Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acquired multidrug resistance to anti-cancer agents has been associated with overexpression of the P-glycoprotein and other members of the ATP-binding cassette superfamily. The present studies demonstrate that SCC-25 cells selected for resistance to the alkylating agent cisplatin (CDDP) overexpress the anti-apoptotic Bcl-xL protein. In contrast to parental cells, the SCC-25/CDDP-resistant variant failed to exhibit activation of caspase-3, cleavage of protein kinase C delta, and other characteristics of apoptosis in response to CDDP. Similar results were obtained when SCC-25/CDDP cells were exposed to the structurally and functionally unrelated antimetabolite 1-beta-D-arabinofuranosyl-cytosine (ara-C). Other cells selected for resistance to doxorubicin or vincristine also exhibited overexpression of Bcl-xL and failed to respond to CDDP and ara-C with activation of caspase-3. The results further demonstrate that multidrug-resistant cells exhibit a block in the release of mitochondrial cytochrome c into the cytosol and that this effect is dependent on overexpression of Bcl-xL. The demonstration that lysates from the resistant cells respond to the addition of cytochrome c with activation of caspase-3 confirms that the block in apoptosis is because of inhibition of mitochondrial cytochrome c release. These findings demonstrate that cells respond to diverse classes of anti-cancer drugs with overexpression of Bcl-xL and that this response represents another mechanism of acquired multidrug resistance.
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PMID:Abrogation of mitochondrial cytochrome c release and caspase-3 activation in acquired multidrug resistance. 964 15

The squamous cell carcinoma antigen (SCC Ag) is a tumour-associated protein and a member of the serine protease inhibitor (serpin) family. The SCC Ag has been used as a serologic tumour marker for SCC progression, and its elevated serum levels are a risk factor for disease relapse. However, the biologic significance of this intracytoplasmic protein in cancer cells remains unknown. In this report, we demonstrated that apoptosis induced by 7-ethyl-10-hydroxycamptothecin, tumour necrosis factor-alpha (TNF-alpha) or interleukin (IL)-2-activated natural killer (NK) cells was significantly inhibited in tumour cells transduced with the SCC Ag-1 cDNA, as compared to control cells in vitro. Also, inhibition of the SCC Ag-1 expression in tumour cells by transfection of antisense SCC Ag-1 cDNA was accompanied by significantly increased sensitivity of these cells to apoptosis induced by etoposide or TNF-alpha. The mechanism of protection of tumour cells from apoptosis involved inhibition of caspase-3 activity and/or upstream proteases. In vivo, tumour cells overexpressing the SCC Ag-1 formed significantly larger tumours in nude mice than the SCC Ag-1-negative controls. Thus, overexpression of the SCC Ag-1, a member of the serpin family, in human cancer cells contributed to their survival by mediating protection from drug-, cytokine- or effector cell-induced apoptosis.
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PMID:Inhibition of apoptosis in human tumour cells by the tumour-associated serpin, SCC antigen-1. 1073 75

Interleukin 13 receptor (IL-13R)-targeted cytotoxin, IL13-PE38QQR, composed of IL-13 and a mutated form of Pseudomonas exotoxin (PE), is found to be highly and specifically cytotoxic to human solid cancer cell lines. However, the mechanism of tumor cell death mediated by IL-13 toxin is still not known. To elucidate the mechanism, we utilized four head and neck cancer cell lines (SCC-25, HN12, KCCT873, and YCUM911), which express high levels of IL-13R, and IL-13 toxin is highly cytotoxic to these cells. We observed chromatin condensation and DNA fragmentation, indicating apoptotic cell death, after treatment with IL-13 toxin, as determined by bis-benzimide staining and DNA ladder assays. However, IL-13 did not induce cell death. Flow cytometric analysis suggested that these cancer cell lines increased the sub-G1/G0 phase DNA population in a dose- and time-dependent manner (ranged between 10 and 30%) after treatment with IL-13 toxin. By Western blot analysis, cleavage of caspase-3 and PARP was observed after treatment with a high concentration of IL-13 toxin, also suggesting apoptotic cell death. In addition, the results of immunofluorescence and RT-PCR assays showed that the apoptosis-regulator, Bcl-2 was downregulated after treatment with IL-13 toxin, while Bax was upregulated. Moreover, significant nitrite production was detected in the HN12 cell line after treatment with IL-13 toxin for 48--96 h. Taken together, our results suggest that IL-13 toxin-induced cytotoxicity is at least partially mediated by the apoptosis and nitric oxide pathways. This information may be useful in developing specific approaches where apoptotic bodies from tumor cells may be used to pulse antigen-presenting cells for immunotherapy of cancer.
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PMID:Apoptotic pathways of cell death induced by an interleukin-13 receptor-targeted recombinant cytotoxin in head and neck cancer cells. 1186 21

Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents with potential for disruption of critical cellular processes in cancer cells. Transcriptional regulation, differentiation, cell cycle arrest, radiation sensitization, and apoptosis have been observed in response to exposure to HDAC inhibitors. In the present study, we observed that several potent HDAC inhibitors, including trichostatin A, suberoylanilide hydroxamic acid, M344 (an analogue of hydroxamic acid), and the cyclic tetrapeptide, depsipeptide (FR90228), modulate cellular responses to ionizing radiation in cells of two human squamous carcinoma lines (SQ-20B and SCC-35), previously characterized as intrinsically resistant to radiation. Also exposure to IC(50) concentrations of these inhibitors, radiation sensitivities were enhanced in both cell lines. Depsipeptide exhibited the greatest effect on SQ-20B cells, decreasing D(0) values from 2.62 Gy to 1.64 Gy. M344 was the most active drug in sensitizing SCC-35 cells, decreasing D(0) values from 1.91 Gy to 1.21 Gy. The mechanisms underlying HDAC inhibitor-induced radiosensitization were further investigated by extending trichostatin A studies to assess cell cycle distributions and levels of apoptosis. Treatment of SQ-20B cells with radiosensitizing concentrations of trichostatin A resulted in cell cycle arrest in G(1) phase (>70%) and inhibition of DNA synthesis. Contrary to previous reports, induction of apoptosis was very low and caspase 3 and 9 were not activated. Taken together, these results implicate G(1) arrest and inhibition of DNA synthesis in the mechanisms underlying radiation sensitization by trichostatin A and support the use of HDAC inhibitors for targeting radioresistant cancers.
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PMID:Enhancement of radiation sensitivity of human squamous carcinoma cells by histone deacetylase inhibitors. 1516 53

Overexpression of hypoxia inducible factor-1alpha (HIF-1alpha) in cancers has been correlated to a more aggressive tumor phenotype. We investigated the effect of HIF-1alpha knockout on the in vitro survival and death of human tongue squamous cell carcinomas (SCC-4 and SCC-9). Under normoxic condition, a basal level of HIF-1alpha protein was constitutively expressed in SCC-9 cells, albeit an undetectable level of HIF-1alpha messages. Exposure to hypoxia induced only a transient increase in mRNA transcript but a prolonged elevation of HIF-1alpha protein and its immediate downstream target gene product, VEGF. Under normoxic or hypoxic conditions, treatment of SCC-9 cells with AS-HIF-1alpha ODN suppressed both constitutive and hypoxia-induced HIF-1alpha expression at both mRNA and protein levels. Knockout of HIF-1alpha gene expression via either AS-HIF-1alpha ODN or siRNA (siRNAHIF-1alpha) treatment resulted in inhibition of cell proliferation and induced apoptosis in SCC-4 and SCC-9 cells. We also demonstrated that exposure of SCC-9 cells to hypoxia led to a time-dependent increase in the expression of bcl-2 and IAP-2, but not p53. The attenuated levels of bcl-2 and IAP-2, and the enhanced activity of caspase-3 after treatment with AS-HIF-1alpha ODN may contribute partly to the effects of HIF-1alpha blockade on SCC-9 cell death. Collectively, our data suggest that a constitutive or hypoxia-induced expression of HIF-1alpha in SCC-9 and SCC-4 cells is sufficient to confer target genes expression essential for tumor proliferation and survival. As a result, interfering with HIF-1alpha pathways by antisense or siRNA strategy may provide a therapeutic target for human tongue squamous cell carcinomas.
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PMID:Treatment with siRNA and antisense oligonucleotides targeted to HIF-1alpha induced apoptosis in human tongue squamous cell carcinomas. 1530 Jul 96

We have investigated whether Ginkgo biloba extract (EGb 761) induces apoptosis of oral cavity cancer cells and attempted to characterize the apoptotic pathway activated by EGb 761. The inhibition of SCC 1483 oral cavity cancer cells proliferation was noted from 250 micro/ml of EGb 761. Apoptosis was observed after 24 h of incubation with 250 microg/ml EGb 761 and occurred in a time- and dose-dependent manner. Apoptosis was confirmed by DNA fragmentation and PARP cleavage. Co-treatment with the caspase inhibitor (z-VAD-fmk) inhibited apoptosis and PARP cleavage induced by EGb 761. Caspase-3 activity was upregulated by EGb 761 but reduced to the control level by co-treating with z-VAD-fmk. In summary, EGb 761 induces apoptosis of oral cavity cancer cells and caspase-3 is activated in this apoptosis. Therefore, EGb 761 may be considered as a possible chemopreventive agent against oral cavity cancer.
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PMID:Ginkgo biloba extract (EGb 761) induces apoptosis by the activation of caspase-3 in oral cavity cancer cells. 1579 10

Evidence has accumulated that dietary polyphenols, in particular, flavonoids, have protective effects against oral cancer. In this study, we have examined the effects of quercetin, a major dietary flavonoid, on cell growth and necrosis/apoptosis and cell cycle regulation in human oral squamous carcinoma SCC-9 cells. Quercetin induced dose- and time-dependent, irreversible inhibition of cell growth and cellular DNA synthesis. Light microscopy and lactate dehydrogenase measurements showed modifications in the morphology and membrane integrity of these cells after quercetin treatment. Propidium iodide/annexin V staining showed that quercetin induced necrosis at 24 h and 48 h, whereas at 72 h cells underwent apoptosis, correlating with caspase-3 activation. Flow cytometry studies of the cell cycle distribution showed that quercetin induced mainly S-phase arrest. Thymidylate synthase (TS), a key S-phase enzyme, was inhibited in a time- and dose-dependent fashion by quercetin at the protein level. A lack of effect on TS mRNA suggested that TS down-regulation occurred at the translational level. In conclusion, our data support a view that quercetin initially induces a stress response, resulting in necrosis of these oral epithelial cells. Prolonged exposure of the surviving cells to quercetin causes apoptosis, presumably mediated by inhibition of TS protein.
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PMID:Quercetin induces necrosis and apoptosis in SCC-9 oral cancer cells. 1657 83

Sulindac sulfide and sulindac sulfone have demonstrated anti-neoplastic and chemo-preventive activity against various human tumors, but few studies have examined the relative effectiveness of these drugs against squamous cell carcinoma of the head and neck (SCCHN). These compounds are metabolites of the nonsteroidal anti-inflammatory drug sulindac and differ in their ability to inhibit cyclooxygenase-2 (COX-2) enzyme function. Sulindac sulfide (the sulindac metabolite with COX-2 inhibitory function) demonstrated strong cell growth inhibition as measured by MTT and growth assays in UM-SCC-1 and SCC-25 cells, while sulindac sulfone had only moderate effect. Growth inhibition by sulindac sulfide was associated with a significant increase in percent G cells and activation of caspase-3. Sulindac sulfide induced expression of p21wafl/cipl in a dose-dependent fashion, decreased cyclin D1 protein levels, and increased Rb hypophosphorylation. p21waf1/cip1 protein levels increased without a significant increase in wild-type p53, suggesting that sulindac sulfide induces a p53-independent pathway regulating p2lwafl/ciP1 protein levels in SCCHN. Sulindac sulfide also induced dose-dependent expression of PPAR-gamma. In contrast, sulindac sulfone did not significantly alter apoptosis, cell cycle distribution or G1 checkpoint protein expression at doses below 200 microM. These results demonstrate the differential activity of sulindac metabolites and support the hypothesis that sulindac sulfide induced perturbations in SCCHN cellular proliferation could be regulated both by p21waf1/cip1-dependent cytostatic and caspase-dependent cytotoxic pathways.
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PMID:Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition. 1717 18

In this study, quantitative isobologram studies showed that treatment with gemcitabine and doxorubicin, known inducers of ceramide generation, in combination, supra-additively inhibited the growth of human UM-SCC-22A cells in situ. Then, possible involvement of the human homologue of yeast longevity assurance gene 1 (LASS1)/C(18)-ceramide in chemotherapy-induced cell death in these cells was examined. Gemcitabine/doxorubicin combination treatment resulted in the elevation of mRNA and protein levels of LASS1 and not LASS2-6, which was consistent with a 3.5-fold increase in the endogenous (dihydro)ceramide synthase activity of LASS1 for the generation of C(18)-ceramide. Importantly, the overexpression of LASS1 (both human and mouse homologues) enhanced the growth-inhibitory effects of gemcitabine/doxorubicin with a concomitant induction of caspase-3 activation. In reciprocal experiments, partial inhibition of human LASS1 expression using small interfering RNA (siRNA) prevented cell death by about 50% in response to gemcitabine/doxorubicin. In addition, LASS1, and not LASS5, siRNA modulated the activation of caspase-3 and caspase-9, but not caspase-8, in response to this combination. Treatment with gemcitabine/doxorubicin in combination also resulted in a significant suppression of the head and neck squamous cell carcinoma (HNSCC) tumor growth in severe combined immunodeficiency mice bearing the UM-SCC-22A xenografts. More interestingly, analysis of endogenous ceramide levels in these tumors by liquid chromatography/mass spectroscopy showed that only the levels of C(18)-ceramide, the main product of LASS1, were elevated significantly (about 7-fold) in response to gemcitabine/doxorubicin when compared with controls. In conclusion, these data suggest an important role for LASS1/C(18)-ceramide in gemcitabine/doxorubicin-induced cell death via the activation of caspase-9/3 in HNSCC.
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PMID:Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas. 1730 67

This study was performed to compare the relative antineoplastic activity of 10 different non-steroidal anti-inflammatory drugs (NSAIDs) in clinical use, and to investigate the underlying mechanisms of this activity in a squamous cell carcinoma of the head and neck model (SCCHN). A standard 5-day MTT assay was used to calculate IC(50) values in UM-SCC-1 cells for 10 NSAIDs, including celecoxib, rofecoxib, sulindac sulfide, sulindac sulfone, indomethacin, ketoprofen, flurbiprofen, naproxen, piroxicam, and aspirin. Celecoxib, a COX-2 specific inhibitor, was by far the most potent NSAID, with an IC(50) of 39.9 +/- 1.1 microM, followed by sulindac sulfide (116.5 +/- 2.34 microM). Celecoxib and sulindac sulfide also induced more activation of caspase-3 than any other NSAID. Cell cycle analysis showed that celecoxib and sulindac sulfide both induced a 3-fold increase in G(1) phase distribution, and this correlated with strong induction of p21(waf1/cip1), inhibition of cyclin D1, and hypophosphorylation of Rb. Celecoxib and sulindac sulfide treatment induced strong downstream inhibition of E2F transactivating activity as determined by a luciferase reporter assay. These data demonstrate the wide range of activity of various NSAID agents, and reveal a mechanism of action through cell cycle inhibition and induction of apoptosis.
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PMID:Relative non-steroidal anti-inflammatory drug (NSAID) antiproliferative activity is mediated through p21-induced G1 arrest and E2F inhibition. 1741 79


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