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)

Prostaglandin (PG) A2 has been reported to inhibit the growth or induce apoptosis of various tumor cells. In the present study, PGA2 inhibited the growth of HL-60 cells and concomitantly-induced nuclear condensation and DNA fragmentation, characteristics of apoptosis. Down-regulation of c-myc mRNA, and activation of caspase-3 were observed in the PGA2 -treated cells. PGA2-induced DNA fragmentation was completely abolished in the presence of zVAD-Fmk or zDEVD-Fmk. But, relative cell survival was not improved up to that of untreated cells by pretreatment of caspase inhibitors, and c-myc down-regulation was not recovered by caspase inhibitors, either. Moreover, cytochrome c release and activation of caspase-9 was also observed in apoptotic cells and a specific inhibitor of caspase-9 (zLEHD-Fmk) prevented both DNA fragmentation and activation of caspase-3, but not relative cell survival, implying the upstream mitochondrial event of caspase-3 activation. In addition, antagonistic Fas antibody (ZB4) exerted no effect on the apoptosis. Taken together, these results suggest that PGA2 may induce the apoptosis as well as growth inhibition in HL-60 cells, and cytochrome c release and caspase activation seem to play a critical role in this apoptosis which might be independent or downstream of growth inhibition associated with c-myc down-regulation.
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PMID:Induction of apoptosis dependent on caspase activities and growth arrest in HL-60 cells by PGA2. 1242 87

The incidence of cancer increases with advancing age, but the biological behavior of cancer is known to be less aggressive in elderly people. Thus, the proliferative activity and extent of apoptosis of cancer cells were assessed in samples from 163 cases of colorectal cancer focusing on the age of patients, using Ki-67 labeling index (LI) and apoptotic index (AI) by terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP nick end labeling method and staining for activated caspase-3. The Ki-67 LI of colorectal cancer ranged from 2.33 to 80.4% (mean 32.2%), while the AI ranged from 0.00 to 14.8% (mean 3.57%). Concerning the aging effect, linear and positive correlations were found for the Ki-67 LI of cancer with age (p<0.05) and the AI of cancer with age (p<0.05). However, in normal colorectal mucosa, aging of patients revealed a significant correlation only with the AI but not with the Ki-67 LI. The AI in earlier stages of cancers (stages 0 and 1) revealed a significant difference between younger cases (age<65) and more elderly cases (age>/=65) (p<0.05), however, the Ki-67 LI did not exhibit a significant difference. Therefore, an increased frequency of apoptosis in colorectal cancer tissues, especially in the earlier stages, may possibly explain the slower growth of colorectal cancers in the elderly. Next, the expressions of several regulatory molecules for the proliferation/apoptosis of tumor cells were determined. The results demonstrated a tendency for stronger and more frequent expressions of c-myc, Bak and Bax despite a rather weaker expression of Bcl-2 in cancer tissues from the elderly compared with those from the younger patients. The potential roles of these regulatory molecules on age-change in the proliferation/apoptosis of colorectal cancers are discussed.
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PMID:Incidence of apoptosis increases with age in colorectal cancer. 1255 16

beta-Catenin and transcriptional factor TCF-4 (human T-cell factor-4) genes comprise the Wnt signal. The Wnt signal pathway plays an important role in malignant transformation. We hypothesize that the beta-catenin and TCF-4 gene and Wnt signal are important in the progression of renal cell carcinoma (RCC). To test this hypothesis, we investigated TCF-4 splicing isoforms, beta-catenin, and Wnt signal pathway (cyclin D1, c-myc, c-jun, and MMP7) in three RCC cell lines (A498, Caki-1, and Caki-2), 38 primary RCCs, and 29 normal kidney samples. We also analyzed the relationship between TCF-4 gene splicing isoforms, proliferation (proliferating cell nuclear antigen labeling index), and apoptosis [antiapoptotic factors (Bcl-2 and Bcl-x(L)), proapoptotic factors (Bak and Bax), and caspase-3] in RCC samples. In 38 RCC samples, four splicing isoforms of the TCF-4 gene were present in the region between exon 12 and exon 17. Thirty (79%) of 38 RCCs and all (100%) of the normal kidney samples showed mixed isoforms with both long and short reading frames in the COOH-terminal region, whereas the remaining 8 RCC samples showed only the long-form reading frame. Two COOH-terminal-binding protein sites were present only in the long-form reading frame. The eight RCCs that demonstrated only the long reading frame isoform showed early disease progression and poor prognosis. In these 8 RCC samples, down-regulation of cyclin D1, c-myc, c-jun, and MMP7 expression was observed at the mRNA level. In addition, a marked reduction of caspase-3 expression was also found at both the mRNA and the protein level. However, the beta-catenin gene was not overexpressed at the mRNA level and protein level, and mutation and deletion were not observed in exon 3. In these three renal cell lines, there was no significant difference in TCF-4 mRNA expression before and after 5-Aza-2'-deoxycytidine treatment, and there appeared to be no splicing isoforms in the region between exon 1 and exon 11. These findings suggest that alteration in beta-catenin is an infrequent event in RCC. In samples in which beta-catenin was not overexpressed, the target genes of Wnt signal were regulated through TCF-4 splicing isoforms. The imbalance between TCF-4 gene splicing isoforms with long and short reading frames is associated with RCC progression through the inhibition of the apoptotic pathway. We demonstrate for the first time that TCF-4 gene splicing isoforms and the Wnt signal pathway can induce progression of RCC by the inhibition of apoptosis and not by the induction of cell proliferation.
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PMID:The human T-cell factor-4 gene splicing isoforms, Wnt signal pathway, and apoptosis in renal cell carcinoma. 1279 77

The mechanism by which apoptosis is induced by local anesthetic bupivacaine, a potent uncoupler of mitochondrial oxidative phosphorylation, was investigated. In promyelocytic leukemia cells HL-60, bupivacaine induced formation of apoptotic bodies and DNA fragmentation in a time- and dose-dependent manner similar to typical apoptosis inducers. Caspase-3, -8 and -9, which play a pivotal role in the initiation and execution of receptor- or mitochondria-mediated apoptosis, were all clearly activated by bupivacaine in good correlation with the degree of DNA fragmentation. However, bupivacaine did not induce either mitochondrial permeability transition (PT) or release of cytochrome c in experiments with isolated mitochondria. These results suggest that an indirect action of bupivacaine on mitochondria occurs and that other mechanisms may be involved in bupivacaine-induced apoptosis. To obtain additional information concerning the mechanism of action involved in bupivacaine-induced apoptosis, a microarray analysis of gene expression in bupivacaine-treated HL-60 cells was carried out. Several apoptosis-related genes were found to be transcriptionally regulated by bupivacaine using a high-density cDNA microarray. The expression levels of heat shock protein 70 (HSP70), c-jun and c-fos genes were remarkably up-regulated and those of c-myc and poly (ADP ribose) polymerase (PARP) were down-regulated in bupivacaine-treated cells. These results are of value in developing a better understanding of the molecular mechanism of bupivacaine-induced apoptosis leading to neuro- or myotoxicity.
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PMID:Biochemical and microarray analyses of bupivacaine-induced apoptosis. 1282 May 40

We employed cDNA microarray analysis to identify, in mammary adenocarcinomas induced by 7,12-dimethylbenz[a] anthracene (DMBA) in the rat, target genes as potential biomarkers for cancer chemoprevention by 1,4-phenylenebis(methylene)selenocyanate (p-XSC). Confirmation of selected genes was conducted by reverse transcription polymerase chain reactions (RT-PCR). The glutathione conjugate, p-XSeSG, a putative metabolite of p-XSC was also employed to test our hypothesis that p-XSeSG is a more effective cancer chemopreventive agent in the mammary cancer model than p-XSC. Mammary adenocarcinomas were induced by a single oral administration of 5 mg DMBA in 0.2 ml olive oil per rat at 50-55 days of age. Consistent with our previous reports, dietary p-XSC at a non-toxic dose (10 p.p.m. as selenium) significantly inhibited adenocarcinoma development, independent of feeding duration. Moreover, p-XSeSG appears to be just as effective as p-XSC when fed after DMBA administration, but was significantly less effective than p-XSC in inhibiting the induction of mammary adenocarcinomas when it was fed before DMBA and continued until termination. To delineate the molecular basis for cancer chemoprevention by organoselenium compounds, we focused our analysis on differential expression of genes known to be involved in DMBA metabolism, as well as those related to cell cycle, cell proliferation and apoptosis. p-XSC and p-XSeSG were significantly and equally effective in inhibiting levels of expression of genes associated with cytochrome P450 isoforms, but the former was more active than the latter in up-regulating the expression of those related to certain phase II enzymes. p-XSC and p-XSeSG were significantly more effective in the up-regulation of pro-apoptotic genes, such as p21CIP1/WAF1, p27KIP1, APO-1 and Caspase-3, while down-regulating cell growth regulatory genes, such as c-myc, cyclin D1, cyclin D2 and proliferating cell nuclear antigen (PCNA). To our knowledge, this is the first report that provides insights into the effects of p-XSC and p-XSeSG at the molecular level that may account for mammary cancer chemoprevention in vivo in the rat.
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PMID:Elucidation of molecular targets of mammary cancer chemoprevention in the rat by organoselenium compounds using cDNA microarray. 1284 80

5-Fluoro-2'-deoxyuridine (FUdR) inhibits thymidylate synthase (TS). The inhibition of TS causes an imbalance of intracellular deoxyribonucleoside triphosphate (dNTP) pools which subsequently induced cell death. We investigated the molecular mechanisms of cell death after treated with FUdR in F28-7 strain (which induced necrosis) and F28-7-A strain (mutant of F28-7 strain which induced apoptosis). After treated with FUdR, we observed different size of DNA fragmentations. F28-7 strain induced DNA cleavaged into 100-200 kbp fragments and F28-7-A strain induced DNA cleavaged into oligonucleosomal sized fragments. In F28-7 strain, FUdR induced the increased mRNA level of c-jun, c-fos and c-myc genes, caspase-3 like protease activity and the changes of mitochondrial membrane potential which were greater and earlier than those of F28-7-A strain. On the other hand, F28-7-A strain induced release of cytochrome c from mitochondrial, but not F28-7 strain. Furthermore, caspase-5 inhibitor was strongly inhibited the cell death of F28-7 strain. We suggest that it is concerned with intensity of intracellular signals in the cell death of F28-7 strain and F28-7-A strain.
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PMID:Mechanisms of cell death induced by 5-fluoro-2'-deoxyuridine (FUdR)--necrosis or apoptosis after treated with FUdR. 1290 97

The influence of carboplatin alone and carboplatin in combination with cytoprotective agent amifostine on the growth, caspase 3 activity and some apoptotic genes expression was investigated in vitro in human acute promyelocytic leukemia HL-60 cells. Proliferation of HL-60 cells exposed to carboplatin dropped down with increasing dose of the drug. This effect was slightly higher when carboplatin was used in combination with amifostine. The cytotoxic index (IC50) was estimated as 6.6 and 4.4 x 10(-4) M (after 24 h) and 3.3 and 2.5 x 10(-5) M (after 48 h) for carboplatin and carboplatin with amifostine, respectively. This effect was accompanied by induction of caspase 3 activity. HL-60 cells treated with carboplatin alone showed about 120-fold increase in caspase 3 activity. Combination of carboplatin with amifostine induced the enzyme activity up to 280 times. Furthermore, the expression of bcl-2, c-myc and bax genes involved in apoptosis as well as p65, which function in this process is unknown, were determined. Semi-quantitative RT-PCR showed a decrease in bcl-2 and an increase in bax, c-myc and p65 expression in HL-60 cells treated with carboplatin in combination with amifostine as compared to the cells treated only with carboplatin. We conclude that amifostine may potentiate carboplatin therapeutic efficiency towards human acute promyelocytic leukemia cells.
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PMID:Induction of caspase 3 and modulation of some apoptotic genes in human acute promyelocytic leukemia HL-60 cells by carboplatin with amifostine. 1292 51

The effects of Saikosaponin-A on human breast cancer cell lines (MDA-MB-231 and MCF-7) were investigated. Results demonstrated that Saikosaponin-A inhibited the proliferation or viability of the MDA-MB-231 and MCF-7 cells in a dose-dependent manner. Saikosaponin-A treatment of MDA-MB-231 for 3 hours and of MCF-7 cells for 2 hours, respectively caused an obvious increase in the sub-G1 population of cell cycles. Apoptosis in MDA-MB-231 cells was independent of the P53/p21 pathway mechanism and was accompanied by an increased ratio of Bax to Bcl-2 and c-myc levels and activation of caspase-3. In contrast, apoptosis of MCF-7 cells may have been initiated by the Bcl-2 family of proteins and involved p53/p21 dependent pathway mechanism, and was accompanied by an increased level of c-myc protein. Both the apoptosis of MDA-MB-231 cells and MCF-7 cells showed a difference worthy of further research.
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PMID:Saikosaponin-A induces apoptotic mechanism in human breast MDA-MB-231 and MCF-7 cancer cells. 1294 68

2-Oxo-3,23-isopropylidene-asiatate (AS2006A), a wound-healing asiatate derivative, exerts anti-inflammatory effect. Macrophages produce cytokines that recruit other inflammatory cells and are responsible for the diverse effects of inflammation. In the present study, we comparatively evaluated the cytotoxicity of AS2006A to Raw264.7, H4IIE and L-929 cells as part of the studies on its anti-inflammatory effect. Among the cells examined, AS2006A was selectively cytotoxic to Raw264.7 cells, a macrophage cell line. AS2006A increased the number of cells positively stained with TdT-mediated dUTP nick end labeling (TUNEL), and upregulated the expression of the genes implicated with apoptosis, which included caspase-8, c-myc, iNOS, mdm2, NF-kappaB1, I-kappaBalpha and NF-kappaB p105 genes, as assessed by the membrane DNA array technique. The expression of the genes related with cell cycle control was not changed. Thus, the primary targets of AS2006A in macrophages might include the genes implicated with apoptosis. Immunoblot analysis revealed that AS2006A caused the release of cytochrome c from the mitochondria to the cytoplasm in macrophages. Caspase-3 activity and poly(ADP-ribose) polymerase cleavage were both increased by AS2006A in macrophages, indicating that AS2006A induced apoptosis. Viability of macrophages activated by lipopolysaccharide and their NO production were also decreased by AS2006A in a concentration-dependent manner. These results demonstrated that AS2006A selectively induces apoptosis of macrophages with cytochrome c release, caspase 3 activation and poly(ADP-ribose) polymerase cleavage, and that cytotoxicity of AS2006A to macrophages may contribute to anti-inflammatory and wound-healing effects.
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PMID:2-Oxo-3,23-isopropylidene-asiatate (AS2006A), a wound-healing asiatate derivative, exerts anti-inflammatory effect by apoptosis of macrophages. 1294 39

Enforced expression of c-myc has been shown to serve as an apoptotic stimulus in cultured cells. Prior studies have also demonstrated that several tissues expressing c-myc transgene display a large number of dead cells, although a morphologic or biochemical verification of apoptosis in these tissues has actually not been presented. In the present study, we examined the morphologic properties of cell death in the mammary tumors developed from MMTV-c-myc transgenic mice. We found that c-myc-expressing mammary tumor cells exhibited malformation of mitochondria, characterized by an amorphous matrix with very few cristae. The mitochondria were also frequently degenerated by lysis of the matrix and cristae. The protein level of cytochrome c was much lower in the areas of c-myc-expressing tumor cells compared with the adjacent tumor foci, which was previously shown to have decreased expression of c-myc, reduced frequencies of cell death, and increased frequencies of proliferating cells. In the c-myc-expressing tumor areas, there were many dying or dead cells organized in clusters, termed "dead cell islands." These cells exhibited shrinkage, DNA breakage as indicated by a positive TUNEL staining, and nuclear localization of apoptosis-inducing factor, but a lack of typical apoptotic morphology, such as nuclear condensation and formation of cell membrane blebs and apoptotic bodies. Many macrophages infiltrated into these dead cell islands, engulfing the dying or dead tumor cells. In the total tumor tissue, the protein level of caspase-3 was very low, and the poly(ADP)-ribose polymerase was present mainly as the unprocessed, inactive form. Collectively, these results suggest that programmed cell death in the c-myc transgenic mammary tumor tissue may not be typical apoptosis and may involve a caspase-independent mechanism.
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PMID:Cell death in MMTV-c-myc transgenic mouse mammary tumors may not be typical apoptosis. 1456 45


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