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)

Flunarizine is a Ca(2+) channel blocker that can be either cytoprotective or cytotoxic, depending on the cell type that is being examined. We show here that flunarizine was cytotoxic for Jurkat T-leukemia cells, as well as for other hematological maligancies, but not for breast or colon carcinoma cells. Treatment of Jurkat cells with flunarizine resulted in caspase-3 activation, poly (ADP-ribose) polymerase cleavage, and laddering of DNA fragments, all of which are hallmarks of apoptosis. Flunarizine-induced DNA fragmentation was inhibited by the caspase-3 inhibitor z-DEVD-fmk, the caspase-8/caspase-10 inhibitor z-IETD-fmk, and the caspase-10 inhibitor z-AEVD-fmk, but was not reduced in caspase-8-deficient Jurkat cells, indicating the involvement of caspase-10 upstream of caspase-3 activation. Interestingly, FADD recruitment to a death receptor was not involved since flunarizine caused DNA fragmentation in FADD-deficient Jurkat cells. Flunarizine treatment of Jurkat cells also resulted in reactive oxygen species production, dissipation of mitochondrial transmembrane potential, release of cytochrome c from mitochondria, and caspase-9 activation, although none of these events were necessary for apoptosis induction. Collectively, these findings indicate that flunarizine triggers apoptosis in Jurkat cells via FADD-independent activation of caspase-10. Flunarizine warrants further investigation as a potential anti-cancer agent for the treatment of hematological malignancies.
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PMID:The Ca(2+) channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells. 2009

Sonodynamic therapy (SDT) has been shown to mediate apoptosis in many experimental systems, but the detailed mechanism of this process is unclear. In this study, we aim to investigate the potential participation of the mitochondria-caspase signaling pathway in the SDT-induced apoptosis in isolated sarcoma 180 (S180) cells. The cell suspension was treated with 1.75MHz continuous ultrasound (US) at an acoustic intensity (I(SATA)) of 1.4W for 3min in the absence or presence of 20mug/ml hematoporphyrin (Hp). At different times after the SDT-treatment, the apoptotic cells were identified under a scanning electron microscope, and the apoptosis index (AI) was determined by flow cytometry. In addition, the mitochondrial membrane potential, permeabilization of the inner mitochondrial membrane, and translocation of apoptosis-related proteins were assessed by confocal microscopy. Simultaneously, the activation of some special apoptosis-associated proteins [caspase-9, caspase-3, polypeptide poly (ADP-ribose) polymerase (PARP), and Bax] was evaluated by western blotting. Our results indicate that the ultrasonically activated Hp can cause obvious cell apoptosis (AI, 57.66%) at 3h after treatment, and this effect can be significantly reduced by caspase-9 inhibitor (AI, 20.76%) and the oxygen scavenger NaN(3) (20.11%). However, the apoptosis induced by ultrasound alone was relatively lower (28.33%) and was not reduced by NaN(3). Further, SDT caused an 82.1% reduction in the mitochondrial membrane potential and a 70.7% reduction in the permeabilization of the inner mitochondrial membrane immediately after treatment, and these two effects were obviously prevented by NaN(3). In comparison with the control cells, the SDT-treated cells showed obvious cytochrome-c and Bax translocations, caspase activation, Bax expression, and PARP cleavage at 1h after SDT-treatment. However, in the cells treated with ultrasound alone, these phenomena partially and weakly occurred 3h after exposure. These results primarily showed that the mitochondria-caspase signaling pathway in S180 cells was activated in the US- and SDT-induced apoptosis. Moreover, Hp significantly accelerates the process of apoptosis and enhances the cytotoxic effect of ultrasonic treatment. Singlet oxygen may be responsible for the mitochondrial damage and the activation of the apoptotic signaling pathway.
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PMID:In vitro activation of mitochondria-caspase signaling pathway in sonodynamic therapy-induced apoptosis in sarcoma 180 cells. 2011 82

Rapid increases in incidence and mortality of human malignant melanoma are observed worldwide; thus, the development of new effective chemicals to control melanoma is urgent. In this study, the cytotoxic effect of oxymatrine, a natural quinolizidine alkaloid, against three human melanoma cell lines (A375, Sk-Mel-28, MM96L) and the underlying mechanisms were investigated. Oxymatrine killed all three human melanoma cell lines in a dose-dependent manner. The compound also dose-dependently caused apoptosis in human melanoma A375 cells. In addition, oxymatrine induced a remarkable change in mitochondrial membrane potential and triggered the release of cytochrome c from mitochondria to cytosol. Furthermore, this small compound resulted in a marked activation of capase-3, caspase-9, and poly (ADP-ribose) polymerase, while caspase-3 inhibitor Z-DEVD-FMK significantly reversed the proapoptotic effect of oxymatrine in A375 cells. Moreover, oxymatrine also dose-dependently increased the generation of reactive oxygen species in A375 cells, and N-acetylcysteine, a reactive oxygen species production inhibitor, almost completely blocked oxymatrine-induced apoptosis. In conclusion, our findings suggest that oxymatrine triggers oxidative stress, resulting in the collapse of the mitochondrial transmembrane potential, which in turn leads to cytochrome c release and apoptosis through the intrinsic caspase-9/caspase-3 pathway in human melanoma A375 cells.
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PMID:The role of endogenous reactive oxygen species in oxymatrine-induced caspase-3-dependent apoptosis in human melanoma A375 cells. 2012 87

Glycyrrhiza uralensis (licorice) is one of the most frequently prescribed ingredients in Oriental medicine, and licorice extract has been shown to exert anti-carcinogenic effects. However, its use as a cancer chemopreventive agent is rather limited, due to the fact that its principal component, glycyrrhizin, is known to induce hypertension. This study determined the effects of a hexane/ethanol extract of G. uralensis (HEGU), which contains undetectable amounts of glycyrrhizin, on the apoptosis of androgen-insensitive DU145 cells. HEGU induced apoptosis and increased the levels of cleaved caspase-9, caspase-7, caspase-3 and poly (ADP-ribose) polymerase (PARP). HEGU also induced mitochondrial membrane depolarization and cytochrome c release to the cytosol. HEGU increased the levels of Fas, death receptor 4 (DR4), cleaved caspase-8, Mcl-1S, and truncated Bid proteins. A caspase-8 inhibitor suppressed HEGU-induced apoptosis. An active fraction of HEGU was separated via column chromatography and the structure of the active compound isoangustone A was identified via 1H-NMR and 13C-NMR. Isoangustone A increased apoptotic cells, the cleavage of PARP and caspases, and the levels of DR4 and Mcl-1S. Transfection with DR4 small interfering RNA attenuated HEGU- and isoangustone A-induced apoptosis. These results demonstrate that the activation of DR4 contributes to HEGU- and isoangustone A-induced apoptosis of DU145 cells.
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PMID:Isoangustone A present in hexane/ethanol extract of Glycyrrhiza uralensis induces apoptosis in DU145 human prostate cancer cells via the activation of DR4 and intrinsic apoptosis pathway. 2022 24

Formaldehyde (FA) is an important substance that induces sick house syndrome and diseases, such as asthma and allergies. Oxidative stress is involved in the development of respiratory disease, and diverse antioxidants may protect respiratory tract cells from apoptosis. Peroxiredoxin is a pivotal endogenous antioxidant. In the present study, FA induced death in A549 cells, a lung epithelial cell line, in a dose-dependent manner. FA also increased lipid peroxide formation (LPO) in A549 cells, suggesting a role for oxidative stress. Additionally, FA decreased peroxiredoxin 2 (Prx 2) protein levels after a 24 or 48h exposure to FA. We also examined whether the FA-induced decrease in Prx 2 was associated with apoptosis. Prx 2 overexpression protected against FA-induced cell apoptosis but not necrosis. Prx 2 overexpression blocked FA-induced increase in Bax, a pro-apoptotic molecule, and a decrease in Bcl-2, an anti-apoptotic molecule. Prx 2 overexpression also protected against FA-induced activation of some special apoptosis-associated proteins [caspase-3, caspase-9, and polypeptide poly (ADP-ribose) polymerase (PARP)]. Furthermore, we examined the signaling molecules involved in the FA-induced decrease in Prx 2 expression. The FA-induced decrease in Prx 2 and increase in cell apoptosis was restored by treatment with SB203580 [a p38 mitogen activated protein kinase (MAPK) inhibitor], but not by SP600125 [a c-jun-N-terminal kinase (JNK) inhibitor]. Also, FA-induced events were blocked by treatment with p38 siRNA, but not by scrambled siRNA. Indeed, FA increased p38 MAPK activation, suggesting a role for p38 MAPK in FA action. In conclusion, FA mediated apoptosis in lung epithelial cells by decreasing Prx 2 via p38 MAPK.
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PMID:Formaldehyde induces apoptosis through decreased Prx 2 via p38 MAPK in lung epithelial cells. 2034

Clinical management of chondrosarcoma remains a challenging problem, largely due to the toxicity and resistance of this tumor to conventional chemotherapy. Programmed Cell Death 5 (PDCD5) is a protein that accelerates apoptosis in different cell types in response to various stimuli, and has been shown to be down-regulated in many cancer tissues. In this study, mRNA and protein levels of PDCD5 were found to be up-regulated in cisplatin-treated SW1353 chondrosarcoma cells compared with untreated cells. Recombinant human PDCD5 (rhPDCD5) was also shown to sensitize chondrosarcoma cells to cisplatin-based chemotherapy, with inhibition of cell growth and apoptosis detected both in vitro and in vivo. Increased expression of Bax and decreased expression of Bcl-2 were also observed, along with release of cytochrome c from mitochondria into the cytosol. Additionally, cleavage of caspase-9 and caspase-3, as well as the cleavage of poly (ADP-ribose) polymerase (PARP), were detected, suggesting that sensitization of chondrosarcoma cells involves the intrinsic mitochondrial apoptosis pathway. In vivo, the treatment of a xenograft model of chondrosarcoma with rhPDCD5 and cisplatin significantly inhibited tumor cell proliferation and induced apoptosis compared to treatment with cisplatin alone. Overall, these data provide a theoretical basis for the administration of rhPDCD5 and cisplatin for the treatment of patients with chondrosarcoma.
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PMID:Recombinant human PDCD5 sensitizes chondrosarcomas to cisplatin chemotherapy in vitro and in vivo. 2034 37

Oleanolic acid (OA) and ursolic acid (UA) are commonly found in plants and herbs and have been reported to possess hepatoprotective, anti-inflammatory and anticancer activities. In the present study, the effects of OA and UA on induction of apoptosis in human hepatocellular carcinoma HuH7 cells and the related mechanisms were investigated. The results demonstrate that OA and UA could inhibit the growth of HuH7 cells with IC(50) values of 100 and 75 microM, respectively. Cell cycle analysis using flow cytometry indicated that the fraction of HuH7 cells in sub-G1 phase progressively increased with increasing concentrations of OA or UA from 20 to 80 microM. Treatment with OA and UA for 8 h induced a dramatic loss of the mitochondria membrane potential and interfered with the ratio of expression levels of pro- and antiapoptotic Bcl-2 family members in HuH7 cells. OA and UA-induced apoptosis involving the release of mitochondria cytochrome c into the cytosol and subsequently induced the activation of caspase-9 and caspase-3, followed by cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, HuH7 cells treated with OA and UA suppressed the activity of NF-kappaB and modulated the mRNA expression of X-linked inhibitor of apoptotic protein (XIAP) as compared with untreated cells. These results demonstrate that OA and UA induce apoptosis in HuH7 cells through a mitochondria-mediated pathway and downregulation of XIAP.
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PMID:Oleanolic acid and ursolic acid induce apoptosis in HuH7 human hepatocellular carcinoma cells through a mitochondrial-dependent pathway and downregulation of XIAP. 2041 21

Ganoderma lucidum, a well-known medicinal mushroom, is highly valued and commonly used in Oriental medicine. Although recent experimental data has revealed the proapoptotic potency of G. lucidum extracts, the underlying mechanisms of this apoptotic activity have not yet been studied in detail. In the present study, the effects of ethanol extracts of G. lucidum (EGL) on the growth of an AGS human gastric carcinoma cell line were investigated. We found that EGL treatment resulted in a dose and time-dependent significant decrease in the viability of AGS cells. This decreased viability was caused by apoptotic cell death, with observed chromatin condensation and an accumulation of apoptotic fraction. EGL treatment induced the expression of death receptor-related proteins such as death receptor 5 and tumor necrosis factor-related apoptosis-inducing ligand, which further triggered the activation of caspase-8 and the cleavage of Bid. In addition, the increase in apoptosis that was induced by EGL was correlated with activation of caspase-9 and -3, downregulation of IAP family proteins such as XIAP and survivin, and concomitant degradation of poly (ADP-ribose) polymerase. Moreover the activity of Akt was downregulated in EGL-treated cells, and the phosphatidylinositol-3 kinase/ Akt inhibitor LY294002 sensitized the cells to EGL-induced apoptosis. The results indicated that EGL induces the apoptosis of AGS cells through a signaling cascade of death receptor-mediated extrinsic, as well as mitochondria-mediated intrinsic, caspase pathways which are associated with inactivation of the Akt signal pathway.
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PMID:Induction of apoptosis by ethanol extracts of Ganoderma lucidum in human gastric carcinoma cells. 2063 12

It has been demonstrated that many flavonoids possess a potent and broad spectrum of antitumor activity. Liquiritigenin is a flavanone extracted from Glycyrrhizae. This study investigated the effects of liquiritigenin on cell viability and apoptosis induction in human cervical carcinoma (HeLa) cells. The results show that liquiritigenin significantly suppressed cell proliferation in a dose- and time-dependent manner in HeLa cells. In addition, liquiritigenin promoted apoptosis in HeLa cells, evidenced by apoptotic morphological changes and Annexin-V binding. The apoptosis induction with liquiritigenin is associated with the up-regulation of p53 and Bax, along with down-regulation of Bcl-2 and survivin. Finally, examination of the mitochondrial pathway of apoptosis revealed that cytochrome c is released from mitochondria to cytosol, associated with the activation of caspase-9 and -3, and the cleavage of poly (ADP-ribose) polymerase (PARP). Overall, the results indicate that liquiritigenin induces apoptosis in part via the mitochondrial pathway, which is associated with p53 up-regulation, release of cytochrome c and elevated activity of caspase-9 and -3 in HeLa cells.
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PMID:Liquiritigenin induces mitochondria-mediated apoptosis via cytochrome c release and caspases activation in HeLa Cells. 2065 71

The pro-apoptotic activity of J-7, a synthetic methyl jasmonate derivative, on the Hep3B human hepatocarcinoma cell line was investigated. Treatment of Hep3B cells with J-7 resulted in growth inhibition and the induction of apoptosis as measured by trypan blue-excluding cells, MTT assay, nuclear staining, DNA fragmentation, and flow cytometry analysis. The increased apoptotic events in Hep3B cells caused by J-7 were associated with the alteration in the ratio of Bax/Bcl-2 protein expression. J-7 treatment induced the expression of death receptor-related proteins such as death receptor 5, which triggered the activation of caspase-8 and the down-regulation of the whole Bid expression. In addition, the apoptosis induction by J-7 was correlated with the activation of caspase-9 and caspase-3, down-regulation IAP family proteins such as XIAP and cIAP-1, and concomitant degradation of poly (ADP-ribose) polymerase. However, the cytotoxic and apoptotic effects induced by J-7 were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role that caspase-3 plays in the process. Furthermore, blocking the extracellular signal-regulated protein kinase and c-Jun N-terminal kinase pathways showed increased apoptosis and the activation of caspases in J-7-induced apoptosis. The results indicated that J-7 induces the apoptosis of Hep3B cells through a signaling cascade of death-receptor-mediated extrinsic as well as mitochondria-mediated intrinsic caspase pathways, which are associated with the activation of the mitogen-activated protein kinases signal pathway.
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PMID:A methyl jasmonate derivative, J-7, induces apoptosis in human hepatocarcinoma Hep3B cells in vitro. 2069 34


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