism by which 2ME2 exerts its effects is still uncertain. This study shows that 2ME2 uses the extrinsic pathway for induction of apoptosis. 2ME2 treatment results in up-regulation of death receptor 5 (DR5) protein expression in vitro and in vivo and renders cells more sensitive to the cytotoxic activities of the DR5 ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). 2ME2-induced apoptosis requires caspase activation and kinetic studies show the sequential activation of caspase-8, caspase-9, and caspase-3. Blockage of death receptor signaling by expression of dominant-negative Fas-associated death domain severely attenuates the ability of 2ME2 to induce apoptosis. Because 2ME2 administration has not manifested dose-limiting toxicity in the clinic, DR5 expression may serve as a surrogate marker for biological response.
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PMID:2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway. 1254 4

Histone deacetylase activity is potently inhibited by hydroaximc acid derivatives such as suberoylanilide hydroxamic acid (SAHA) and trichostatin-A (TSA). These inhibitors specifically induce differentiation/apoptosis of transformed cells in vitro and suppress tumor growth in vivo. Because of its low toxicity, SAHA is currently evaluated in clinical trials for the treatment of cancer. SAHA and TSA induce apoptosis, which is characterized by mitochondrial stress, but so far, the critical elements of this apoptotic program remain poorly defined. To characterize in more detail this apoptotic program, we used human cell lines containing alterations in important elements of apoptotic response such as: p53, Bcl-2, caspase-9, and caspase-3. We demonstrate that caspase-9 is critical for apoptosis induced by SAHA and TSA and that efficient proteolytic activation of caspase-2, caspase-8, and caspase-7 strictly depends on caspase-9. Bcl-2 efficiently antagonizes cytochrome c release and apoptosis in response to both histone deacetylase inhibitors. We provide evidences that translocation into the mitochondria of the Bcl-2 family member Bid depends on caspase-9 and that this translocation is a late event during TSA-induced apoptosis. We also demonstrate that the susceptibility to TSA- and SAHA-induced cell death is regulated by p53.
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PMID:Role of caspases, Bid, and p53 in the apoptotic response triggered by histone deacetylase inhibitors trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA). 1255 48

Thalidomide is clinically useful in a number of cancers. Antitumor activity may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-alpha and T-cell costimulatory and antiangiogenic activities. However, it may also involve direct antitumor effects. A series of second generation thalidomide analogues have been separated into two distinct groups of compounds, each with enhanced therapeutic potential, i.e., SelCIDs, which are phosphodiesterase (PDE) type IV inhibitors, and IMiDs, which have unknown mechanism(s) of action. We report here our efforts to determine direct antitumor effects of thalidomide and compounds from both groups. We found that one of the SelCID analogues (SelCID-3) was consistently effective at reducing tumor cell viability in a variety of solid tumor lines but had no effect on non-neoplastic cells. The antitumor activity was independent of known PDE4 inhibitory activity and did not involve cAMP elevation. Growth arrest was preceded by the early induction of G(2)-M cell cycle arrest, which led to caspase 3 mediated apoptosis. This was associated with increased expression of pro-apoptotic proteins and decreased expression of antiapoptotic bcl-2. Furthermore, extensive apoptosis in vivo was detected during SelCID-3-mediated inhibition of tumor growth in a murine xenotransplantation cancer model. Our results suggest that SelCID-3 represents a novel antitumor agent distinct from thalidomide and from previously characterized analogues with therapeutic potential against a range of solid tumors. This effect appears to be mediated via alterations in the expression of bcl-2 family proteins.
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PMID:A novel subclass of thalidomide analogue with anti-solid tumor activity in which caspase-dependent apoptosis is associated with altered expression of bcl-2 family proteins. 1256 1


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