Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is an active component from the root and rhizome of Rheum palmatum that has been reported to exhibit antitumour effects, but the mechanism is not known. The study investigated the effects and mechanisms of emodin-induced cell death in human lung squamous carcinoma cell line CH27. 2. Emodin (50 microM)-induced CH27 cell apoptosis was confirmed by cell morphological change, sub-G1 formation in flow cytometry analysis, viability assay and degradation of focal adhesion kinase in this study. 3. Emodin-induced apoptosis of CH27 cells does not involve modulation of endogenous Bcl-X(L) protein expression, but appears to be associated with the increased expression of cellular Bak and Bax proteins. This study also demonstrated the translocation of Bak and Bax from cytosolic to particulate fractions. 4. This study has shown that emodin-treated CH27 cells revealed the increases in the relative abundance of cytochrome c for the indicated time intervals in cytosolic fraction. 5. This study demonstrates that the activation of caspase-3, caspase-9 and caspase-8 is an important determinant of apoptotic death induced by emodin. 6. These results suggested that emodin induces CH27 cell death by Bax death pathway and Fas pathway.
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PMID:Effects and mechanisms of emodin on cell death in human lung squamous cell carcinoma. 1152 92

Cepharanthine (CEP) is a known membrane stabilizer that has been widely used in Japan for the treatment of several disorders such as anticancer therapy-provoked leukopenia. We here report that apoptosis was induced by low concentrations (1-5 microM) of CEP in a human leukemia T cell line, Jurkat, and by slightly higher concentrations (5-10 microM) in a human chronic myelogenous leukemia (CML) cell line K562, which expresses a p210 antiapoptotic Bcr-Abl fusion protein. Induction of apoptosis was confirmed in both Jurkat and K562 cells by DNA fragmentation and typical apoptotic nuclear change, which were preceded by disruption of mitochondrial membrane potential and were induced through a Fas-independent pathway. CEP treatment induced activation of caspase-9 and -3 accompanied by cleavage of PARP, Bid, lamin B1, and DFF45/ICAD in both Jurkat and K562 cells, whereas caspase-8 activation and Akt cleavage were observed only in Jurkat cells. The CEP-induced apoptosis was completely blocked by zVAD-fmk, a broad caspase inhibitor. Interestingly, CEP treatment induced remarkable degradation of the Bcr-Abl protein in K562 cells, and this degradation was prevented partially by zVAD-fmk. When used in combination with a nontoxic concentration of herbimycin A, lower concentrations (2-5 microM) of CEP induced obvious apoptosis in K562 cells with rapid degradation or decrease in the amount of Bcr-Abl and Akt proteins. Our results suggest that CEP, which does not have bone marrow toxicity, may possess therapeutic potential against human leukemias, including CML, which is resistant to anticancer drugs and radiotherapy.
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PMID:Cepharanthine activates caspases and induces apoptosis in Jurkat and K562 human leukemia cell lines. 1152 46

Macrophage death in advanced atherosclerotic lesions leads to lesional necrosis and possibly plaque rupture and acute vascular occlusion. Among the likely causes of lesional macrophage death is intracellular accumulation of excess free cholesterol (FC), which is known to occur in vivo. We recently showed that FC loading of macrophages causes apoptosis, approximately 50% of which is mediated by activation of cell-surface FasL and triggering of the Fas pathway (Yao, P. M., and Tabas, I. (2000) J. Biol. Chem. 275, 23807-23813). To elucidate other pathways of death in FC-loaded macrophages, we investigated mitochondrial transmembrane potential (DeltaPsi(m)) and the mitochondrial apoptosis pathway in FC-loaded mouse peritoneal macrophages. Starting between 3 and 6 h of FC loading, DeltaPsi(m) was markedly decreased in the majority of macrophages and was independent of the Fas pathway. The decrease in DeltaPsi(m) by FC loading was not prevented by GSH, thus distinguishing it from 7-ketocholesterol-induced mitochondrial dysfunction. Cytochrome c release into the cytosol was noted by 4 h of FC loading, and activation of caspase-9 and effector caspases was observed at 6 h. Finally, we found that both cellular and mitochondrial levels of the pro-apoptotic protein Bax were increased severalfold as early as 4 h after FC loading. Thus, FC loading, perhaps via increased levels of Bax and/or cholesterol overloading of mitochondria, triggers cytochrome c release and activation of caspase-9 and the effector caspases, leading to macrophage apoptosis. These findings and our previous data support a model in which FC loading of macrophages promotes a dual program of caspase-mediated death.
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PMID:Free cholesterol loading of macrophages is associated with widespread mitochondrial dysfunction and activation of the mitochondrial apoptosis pathway. 1153 46

Caspase-3 is a cysteine protease located in both the cytoplasm and mitochondrial intermembrane space that is a central effector of many apoptotic pathways. In resting cells, a subset of caspase-3 zymogens is S-nitrosylated at the active site cysteine, inhibiting enzyme activity. During Fas-induced apoptosis, caspases are denitrosylated, allowing the catalytic site to function. In the current studies, we sought to identify the subpopulation of caspases that is regulated by S-nitrosylation. We report that the majority of mitochondrial, but not cytoplasmic, caspase-3 zymogens contain this inhibitory modification. In addition, the majority of mitochondrial caspase-9 is S-nitrosylated. These studies suggest that S-nitrosylation plays an important role in regulating mitochondrial caspase function and that the S-nitrosylation state of a given protein depends on its subcellular localization.
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PMID:S-Nitrosylation of mitochondrial caspases. 1155 79

Anticancer treatment using cytotoxic drugs is considered to mediate cell death by activating key elements of the apoptosis program and the cellular stress response. While proteolytic enzymes (caspases) serve as main effectors of apoptosis, the mechanisms involved in activation of the caspase system are less clear. Two distinct pathways upstream of the caspase cascade have been identified. Death receptors, eg, CD95 (APO-1/Fas), trigger caspase-8, and mitochondria release apoptogenic factors (cytochrome c, Apaf-1, AIF), leading to the activation of caspase-9. The stressed endoplasmic reticulum (ER) contributes to apoptosis by the unfolded protein response pathway, which induces ER chaperones, and by the ER overload response pathway, which produces cytokines via nuclear factor-kappaB. Multiple other stress-inducible molecules, such as p53, JNK, AP-1, NF-kappaB, PKC/MAPK/ERK, and members of the sphingomyelin pathway have a profound influence on apoptosis. Understanding the complex interaction between different cellular programs provides insights into sensitivity or resistance of tumor cells and identifies molecular targets for rational therapeutic intervention strategies.
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PMID:Cellular stress response and apoptosis in cancer therapy. 1167 28

We previously reported that apicidin arrested human cancer cell growth through selective induction of p21(WAF1/Cip1). In this study, the apoptotic potential of apicidin and its mechanism in HL60 cells was investigated. Treatment of HL60 cells with apicidin caused a decrease in viable cell number in a dose-dependent manner and an increase in DNA fragmentation, nuclear morphological change, and apoptotic body formation, concomitant with progressive accumulation of hyperacetylated histone H4. In addition, apicidin converted the procaspase-3 form to catalytically active effector protease, resulting in subsequent cleavages of poly(ADP-ribose) polymerase and p21(WAF1/Cip1). Incubation of HL60 cells with z-DEVD-fmk, a caspase-3 inhibitor, almost completely abrogated apicidin-induced activation of caspase-3, DNA fragmentation, and cleavages of poly(ADP-ribose) polymerase and p21(WAF1/Cip1). Moreover, these effects were preceded by an increase in translocation of Bax into the mitochondria, resulting in the release of cytochrome c and cleavage of procaspase-9. The addition of cycloheximide greatly inhibited activation of caspase-3 by apicidin by interfering with cleavage of procaspase-3 and DNA fragmentation, suggesting that apicidin-induced apoptosis was dependent on de novo protein synthesis. Consistent with these results, apicidin transiently increased the expressions of both Fas and Fas ligand. Preincubation with NOK-1 monoclonal antibody, which prevents the Fas-Fas ligand interaction and is inhibitory to Fas signaling, interfered with apicidin-induced translocation of Bax, cytochrome c release, cleavage of procaspase-3, and DNA fragmentation. Taken together, the results suggest that apicidin might induce apoptosis through selective induction of Fas/Fas ligand, resulting in the release of cytochrome c from the mitochondria to the cytosol and subsequent activation of caspase-9 and caspase-3.
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PMID:Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells. 1169 95

In this study, we investigated the molecular pathways targeted by curcumin during apoptosis of human melanoma cell lines. We found that curcumin caused cell death in eight melanoma cell lines, four with wild-type and four with mutant p53. We demonstrate that curcumin-induced apoptosis is both dose- and time-dependent. We found that curcumin did not induce p53, suggesting that curcumin activates other apoptosis pathways. Our data show that curcumin activates caspases-3 and -8 but not caspase-9, supporting the rationale that apoptosis occurs via a membrane-mediated mechanism. Both a caspase-8 and broad-based caspase inhibitor, but not a caspase-9 specific inhibitor, suppressed curcumin-induced cell death. To further support our hypothesis that curcumin induces activation of a death receptor pathway, we show that curcumin induces Fas receptor aggregation in a FasL-independent manner and that low-temperature incubation, previously shown to inhibit receptor aggregation, prevented curcumin-induced cell death. Moreover, we demonstrate that expression of dominant negative FADD significantly inhibited curcumin-induced cell death. In addition, our results indicate that curcumin also blocks the NF-kappaB cell survival pathway and suppresses the apoptotic inhibitor, XIAP. Since melanoma cells with mutant p53 are strongly resistant to conventional chemotherapy, curcumin may overcome the chemoresistance of these cells and provide potential new avenues for treatment.
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PMID:Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. 1171 43

Aloe-emodin (1,8-dihydroxy-3-(hydroxymethyl)-anthraquinone) is an active component from the root and rhizome of Rheum palmatum. The study investigated the effects and mechanisms of aloe-emodin-induced cell death in human lung squamous cell carcinoma cell line CH27. Aloe-emodin (40 microM)-induced CH27 cell apoptosis was confirmed by DNA fragmentation (DNA ladders and sub-G(1) formation). Aloe-emodin-induced apoptosis of CH27 cells involved modulation of the expression of Bcl-2 family proteins, such as BclX(L), Bag-1, and Bak, and was associated with the translocation of Bak and Bax from cytosolic to particulate fractions. Aloe-emodin-treated CH27 cells had an increased relative abundance of cytochrome c in the cytosolic fraction. Results demonstrated that the activation of caspase-3, caspase-8, and caspase-9 is an important determinant of apoptotic death induced by aloe-emodin. These results suggest that aloe-emodin induces CH27 cell death by the Bax and Fas death pathway.
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PMID:Effects and mechanisms of aloe-emodin on cell death in human lung squamous cell carcinoma. 1173 Jul 20

We observed that N-(4-hydroxyphenyl)retinamide (4HPR), a chemopreventive and chemotherapeutic agent, effectively induced apoptosis in hepatoma cells. Interestingly, Fas-negative (Hep 3B and PLC/PRF/5) hepatoma cells were shown to be more susceptible to apoptosis induced by 4HPR than were Fas-positive (Hep G2 and SK-HEP-1) hepatoma cells. Thus, we explored the mechanisms underlying 4HPR-induced apoptosis in Fas-defective hepatoma cells. Hep 3B cells stably expressing the dominant-negative Fas-associated death domain (dnFADD) showed no alteration in 4HPR drug susceptibility, but when stably expressing E1B19K, Crm A, or dominant-negative FLICE (dnFLICE), Hep 3B cells were resistant, suggesting that 4HPR-induced apoptosis was mediated by caspase-8 activation. Furthermore, apoptosis could be completely blocked by Z-VAD-FMK (a general caspase inhibitor) or by IETD-CHO (a caspase-8 inhibitor), but was only partially blocked by Ac-DEVD-CMK (a caspase-3 inhibitor), by N-acetyl-L-cysteine (NAC) (an antioxidant), by N-acetyl-leucyl-leucyl-norleucinal (ALLN) (a calpain inhibitor I), or by Z-LEHD-FMK (a caspase-9 inhibitor). Time-sequence analysis of the induction of apoptosis by 4HPR revealed that an initial caspase-8 activation was followed by late mitochondrial cytochrome c release and minor caspase-9 activation, which suggested that caspase-8 activation is the primary upstream regulatory point. Activation of Bid or induction of proapoptotic Bax was not observed during apoptosis. In contrast, Bcl-xL expression was decreased during 4HPR-induced apoptosis. Taken together, these results indicate that 4HPR may be a potential chemotherapeutic drug, which is able to induce apoptosis in Fas-defective hepatoma cells through caspase-8 activation.
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PMID:Activation of caspase-8 during N-(4-hydroxyphenyl)retinamide-induced apoptosis in Fas-defective hepatoma cells. 1173 1

Magnolol has been reported to have anticancer activity. In this study we found that treatment with 100 microm magnolol induced apoptosis in cultured human hepatoma (Hep G2) and colon cancer (COLO 205) cell lines but not in human untransformed gingival fibroblasts and human umbilical vein endothelial cells. Our investigation of apoptosis in Hep G2 cells showed a sequence of associated intracellular events that included (a) increased cytosolic free Ca(2+); (b) increased translocation of cytochrome c (Cyto c) from mitochondria to cytosol; (c) activation of caspase 3, caspase 8, and caspase 9; and (d) downregulation of bcl-2 protein. Pretreatment of the cells with the phospholipase C inhibitor 1-[6-[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1 H-pyrrole-2,5-dione (U73122) or the intracellular chelator of Ca(2+) 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA/AM) inhibited the subsequent magnolol augmentation of [Ca(2+)](i) and also the activation of caspase-8 and caspase-9, so that the occurrence of apoptosis in those cells was greatly reduced. Pretreatment of the cells with ZB4 (which disrupts the Fas response mechanism) also decreased the subsequent magnolol-induced caspase-8 activation and reduced the occurrence of apoptosis. We interpreted these findings to indicate that the above-listed sequence of intracellular events led to the apoptosis seen in Hep G2 cells and that [Ca(2+)](i), Cyto c, and Fas function as intracellular signals to coordinate those events.
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PMID:Molecular mechanisms of apoptosis induced by magnolol in colon and liver cancer cells. 1174 19


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