Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-related apoptosis-inducing-ligand (TRAIL/Apo-2 ligand) induces apoptosis in the majority of cancer cells without appreciable effect in normal cells. Here, we report the effects of TRAIL on apoptosis in several human breast cancer cell lines, primary memory epithelial cells, and immortalized nontransformed cell lines, and we examine whether chemotherapeutic agents augment TRAIL-induced cytotoxicity in breast cancer cells in vitro and in vivo. TRAIL induced apoptosis with different sensitivities, and the majority of cancer cell lines were resistant to TRAIL. The chemotherapeutic drugs (paclitaxel, vincristine, vinblastine, etoposide, camptothecin, and Adriamycin) induced death receptors (DRs) TRAIL receptor 1/DR4 and TRAIL receptor 2/DR5, and successive treatment with TRAIL resulted in apoptosis of both TRAIL-sensitive and -resistant cells. Actinomycin D sensitized TRAIL-resistant cells through up-regulation of caspases (caspase-3, -9, and -8). TRAIL induces apoptosis in Adriamycin-resistant MCF7 cells already expressing high levels of death receptors DR4 and DR5. The pretreatment of breast cancer cells with chemotherapeutic drugs followed by TRAIL reversed their resistance by triggering caspase-3, -9, and -8 activation. The sequential treatment of nude mice with chemotherapeutic drugs followed by TRAIL induced caspase-3 activity and apoptosis in xenografted tumors. Complete eradication of established tumors and survival of mice were achieved without detectable toxicity. Thus, the sequential administration of chemotherapeutic drugs followed by TRAIL may be used as a new therapeutic approach for cancer therapy.
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PMID:Synergistic interactions of chemotherapeutic drugs and tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand on apoptosis and on regression of breast carcinoma in vivo. 1450 Mar 73

Apoptosis pathways activated by death receptors of the tumour necrosis factor (TNF) family such as Fas, TNFR1, or the TRAIL receptors DR4 and DR5 are implicated in diverse diseases. These are also the best-understood apoptosis pathways and many of our ideas about apoptosis regulation come from studying these pathways. Cell killing from such receptors occurs because of recruitment to the receptor of the adaptor protein FADD, which in turn recruits the pro form of caspase-8. Aggregation of pro-caspase-8 leads to its auto-activation and subsequent activation of effector caspases such as caspase-3. The apoptotic signal can be amplified through the mitochondria and inhibited through the action of competing molecules such as the inhibitor c-FLIP, which binds to the receptor complex in place of caspase-8. This simple mechanism explains much of the cell death that is induced by death receptors. However, recent studies indicate that we must incorporate new information into this model. Some examples that add new layers of complexity will be discussed in this review.
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PMID:Death receptor-induced cell killing. 1463 84

To reveal the molecular mechanism of selective follicular atresia in porcine ovaries, we investigated the changes in the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor (DR4) proteins and TRAIL mRNA in granulosa cells during follicular atresia. Immunohistochemical, Western immunoblotting and reverse transcription-polymerase chain reaction analyses (RT-PCR) revealed that significant increases in TRAIL protein and mRNA levels but not DR4 protein were changed during atresia. The RT-PCR product was confirmed to be porcine TRAIL by the cDNA sequence determination. An in vitro apoptosis inducing assay using cultured granulosa cells prepared from healthy follicles showed that TRAIL could activate caspase-3 and induce apoptotic cell death in the cells. The present findings confirm that TRAIL induces apoptosis in granulosa cells during atresia in porcine ovaries.
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PMID:Roles of tumor necrosis factor-related apoptosis-inducing ligand signaling pathway in granulosa cell apoptosis during atresia in pig ovaries. 1496 24

Present studies demonstrate that treatment with the histone deacetylases inhibitor LAQ824, a cinnamic acid hydroxamate, increased the acetylation of histones H3 and H4, as well as induced p21(WAF1) in the human T-cell acute leukemia Jurkat, B lymphoblast SKW 6.4, and acute myelogenous leukemia HL-60 cells. This was associated with increased accumulation of the cells in the G(1) phase of the cell cycle, as well as accompanied by the processing and activity of caspase-9 and -3, and apoptosis. Exposure to LAQ824 increased the mRNA and protein expressions of the death receptors DR5 and/or DR4, but reduced the mRNA and protein levels of cellular FLICE-inhibitory protein (c-FLIP). As compared with treatment with Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or LAQ824 alone, pretreatment with LAQ824 increased the assembly of Fas-associated death domain and caspase-8, but not of c-FLIP, into the Apo-2L/TRAIL-induced death-inducing signaling complex. This increased the processing of caspase-8 and Bcl-2 interacting domain (BID), augmented cytosolic accumulation of the prodeath molecules cytochrome-c, Smac and Omi, as well as led to increased activity of caspase-3 and apoptosis. Treatment with LAQ824 also down-regulated the levels of Bcl-2, Bcl-x(L), XIAP, and survivin. Partial inhibition of apoptosis due to LAQ824 or Apo-2L/TRAIL exerted by Bcl-2 overexpression was reversed by cotreatment with LAQ824 and Apo-2L/TRAIL. Significantly, cotreatment with LAQ824 increased Apo-2L/TRAIL-induced apoptosis of primary acute myelogenous leukemia blast samples isolated from 10 patients with acute myelogenous leukemia. Taken together, these findings indicate that LAQ824 may have promising activity in augmenting Apo-2L/TRAIL-induced death-inducing signaling complex and apoptosis of human acute leukemia cells.
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PMID:Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. 1505 15

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) super-family, induces apoptosis in various cancer cells with little or no effect on normal cells. 8-Chloro-adenosine (8-Cl-Ado) is a potential anti-cancer chemical agent now in clinical trail phase II, though its molecular mechanism remains poorly understood. In the present study, we report that 8-Cl-Ado can promote TRAIL killing activity in the hepatoma cell line BEL-7402 in dose- and time-dependent manner when jointly used in vitro. We showed that the expression of death receptor DR5, but not DR4 was up-regulated and the decoy receptor DcR1 was down-regulated in the cells treated with 8-Cl-Ado and the recombinant soluble TRAIL (rsTRAIL, 95-281 a.a.). Further experiments demonstrated that caspase-family inhibitor z-VAD-fmk prevented the cells from apoptosis induced by co-treatment with 8-Cl-Ado and rsTRAIL for 6 h, however, apoptosis occurred in the cells cultured for 24 h, suggesting that co-treatment induce a caspase-dependent and -independent signaling pathway in the BEL-7402 cells. This phenomenon was confirmed by cleavage analysis of caspase-3 and poly(ADP-ribose) polymerase (PARP), and ROS (reactive oxygen species) assay, respectively. Moreover, transcriptional activity test showed that NF-kappaB was inhibited in the BEL-7402 cells during co-treatment. Our results provided evidence for the first time that 8-Cl-Ado sensitizes the human hepatoma cells BEL-7402 to rsTRAIL-induced apoptosis by up-regulating DR5 expression, inactivating the NF-kappaB activity, and signaling by the caspase-dependent and -independent pathway.
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PMID:8-Chloro-adenosine sensitizes a human hepatoma cell line to TRAIL-induced apoptosis by caspase-dependent and -independent pathways. 1520 83

Bcr-Abl-expressing primary or cultured leukemia cells display high levels of the antiapoptotic heat shock protein (hsp) 70 and are resistant to cytarabine (Ara-C), etoposide, or Apo-2L/TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis. Conversely, a stable expression of the cDNA of hsp70 in the reverse orientation attenuated not only hsp70 but also signal transducers and activators of transcription 5 (STAT5) and Bcl-x(L) levels. This increased apoptosis induced by cytarabine, etoposide, or Apo-2L/TRAIL. Ectopic expression of hsp70 in HL-60 cells (HL-60/hsp70) inhibited Ara-C and etoposide-induced Bax conformation change and translocation to the mitochondria; attenuated the accumulation of cytochrome c, Smac, and Omi/HtrA2 in the cytosol; and inhibited the processing and activity of caspase-9 and caspase-3. Hsp70 was bound to death receptors 4 and 5 (DR4 and DR5) and inhibited Apo-2L/TRAIL-induced assembly and activity of the death-inducing signaling complex (DISC). HL-60/hsp70 cells exhibited increased levels and DNA binding activity of STAT5, which was associated with high levels of Pim-2 and Bcl-x(L) and resistance to apoptosis. Expression of the dominant negative (DN) STAT5 resensitized HL-60/hsp70 cells to cytarabine, etoposide, and Apo-2L/TRAIL-induced apoptosis. Collectively, these findings suggest that hsp70 inhibits apoptosis upstream and downstream of the mitochondria and is a promising therapeutic target for reversing drug-resistance in chronic myeloid leukemia-blast crisis and acute myeloid leukemia cells.
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PMID:Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. 1538 81

Ginsenoside Rh2 (Rh2), a purified ginseng saponin, has been shown to have antiproliferative effects in certain cancer cell types. However, the molecular mechanisms of Rh2 on cell growth and death have not been fully clarified. In this study, the antiproliferative effect of Rh2 in human lung adenocarcinoma A549 cells was investigated. Treatment of A549 cells with 30 mug/ml Rh2 resulted in G(1) phase arrest, followed by progression to apoptosis. This Rh2-mediated G(1) arrest was accompanied by downregulation of the protein levels and kinase activities of cyclin-D1, cyclin-E and Cdk6, and the upregulation of pRb2/p130. In addition, Rh2-induced apoptosis was confirmed by TUNEL assay and DNA fragmentation analysis. Administration of Rh2 caused an increase in the expression levels of TRAIL-RI (DR4) death receptor but did not alter the levels of other death receptors or Bcl-2 family molecules. Furthermore, the Rh2-induced apoptosis was significantly inhibited by DR4:Fc fusion protein, which inhibits TRAIL-DR4-mediated apoptosis. In addition, caspase-2, caspase-3 and caspase-8 were highly activated upon Rh2 treatment. Inhibitors of caspase-2, caspase-3 and caspase-8 markedly prevented the cell death induced by Rh2. Inhibitor of caspase-8 significantly inhibited the activation of caspase-2, caspase-3 and caspase-8. These observations indicate that multiple G(1)-related cell cycle regulatory proteins are regulated by Rh2 and contribute to Rh2-induced G(1) growth arrest. The increase in the expression level of DR4 death receptor may play a critical role in the initiation of Rh2-triggered apoptosis, and the activation of the caspase-8/caspase-3 cascade acts as the executioner of the Rh2-induced death process.
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PMID:Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells. 1573 95

The mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of alpha-boswellic acid acetate and beta-boswellic acid acetate, isolated from Boswellia carterri Birdw on myeloid leukemia cells was investigated in six human myeloid leukemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). Morphologic and DNA fragmentation assays indicated that the cytotoxic effect of boswellic acid acetate was mediated by induction of apoptosis. More than 50% of the cells underwent apoptosis after treatment with 20 mug/mL boswellic acid for 24 hours. This apoptotic process was p53 independent. The levels of apoptosis-related proteins Bcl-2, Bax, and Bcl-XL were not modulated by boswellic acid acetate. Boswellic acid acetate induced Bid cleavage and decreased mitochondrial membrane potential without production of hydrogen peroxide. A general caspase inhibitor (Z-VAD-FMK) and a specific caspase-8 inhibitor II (Z-IETD-FMK) blocked boswellic acid acetate-induced apoptosis. The mRNAs of death receptors 4 and 5 (DR4 and DR5) were induced in leukemia cells undergoing apoptosis after boswellic acid acetate treatment. These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential.
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PMID:Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells. 1576 47

Most tumor cells are sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis but sparing to normal cells, thus providing therapeutic potential for clinical use. Some tumor cells are resistant to TRAIL-induced cell death while the sensitivity could be recruited with the existence of some chemical agents. In this study, human prostatic cancer cell line LNCaP was found to be resistant to TRAIL-induced apoptosis while it could be restored to TRAIL sensitivity with combination treatment of low concentration of doxorubicin. TRAIL receptor-1 (DR4) and TRAIL receptor-2 (DR5) were upregulated under the treatment of doxorubicin and verified to be responsible for TRAIL-mediated signal transduction. Furthermore, caspase-8 and caspase-3 were activated and drove their autocleavage into programmed cell death. Interestingly, apoptosis-inhibitory protein c-FLIP, but not Bcl-2 and XIAP was downregulated after doxorubicin treatment. Taken together, these findings suggested that the pathway of cell apoptosis induced by TRAIL was intact but under negative control. Subtoxic concentration of doxorubicin effectively boosted TRAIL sensitivity via depletion of antiapoptotic protein. These findings support the new strategies for killing tumors with TRAIL and chemical agents.
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PMID:Subtoxic concentration of doxorubicin enhances TRAIL-induced apoptosis in human prostate cancer cell line LNCaP. 1589 17

The objective of this study was to investigate the antiproliferative effect and the mechanism of the methanol extracts of mycelia (MEM) form Antrodia camphorata in submerged culture toward HepG2 cells. The results showed that MEM-induced cell apoptosis involved up-regulation of Fas and down-regulation of Bcl-2, DR3, DR4, TNFRI, and TNFRII in HepG2 cells, while no changes on the levels of Bax, Bid, Bad, and Bak protein were observed. On the basis of these results, the involvement of the Fas/Fas ligand (FasL) death-receptor pathway, in MEM-induced apoptosis in HepG2 cells, was investigated. The apoptosis inducing activity was significantly enhanced by a Fas activator and inhibited by a Fas antagonist. To know about the effect of MEM on the activation of the apoptotic pathway, the adenovirus transfected with Bcl-2 was infected on HepG2 cells. The data showed that the percentage of apoptotic cells induced by MEM in Bcl-2-infected HepG2 (Bcl-2 overexpression) was not significantly different from that of uninfected HepG2. These results demonstrate that MEM induces HepG2 apoptosis through inhibition of cell growth and up-regulation of Fas/FasL to activate the pathway of caspase-3 and -8 cascades.
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PMID:Mycelia from Antrodia camphorata in Submerged culture induce apoptosis of human hepatoma HepG2 cells possibly through regulation of Fas pathway. 1599 14


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