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)

We have previously reported that cisplatin induces caspase-9 (Casp9) activation in head and neck squamous cell carcinoma cells in vitro (HNSCCs). Our purpose here was to examine whether HNSCCs selected for resistance to cisplatin fail to exhibit Casp9 activation in response to cisplatin. The cisplatin-resistant HNSCCs (HSC-2CR) were selected from cisplatin-sensitive HNSCCs (HSC-2) for growth in the presence of cisplatin. Following cisplatin treatment, protelyzed Casp9 subunits were detected in HSC-2, but not detected in HSC-2CR. Using a direct enzymatic assay measuring cleavage of the synthetic peptide substrate (LEHD-AFC), Casp9 activity in cisplatin-treated HSC-2CR was less than that in cisplatin-treated HSC-2. Apoptotic protease-activating factor 1 (Apaf-1) has been shown to participate as an adaptor molecule in Casp9 activation. In the presence of cytochrome c (Cyt c) released from mitochondria, Apaf-1 binds to Casp9 and causes its activation. HSC-2 expressed 2-fold higher levels of Apaf-1 compared with HSC-2CR. On the other hand, following cisplatin treatment, the same degree of increase in cytoplasmic Cyt c was detected in both HSC-2 and HSC-2CR. These results suggest that in a certain type of HNSCCs, the inhibition of Casp9 activity and Apaf-1 expression may represent a mechanism of acquired cisplatin resistance.
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PMID:Inhibition of caspase-9 activity and Apaf-1 expression in cisplatin-resistant head and neck squamous cell carcinoma cells. 1254 67

Our study was conducted to investigate whether anticancer drugs, cisplatin (CDDP) and/or 5-fluorouracil (5-FU), can modulate Fas-mediated apoptosis in oral squamous cell carcinoma (OSCC) cell lines. When OSCC cell lines, NA and HSC-4, were treated with CDDP and/or 5-FU, Fas and its mRNA expression on the plasma membrane were enhanced. An increase in caspase-3 and -8 activities was then observed by the addition of agonistic anti-Fas antibody, CH-11. Apoptosis of OSCC cells treated with anticancer drugs were significantly enhanced by CH-11, whereas untreated cells were nearly resistant to apoptosis. Moreover, the combination of CDDP and 5-FU resulted in an increasing susceptibility to apoptosis. Caspase-3 and -8 inhibitors, but not caspase-9 inhibitor, reduced Fas-mediated apoptosis enhanced by the anticancer drugs. Furthermore, OSCC cells treated with anticancer drugs exhibited decreased cellular FADD-like interleukin 1-converting enzyme-inhibitory protein (c-FLIP) levels, whereas neither the Fas-associated death domain-containing protein (FADD) nor procaspase-8 changed the expression. Moreover, antisense oligonucleotide to c-FLIP confirmed that down-regulation of c-FLIP induced sensitization to Fas-mediated apoptosis. These results suggest that CDDP and 5-FU may enhance the susceptibility to Fas-mediated apoptosis through down-regulation of c-FLIP. From these findings, a new potential strategy may be developed to improve the efficacy of anticancer drugs.
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PMID:Enhanced susceptibility of oral squamous cell carcinoma cell lines to FAS-mediated apoptosis by cisplatin and 5-fluorouracil. 1284 62

The aim of our study was to clarify the apoptosis pathway induced by aloe emodin, an hydroxyanthraquinone present in aloe vera leaves, in rat hepatic stellate cells transformed by simian virus 40 (t-HSC/Cl-6), which retain the features of activated rat stellate cells. Apoptosis was determined by DNA fragmentation, caspase activity assay and western blotting analysis. Treatment of t-HSC/Cl-6 cells with 12.5, 25, or 50 microM aloe emodin inhibited t-HSC/Cl-6 cell viability in a dose- and time-dependent manner. The induction of apoptosis by aloe emodin was confirmed by typical DNA ladder formation and annexin v-propidium iodide flow-cytometric analysis. Aloe emodin treatment of t-HSC/Cl-6 cells caused activation of caspase-3 and caspase-9, detected with a caspase activity assay, although no change was observed in caspase-8 activity. Western blotting showed caspase-3 and caspase-9 active forms and the subsequent proteolytic cleavage of poly(ADP-ribose) polymerase. Aloe emodin induced mitochondrial membrane depolarization. Our data also show that cytochrome c increased in the cytosol but decreased in the mitochondria in a time-dependent manner. Increased Bax and unchanged Bcl-2 levels resulted in an increased Bax/Bcl-2 ratio. Thus, our research provides evidence that aloe emodin-induced apoptosis involves a mitochondria-associated apoptosis pathway.
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PMID:Aloe emodin-induced apoptosis in t-HSC/Cl-6 cells involves a mitochondria-mediated pathway. 1591 Apr 15

Selenium (Se) is a very effective anti-cancer agent. We studied the effects of inorganic Se compounds on induction of apoptosis by which Se compounds exert cancer chemopreventive activity. With the use of HSC-3 human oral squamous cell carcinoma cells, the present study showed that treatment with Se for 72 h, in the form of SeO2 and Na2SeO3, but not Na2SeO4, markedly induced apoptosis in a dose-dependent manner. Treatment of HSC-3 cells with 100 microM SeO2 resulted in the caspase-3-like and -9-like activation. Se compounds induced a loss of mitochondrial membrane potential (DeltaPsim), but did not induce the generation of reactive oxygen species. Treatment with SeO2 for 18 h resulted in 80% loss of reduced glutathione (GSH), which is known to be involved in the metabolism of Se. Treatment with N-acetyl-L-cysteine, or exogenous GSH, prevented the SeO2-induced apoptosis. Treatment with GSH led to the partial reverse in reduction of DeltaPsim caused by SeO2, while buthionine sulfoximine augmented the SeO2- or Na2SeO3-induced apoptosis. These results suggest that modulation of the mitochondrial redox equilibrium by Se contributes to the mitochondrial pathway, regulating caspase-9-mediated apoptosis without a concurrent increase in ROS.
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PMID:Possible role of glutathione in mitochondrial apoptosis of human oral squamous cell carcinoma caused by inorganic selenium compounds. 1601 Apr 32

BPA (bisphenol A or 2,2-bis(4-hydroxy-phenol)propane) and hydroquinone (HQ, 1,4-benzenediol) are present in dental resin materials, and small quantities of these substances may be eluted from the resins. Recently, attention has focused on the estrogen-like and carcinogenic adverse effects of BPA and HQ. Thus, it is important to investigate the cytotoxicity and apoptosis-inducing activity of these compounds. BPA and HQ reduced the viable cell number of human promyelocytic leukemia (HL-60), human oral squamous cell carcinoma (HSC-2) and human submandibular gland (HSG) cell lines in a concentration-dependent manner. The cytotoxic activity of HQ, but not of BPA, was significantly reduced by the addition of N-acetyl-L-cysteine (NAC). In biomimetic studies of the prooxidant/antioxidant activity of thiols during oxidation of BPA or HQ, the radical-scavenging activities of mixtures of BPA or HQ and 2-mercapto-1-methylimidazole (MMI, a thiol) were investigated by the induction period method. BPA without MMI showed a higher induction period (antioxidant activity) than did HQ, but BPA with MMI did not cause oxygen uptake. In contrast, HQ with MMI caused oxygen uptake, suggesting formation of MMI thiyl radicals during oxidation of HQ followed by reaction with molecular oxygen. This indicates that HQ may produce intracellular reactive oxygen species (ROS) and provides an explanation for the decrease in the cytotoxicity of HQ by NAC. BPA induced internucleosomal DNA fragmentation, a biochemical marker of apoptosis, only in HL-60 cells. BPA activated caspase-9 and caspase-3, suggesting induction of apoptosis via caspase activation by the caspase recruitment domain. The cytotoxicity of BPA was 2-fold less than that of HQ, whereas the apoptosis-inducing activity of BPA was 10-fold less than that of HQ.
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PMID:Cytotoxicity and apoptosis-inducing activity of bisphenol A and hydroquinone in HL-60 cells. 1615 70

The possible apoptosis-inducing activity of codeinone, an oxidative metabolite of codeine, without or with anticancer drugs, was investigated. Codeinone induced internucleosomal DNA fragmentation in human promyelocytic leukemia cells (HL-60), but not in human squamous cell carcinoma cells (HSC-2). Codeinone dose-dependently activated caspase-3 in both of these cells, but to a much lesser extent than that attained by actinomycin D. This property of codeinone was similar to what we have found previously in alpha,beta-unsaturated ketones. Codeinone did not activate caspase-8 or caspase-9 in these cells. The cytotoxic activity of codeinone against HSC-2 cells was inhibited by N-acetyl-L-cysteine, but somewhat additively stimulated by sodium ascorbate, epigallocatechin gallate, hydrogen peroxide, sodium fluoride, 5-fluorouridine, cisplatin, doxorubicin and methotrexate. These data suggest that codeinone has possible antitumor potential, in addition to its action as a narcotic analgesic, even though it induces incomplete apoptosis-associated characteristics.
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PMID:Effect of anticancer agents on codeinone-induced apoptosis in human cancer cell lines. 1630 96

Estrogen affects skeletal growth and promotes growth plate fusion in humans. High doses of estrogen have been used to limit growth in girls with predicted extreme tall stature; a treatment which has been associated with severe side effects. Selective estrogen receptor modulators (SERMs) could potentially be used as an alternative treatment. We chose to study the effects of Tamoxifen (Tam), a first generation SERM that has been used in the treatment of pubertal gynecomastia or McCune-Albright syndrome. Cultured fetal rat metatarsal bones were used to study the effects of Tam on longitudinal bone growth. In sectioned bones, chondrocyte apoptosis and proliferation were analyzed by TUNEL assay and BrdU incorporation, respectively. We also used a human chondrocytic cell line, HSC-2/8, to study the effects of Tam on apoptosis (FACS analysis and Cell Death detection ELISA) and caspase activation (caspase substrate cleavage and Western immunoblotting). Tam caused a dose-dependent growth retardation of cultured metatarsal bones. No catch-up growth was observed after Tam was removed from the culture medium. Detailed analysis of sectioned growth plate cartilage revealed increased apoptosis of chondrocytes within the resting and hypertrophic zones. HCS-2/8 cells also underwent apoptosis upon Tam treatment. Tam-induced apoptosis was caspase-dependent and completely abrogated by either caspase-8 or -9 inhibitors. A substrate assay revealed that caspase-8 is first activated followed by caspase-9 and -3. Finally, FasL secretion was stimulated by Tam and blocking of either FasL or Fas decreased Tam-induced apoptosis in chondrocytes. We here describe a novel mechanism of tamoxifen-induced apoptosis in chondrocytes, involving the activation of caspases and the FasL/Fas pathway, which diminishes the potential for bone growth.
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PMID:Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones. 1729 77

Molecular inhibition of epidermal growth factor receptor (EGFR) signaling is a promising cancer treatment strategy. We examined whether inhibition of EGFR signaling would affect the susceptibility of oral squamous cell carcinoma (OSCC) cells to Fas-mediated apoptosis. Treatment of OSCC cells with an anti-EGFR monoclonal antibody, C225, and an EGFR tyrosine kinase inhibitor, AG1478, which target the extracellular and intracellular domains of the receptor, respectively, inhibited phosphorylation of EGFR and its downstream effector molecule Akt and amplified the induction of Fas-mediated apoptosis. In OSCC cells treated with EGFR inhibitors, Fas-mediated apoptosis was accompanied by caspase-8 activation but not Bid cleavage. Caspase-3 and -8 inhibitors reduced the effect of EGFR inhibitors on Fas-mediated apoptosis in OSCC cells, but a caspase-9 inhibitor did not. These results indicate that the pro-apoptotic activity of EGFR inhibitors in OSCC cells depends on the extrinsic pathway of the caspase cascade. Although EGFR inhibitors did not affect the expression of Fas, the Fas-associated death domain protein, or procaspase-8 in OSCC cells, the inhibition downregulated cellular FLICE-inhibitory protein (c-FLIP). Moreover, knockdown of c-FLIP in HSC-2 cells with a small interfering RNA strongly enhanced Fas-mediated apoptosis. These results suggest that the EGFR signaling pathway may, in part, regulate Fas-mediated apoptosis in OSCC cells through c-FLIP expression.
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PMID:Epidermal growth factor receptor inhibitors enhance susceptibility to Fas-mediated apoptosis in oral squamous cell carcinoma cells. 1768 85

The cytotoxic activity of sodium 5,6-benzylidene-L-ascorbate (SBA) against eight human cancer cell lines and three human normal cells was investigated, SBA showed slightly higher cytotoxicity against human tumor cell lines, as compared with normal cells, with a tumor-specificity index of 2.0. The human myelogenous leukemia cell lines (HL-60, ML-1, KG-1) were the most sensitive to SBA, followed by human oral squamous cell carcinoma (HSC-2, HSC-3, HSC-4) and human glioblastoma (T98G, U87MG). Human oral normal cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast) were the most resistant. In contrast to actinomycin D, SBA induced little or no activation of caspase-3, caspase-8 and caspase-9 in the HSC-2, HSC-4, T98G and HL-60 cells, regardless of incubation time (either 6 or 24 h). SBA induced little or no internucleosomal DNA fragmentation after 6 h in all of these cells. However, prolonged treatment with SBA (24 h) induced a smear pattern of DNA fragmentation in the HSC-2, HSC-4 and T98G cells and a low level of internucleosomal DNA fragmentation in the HL-60 cells. Electron microscopy demonstrated the destruction of mitochondrial structure and autophagocytosis of broken organelles by SBA in the HSC-2, HSC-4 and HL-60 cells. At higher concentrations of SBA, necrotic cell death was observed in the HSC-2 cells, but not in the T98G cells, where the production of acidic organelles (detected by acridine orange staining) was much lower than that attained by nutritional starvation, a well-defined method of inducing autophagy. The present study suggests that SBA induces various degrees of autophagic cell death, followed by either necrosis or apoptosis at laters stage, depending on the cell type.
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PMID:Tumor-specific cytotoxicity and type of cell death induced by sodium 5,6-benzylidene-L-ascorbate. 1903 81

In this report, we investigated the role of oxidative stress in Physalis angulata-induced apoptosis of human oral cancer cells. P. angulata-induced apoptosis was characterized by nuclear morphological changes, membrane blebbing and activation of caspase-9. Exposure of HSC-3 cells to P. angulata caused production of reactive oxygen species and up-regulation of oxidative stress markers heme oxygenase-1 (HO-1), superoxide dismutase (SOD), heat shock protein 70 (HSP70) and caspase-4. Down-regulation of HO-1, SOD and HSP70 proteins expression by attenuation of oxidative stress, pretreatment with glutathione or N-acetylcysteine, significantly decreased P. angulata-triggered cell death. The present study also demonstrated that the mitochondria and the endoplasmic reticulum are the targets of P. angulata in HSC-3 cells. Our results revealed that: (1) reactive oxygen species may play a dominant role in this process, (2) P. angulata induces oxidative stress in HSC-3 cells, (3) P. angulata-initiated apoptosis is caused through oxidative stress-dependent induction of heme oxygenase-1, Cu/Zn SOD and HSP70 proteins expression and (4) antioxidants inhibited P. angulata-induced cell death through inhibition of the proteins expression of HO-1, Cu/Zn SOD and HSP70.
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PMID:Oxidative stress involvement in Physalis angulata-induced apoptosis in human oral cancer cells. 1913 22


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