Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Staurosporine (STP) was shown to induce cell apoptosis through formation of reactive oxygen species, but a role for cellular redox has not been defined. In this study, we report that STP (2 microM) caused apoptosis (24+/-3% at 24 h) of human colon adenocarcinoma epithelial cell line HT29 that was preceded by significant glutathione (GSH) and glutathione disulfide (GSSG) efflux (6 h), but independent of changes in cellular glutathione/glutathione disulfide (GSH/GSSG) redox status. The blockade of GSH efflux by gamma-glutamyl glutamate (gamma-GG) or ophthalmic acid was associated with apoptosis attenuation; however, gamma-GG administration after peak GSH efflux (8 h) did not confer cytoprotection. Moreover, lowering cellular GSH through inhibition of its synthesis prevented extracellular GSH accumulation and cell apoptosis, thus validating a link between cellular GSH export and the trigger of cell apoptosis. Inhibition of gamma-glutamyl transferase (GGT1, EC 2.3.2.2)-catalyzed extracellular GSH degradation with acivicin significantly blocked GSH efflux, suggesting that GSH breakdown is a driving force for GSH export. Interestingly, acivicin treatment enhanced extracellular GSSG accumulation, consistent with GSH oxidation. STP-induced HT29 cell apoptosis was associated with caspase-3 activation independent of caspase-8 or caspase-9 activity; accordingly, inhibitors of the latter caspases were without effect on STP-induced apoptosis. STP similarly induced GSH efflux and apoptosis in a non-malignant human NCM460 colonic cell line in association with caspase-3 activation. Collectively, our results demonstrate that STP induction of apoptosis in malignant and non-malignant colonic cells is temporally linked to the export of cellular GSH and the activation of caspase-3 without caspase-8 or -9 involvement.
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PMID:The role of GSH efflux in staurosporine-induced apoptosis in colonic epithelial cells. 1884 Apr 13

Caspase-3 is responsible for the cleavage of several proteins including the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Designed on the cleavage site of PARP, Ac-Asp-Glu-Val-Asp-H has been reported as a highly specific inhibitor. To overcome the susceptibility to proteolysis, the intrinsic instability, and the scarce membrane permeability of tetra-peptidyl aldehydes, di- and tri-peptidyl caspase-3 inhibitors have been synthesized. Here, the synthesis and the inhibition properties of peptidyl aldehydes Z-tLeu-Asp-H, Z-tLeu-Val-Asp-H, and Z-Val-tLeu-Asp-H are reported. Z-tLeu-Asp-H, Z-tLeu-Val-Asp-H, and Z-Val-tLeu-Asp-H inhibit competitively human caspase-3 activity in vitro with K(i)(0)=3.6nM, 18.2nM, and 109nM, respectively (pH 7.4 and 25 degrees C). Moreover, Z-tLeu-Asp-H impairs apoptosis in human DLD-1 colon adenocarcinoma cells without affecting caspase-8. Therefore, Ac-Asp-Glu-Val-Asp-H can be truncated to Z-tLeu-Asp-H retaining nanomolar inhibitory activity in vitro and displaying action in whole cells, these properties reflect the unprecedented introduction of the bulky and lipophilic tLeu residue at the P(2) position.
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PMID:Human caspase-3 inhibition by Z-tLeu-Asp-H: tLeu(P2) counterbalances Asp(P4) and Glu(P3) specific inhibitor truncation. 1885 75

Pyrogallol (PG) is a polyphenol compound and is known to be an O2.- generator. In the present study, we evaluated the anti-apoptotic effects of caspase inhibitors in relation to changes in reactive oxygen species (ROS) and glutathione (GSH) levels in PG-treated human pulmonary adenocarcinoma Calu-6 cells. Treatment with 50 microM PG inhibited the growth of Calu-6 cells approximately 60% and induced apoptosis approximately 17% at 24 h, accompanied by mitochondrial membrane potential loss (DeltaPsim). Treatment with pan-caspase inhibitor (Z-VAD-FMK), caspase-3 inhibitor (Z-DEVD-FMK), caspase-8 inhibitor (Z-IETD-FMK) and caspase-9 inhibitor (Z-LEHD-FMK) significantly prevented apoptosis in PG-treated Calu-6 cells at 24 h. PG increased the ROS and depleted GSH contents in Calu-6 cells. Treatment with each caspase inhibitor did not significantly change the ROS and GSH levels in PG-treated Calu-6 cells at 24 h. However, Z-VAD significantly prevented GSH depletion in PG-treated Calu-6 cells at the late time phase of 72 h. Conclusively, the anti-apoptotic effect of caspase inhibitor on PG-induced Calu-6 cell death was closely related to changes in GSH content rather than ROS levels.
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PMID:Caspase inhibitor decreases apoptosis in pyrogallol-treated lung cancer Calu-6 cells via the prevention of GSH depletion. 1894 74

Pyrogallol (PG) is a polyphenol compound and a known O2- generator. We evaluated the effects of PG on the growth and apoptosis of human pulmonary adenocarcinoma Calu-6 cells. PG decreased the viability of Calu-6 cells in a dose- and time-dependent manner. The induction of apoptosis by PG was accompanied by the loss of mitochondrial membrane potential (DeltaPsi(m)), cytochrome c release from mitochondria and activation of caspase-3 and caspase-8. All tested caspase inhibitors, especially the pan-caspase inhibitor (Z-VAD), markedly rescued Calu-6 cells from PG-induced cell death. Rescue was accompanied by inhibition of caspase-3 activation and PARP cleavage. Treatment with Z-VAD also prevented the loss of mitochondrial membrane potential (DeltaPsi(m)). In conclusion, PG inhibits the growth of Calu-6 cells via caspase-dependent apoptosis.
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PMID:Pyrogallol inhibits the growth of lung cancer Calu-6 cells via caspase-dependent apoptosis. 1900 Jun 62

In the present study, we investigated the effects of 3-oxoolean-12-en-27-oic acid (3-OA) isolated from the underground parts of Aceriphyllum rossii (Saxifragaceae) on the viability and apoptosis of HL-60 human promyelocytic leukemia cells, and the mechanisms underlying its action. 3-OA-treated HL-60 cells and HeLa human cervix adenocarcinoma cells displayed several apoptotic features, such as, DNA fragmentation, DNA laddering by agarose gel electrophoresis, and hypodiploid DNA contents by flow cytometry, and 3-OA also caused the activations of caspase-8, -9 and -3. Pretreatment with z-VAD-fmk (a broad-caspase inhibitor) almost completely suppressed 3-OA-induced DNA ladder formation and hypodiploid DNA contents, thereby implicating the caspase cascade in the apoptotic process. In addition, z-IETD-fmk (a caspase-8 inhibitor) and z-DEVD-fmk (a caspase-3 inhibitor) also completely neutralized the apoptotic effect of 3-OA in HL-60 cells. Furthermore, 3-OA increased Fas-related protein contents and the mRNA expressions of Fas ligand (FasL), Fas, and Fas-associated death domain (FADD). Preincubation with anti-Fas or anti-FasL blocking antibodies completely prevented 3-OA-induced apoptosis. Taken together, these results suggest that 3-oxoolean-12-en-27-oic acid induces apoptosis by activating caspase-8 via FasL-stimulated death receptor signaling.
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PMID:3-Oxoolean-12-en-27-oic acid isolated from Aceriphyllum rossii induces caspase-8-dependent apoptosis in human promyelocytic leukemia HL-60 cells. 1912 87

We explored the in vitro and in vivo mechanism of antitumor action of the synthetic flavonoid 2'-nitroflavone on LM3 murine mammary adenocarcinoma cells. In vitro assays showed that 2'-nitroflavone increased the population of LM3 hypodiploid cells and produced a typical ladder of DNA fragmentation. Apoptotic cell death was also characterized by the activation of caspase-8, -9 and -3, by an increment in the expression levels of the proapoptotic protein Bax and by the release of cytochrome c to cytosol. The in vivo effect of 2'-nitroflavone on tumor growth was studied in BALB/c mice injected subcutaneously with LM3 cells. Results showed that tumor volume and weight were significantly reduced at doses of 10 and 40 mg/kg of 2'-nitroflavone, respectively. Apoptotic cells were identified by TUNEL assay in tumor slices from mice treated with 10 mg/kg of 2'-nitroflavone. Western blot analysis of tumor lysate supernatants from treated mice revealed an upregulation of the total levels of Bax and Fas receptor. In addition, administration of 40 mg/kg of 2'-nitroflavone to nontumor-bearing mice showed no histopathological effects on different organ tissues. This is the first report of the in vivo growth inhibitory effect of 2'-nitroflavone as an apoptotic agent likely useful for mammary adenocarcinoma treatment.
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PMID:In vitro induction of apoptosis and in vivo effects of a flavone nitroderivative in murine mammary adenocarcinoma cells. 1935 71

MMPT, a thiazolidin compound, was identified in our laboratory as a novel antineoplastic agent with a broad spectrum of antitumor activity against many human cancer cells. However, the related mechanism has yet not been revealed. In this study, we investigated the cellular and molecular events underlying the antitumor function of this compound in human lung adenocarcinoma H1792 cells, focusing on the early cytotoxic effect. Treatment of H1792 cancer cells with MMPT (0.1-100 microM for 24-72 h) resulted in a growth inhibition in a dose and time-dependent manner, determined by MTT assay. This effect was accompanied by apoptosis, evidenced by Nucleosome ELISA, H33258 stained assay, and Sub-G1 analysis. Our data showed that MMPT caused activation of caspase-3, caspase-6 and caspase-8, but not caspase-9. The finding that MMPT induced apoptosis through a membrane-mediated mechanism was supported by the up-regulated expression of Fas (CD95/APO-1), and Fas ligand. Overall, our results demonstrated that MMPT induced growth inhibition of H1792 cells through a Fas-mediated and caspase-dependent apoptosis pathway, which suggested that MMPT might be used as a Fas/FasL and caspases promoter to initiate lung cancer cell apoptosis.
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PMID:MMPT: a thiazolidin compound inhibits the growth of lung cancer H1792 cells via Fas-mediated and caspase-dependent apoptosis pathway. 1941 23

High intake of whole grain food has been suggested as an important factor for reducing the risk of colon cancer, owing to the abundance of indigestible fibers. Our findings demonstrated that, among various rice bran phenolic compounds tested, cycloartenyl ferulate (CF) showed the most prominent in vitro growth inhibition on human colorectal adenocarcinoma SW480, but had low toxicity on normal colon CCD-18-Co cells. The anticancer activity of CF was further illustrated by its ability to induce significant regression of SW480 xenograft in nude mice. CF elevated the death receptors DR4 and DR5 and triggered both the death receptor and the mitochondrial apoptosis pathways. Depletion of anti-apoptotic Bcl-2 and up-regulation of pro-apoptotic Bak were observed, accompanied by dissipation of the mitochondrial membrane potential and release of cyto c and SMAC/DIABLO from mitochondria into the cytosol. Bid was found to be cleaved by caspase-8, so that the death receptor pathway might be exaggerated by the mitochondrial pathway. Strikingly, we showed for the first time that CF also sensitized the metastatic and resistant colon cancer SW620 to TRAIL-induced apoptosis and the mechanisms involved at least enhanced activation of caspase-8 and -3. This study provides a clear evidence that the health-beneficial properties of whole grain consumption are not only limited by the presence of dietary fibers but also other molecules that can either act as a chemopreventive agent to directly induce tumor regression or as a sensitizer to enhance TRAIL-induced apoptosis in metastatic cancer cells.
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PMID:A rice bran polyphenol, cycloartenyl ferulate, elicits apoptosis in human colorectal adenocarcinoma SW480 and sensitizes metastatic SW620 cells to TRAIL-induced apoptosis. 1942 86

Propyl gallate (PG) as a synthetic antioxidant is widely used in processed food, cosmetics and medicinal preparations. Despite the assumed low toxicity of PG, it exerts a variety of effects on tissue and cell functions. In the present study, we evaluated the anti-apoptotic effects of caspase inhibitors on PG-treated human cervix adenocarcinoma HeLa cells in relation to the changes of reactive oxygen species (ROS) and glutathione (GSH) levels. PG induced apoptosis in a dose-dependent manner, as evidenced by sub-G1 cells and annexin V staining cells. Treatment with pan-caspase inhibitor, caspase-3 inhibitor, caspase-8 inhibitor or caspase-9 inhibitor significantly prevented apoptosis in PG-treated HeLa cells at 24 h. The intracellular ROS levels including O (2) (*-) were increased or decreased in PG-treated HeLa cells depending on the incubation times (1 or 24 h). PG depleted intracellular GSH content in HeLa cells at 24 h. Treatment with caspase inhibitor reduced ROS levels and significantly prevented GSH depletion in PG-treated HeLa cells at 24 h. In conclusion, PG induced apoptosis in HeLa cells. The anti-apoptotic effect of caspase inhibitor on PG-induced HeLa cell death was closely related to the reduction of ROS levels, especially mitochondrial O (2) (*-) , as well as to the inhibition of GSH depletion.
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PMID:The anti-apoptotic effects of caspase inhibitors on propyl gallate-treated HeLa cells in relation to reactive oxygen species and glutathione levels. 1943 96

We investigated the response of human cervix adenocarcinoma HeLa cells to Corosolic acid (CRA) treatment. Our results showed that CRA significantly inhibited cell viability in both a dose- and a time-dependent manner. CRA treatment induced S cell-cycle arrest and caused apoptotic death in HeLa cells. We found that CRA increased in Bax/Bcl-2 ratios by up-regulating Bax expression, disrupted mitochondrial membrane potential and triggered the release of cytochrome c from mitochondria into the cytoplasm. Moreover, CRA treatment triggered the activation of caspase-8, -9 and -3 in HeLa cells. All these results indicate that CRA-induced apoptosis is associated with the activation of caspases via a mitochondrial pathway. Taken together, we believe that CRA could have strong potentials for clinical application in treating human cervix adenocarcinoma and improving cancer chemotherapy.
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PMID:Corosolic acid induces apoptosis through mitochondrial pathway and caspase activation in human cervix adenocarcinoma HeLa cells. 1945 6


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