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)

We investigated the proportion of apoptotic cells and the expression of apoptosis-associated proteins after the delivery of the first week of irradiation for stage IIIb uterine cervical cancer. Thirty patients with stage IIIb squamous cell carcinoma of the uterine cervix who received only irradiation therapy were registered in this study. Specimens were obtained before irradiation therapy and at the end of the first week of irradiation. The apoptotic index (AI) of each tissue specimen was calculated by counting the apoptotic cells and expressed as a percentage. Immunohistochemical evaluation for apoptosis-related proteins, p53, Bcl-2, Bax, caspase-1 and caspase-3 was also performed. The AI was 0.8+/-0.9% (mean+/-SD) before irradiation and 1.7+/-1.3% at the end of the first week of irradiation. We observed that the patients who survived more than 5 years had AI levels of 2.1+/-1.3% at the end of their first week of therapy. This rate was significantly higher than the rate of 1.1+/-0.8% (P=0.02) of the patients who died within 5 years. When the cut-off value of the AI was set at 1.7%, the sensitivity, specificity, positive predictive value, and negative predictive value for the prediction of patients' prognosis after irradiation therapy were 73.4%, 72.4%, 82.4%, and 61.5%, respectively. In 17 of the AI-positive cases, expressions of Bax (P=0.006), caspase-1 (P=0.045), and caspase-3 (P=0.013) at the end of the first week were significantly higher than before irradiation. The proportion of apoptotic cells and the expression of apoptosis-associated proteins, Bax, caspase-1, and caspase-3, at the end of the first week of irradiation could be useful predictors of the prognosis in stage IIIb squamous cell carcinoma of the uterine cervix treated by irradiation therapy.
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PMID:Detection of apoptosis and expression of apoptosis-associated proteins as early predictors of prognosis after irradiation therapy in stage IIIb uterine cervical cancer. 1074 54

Dietary indole-3-carbinol (I3C) has clinical benefits for both cervical cancer and laryngeal papillomatosis, and causes apoptosis of breast cancer cells in vitro. We asked whether I3C and its major acid-catalyzed condensation product diindolylmethane (DIM), which is produced in the stomach after consumption of cruciferous vegetables, could induce apoptosis of cervical cancer cell lines. We also asked whether this effect could be observed in vivo. In vitro, both I3C and DIM caused accumulation of DNA strand breaks in three cervical cancer cell lines. Induction of apoptosis was confirmed by nuclear morphology, nucleosome leakage, altered cytoplasmic membrane permeability and caspase 3 activation. Neither I3C nor DIM caused apoptotic changes in normal human keratinocytes. In C33A cervical cancer cells, DIM was more potent than I3C [dose at which the number of viable cells was 50% of that in untreated cultures (LD(50)) = 50-60 micromol/L for DIM and 200 micromol/L for I3C in a mitochondrial function assay] and faster acting. Furthermore, I3C reduced Bcl-2 protein in a time- and dose-dependent manner. In HPV16-transgenic mice, which develop cervical cancer after chronic estradiol exposure, apoptotic cells were detected in cervical epithelium by TdT-mediated dUTP nick-end labeling staining and by immunohistochemical staining of active caspase 3 only in mice exposed to 17beta-estradiol (E2) and fed I3C. Rare apoptotic cells were also observed by hematoxylin and eosin staining in the spinous layer of the cervical epithelium in both control and transgenic mice. Estradiol reduced the percentage of these late-stage apoptotic cells in the cervical epithelium of transgenic, E2-treated mice, but this reduction was prevented by I3C. These data confirm the proapoptotic action of I3C on transformed cells in vitro, extend the observations to cervical cancer cells and to DIM and show for the first time that dietary I3C results in increased apoptosis in target tissues in vivo.
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PMID:Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. 1173 83

The p53 tumor suppressor pathway is disrupted by human papillomavirus (HPV) in most cervical cancer cells. The E6 proteins, which could mediate p53 degradation, are related to cellular immortalization, transformation, and tumor formation. In order to study the E6 abrogated p53 function in stress, we transfected HPV-16 E6 gene to TK6 cells in this study. Here we showed that HPV-16 E6 mRNA levels decreased in a dose dependent manner after sodium arsenite (SA) treatment, but not after X-irradiation. P53, p21, and MDM2 were induced in E6-transfected TK6 cells, as well as in parental TK6 cells after arsenite treatment. But the above proteins were only induced in TK6 cells after X-irradiation. It indicated that arsenite, but not X-ray, could suppress the transcription of E6 gene and therefore activate the p53 tumor suppressor pathway in TK6-E6 cells. After arsenite treatment, TK6-E6 cells showed more sub-G1 apoptosis, activated caspase-3/CPP32 fragment, DNA ladder, and less viability than parental TK6 cells, indicating that arsenite enhanced apoptosis in E6-transfected TK6 cells. In contrast, after X-irradiation, TK6-E6 cells showed less sub-G1 apoptosis and higher viability than parental TK6 cells. Thus, it would be another possible strategy to promote arsenite as another potential candidate for the therapeutic purpose in HPV-positive cancer cells.
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PMID:Sodium arsenite suppresses human papillomavirus-16 E6 gene and enhances apoptosis in E6-transfected human lymphoblastoid cells. 1181 66

Dioscin, a saponin extracted from the root of Polygonatum Zanlanscianense Pamp, markedly inhibited proliferation of Hela cells. The results indicated that Hela cells underwent apoptosis in dose- and time-dependent manners when treated with Dioscin. Caspase-3, -8 and -9 activities were also detected. The low enzymatic activity of caspase-8 and high activity of caspase-9 showed that the mitochondrial pathway was activated in apoptosis. The reduced expression of the survival protein Bcl-2 also confirmed this result. These studies may be significant in finding a new drug to treat human cervical cancer.
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PMID:Apoptosis induced by dioscin in Hela cells. 1185 64

Insufficient apoptosis is implicated in many human cancers, including cervical carcinoma. The objectives of this study were to explore changes of apoptosis-regulating gene expression and their clinical significance in cervical cancer. The expression of apoptosis-regulating genes, including five Bcl-2 family and two caspase family members, was evaluated in 43 cervical invasive squamous cell carcinomas, using immunohistochemistry. Specimens in which >or=10% of the neoplastic cells showed cytosolic immunoreactivity were considered to be immunopositive. Results were correlated with clinico-pathologic characteristics of the subjects. All seven apoptotic regulators examined were positive in a proportion of the tumors. The percentage of cases expressing Bax was higher in the patients without evidence of disease after treatment than in the patients alive with disease or who died of disease (P<0.05). A significant difference in disease-free survival was detected between Bax-positive and -negative groups (P<0.05), and in overall survival between Mcl-1-positive and -negative groups (P<0.05). Significant association between the seven markers tested was only found for caspase 3 and Bak immunoreactivity in cervical carcinoma (P<0.05). The results demonstrate expression of multiple apoptosis-modulating proteins in cervical cancer. There appears to be complex regulation of apoptosis protein levels in association with clinical behavior of cervical squamous cell carcinoma.
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PMID:Expression of apoptotic regulators and their significance in cervical cancer. 1191 71

Arsenic trioxide (As2O3) inhibits cell growth and induces apoptosis in certain types of cancer cells including acute promyelocytic leukemia, prostate and ovarian carcinomas, but its effect on response of tumor cells to ionizing radiation has never been explored before. Here we demonstrate that As2O3 can sensitize human cervical cancer cells to ionizing radiation both in vitro and in vivo. As2O3 in combination with ionizing radiation have a synergistic effect in decreasing clonogenic survival and in the regression of established human cervical tumor xenografts. Pretreatment of the cells with As2O3 also synergistically enhanced radiation-induced apoptosis. Apoptosis of the cells by combined treatment of As2O3 and radiation was associated with reactive oxygen species generation and loss of mitochondrial membrane potential, resulting in the activation of caspase-9 and caspase-3. The combined treatment also resulted in an increased G2/M cell cycle distribution at the concentration of As2O3 which did not alter cell cycle when applied alone. These results indicate that As2O3 can synergistically enhance radiosensitivity of human cervix carcinoma cells in vitro and in vivo, suggesting a potential clinical applicability of combination treatment of As2O3 and ionizing radiation in cancer therapies.
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PMID:Enhancement of radiation response in human cervical cancer cells in vitro and in vivo by arsenic trioxide (As2O3). 1202 44

C8-ceramide, a synthetic cell-permeable analog of endogenous ceramides, interfered with cell proliferation, and was cytotoxic to papilloma virus-containing human cervix carcinoma cells, CALO, INBL, and HeLa, that match two clinical stages of tumor progression. C8-ceramide (3 microM) markedly reduced the tumor cell number after 48 h of treatment, an effect that endured even after the removal of C8-ceramide. The carcinoma cells showed morphologic changes, characteristic of necrosis and released lactate dehydrogenase (LDH). A biologically inactive analog C8-dihydro-ceramide had no effect on cell viability in any of the cell lines tested. Seventy-two hours after C8-ceramide treatment none of the biochemical and morphological markers characteristic of apoptosis: (a) nuclear chromatin condensation, (b) DNA fragmentation, (c) proteolysis of the caspase-3 substrate poly-(ADP-ribose)-polymerase (PARP), and (d) appearance of phosphatidylserine on the external cell membrane, were observed. C8-ceramide had no effect on human cervix fibroblasts and induced a mild reduction (30%) in the proliferation of normal human cervix epithelia and HeLa cells (IV-B metastatic stage). The cytotoxicity of C8-ceramide was restricted to CALO (early II-B) and INBL (IV-A non-metastatic) carcinoma cells. The possible application of ceramide in the treatment of early stages of cervical cancer is discussed.
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PMID:Ceramide promotes the death of human cervical tumor cells in the absence of biochemical and morphological markers of apoptosis. 1205 63

Arsenic trioxide (As2O3) can induce clinical remission in patients with acute promyelocytic leukemia (APL) through induction of apoptosis. To investigate the potential therapeutic usage of As2O3 in cervical cancer and its possible mechanisms, human cervical cancer cell line HeLa was employed. The cells underwent apoptosis in response to As2O3, accompanied by a decrease of mitochondrial membrane potential and caspase-3 activation. Overexpression of Bcl-2, however, prevented the dissipation of mitochondrial membrane potential, subsequently protecting the cells from As2O3-induced apoptosis. As2O3 increased cellular content of reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), and the antioxidant N-acetyl-L-cysteine completely suppressed As2O3-induced apoptosis. Furthermore, incubation of the cells with catalase resulted in significant suppression of As2O3-induced apoptosis. The above results indicate that the induction of HeLa cell apoptosis by As2O3 involved an early decrease in cellular mitochondrial membrane potential and increase in ROS content, predominantly H2O2, followed by caspase-3 activation and DNA fragmentation.
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PMID:Arsenic trioxide induces apoptosis through a reactive oxygen species-dependent pathway and loss of mitochondrial membrane potential in HeLa cells. 1206 50

Cervical cancer is known to be highly associated with viral oncogene E6 and E7 of human papilloma virus. Down-regulation of oncogene expression by antisense-based gene therapy has been extensively studied. To investigate the effect of HPV 16 E6 antisense nucleic acid (AS) on cervical cancer cells, human cervical cancer cell lines, CaSki and SiHa cells harboring HPV 16 genome were transfected with plasmid containing E6(AS). The decreased viability and the apoptotic morphology were observed in E6(AS)-transfected cervical cancer cell lines. By 6 h after transfection, inhibition of E6 splicing, rapid upregulations of p53 and a p53-responsive protein, GADD45, were displayed in E6(AS)-transfected CaSki cells. Furthermore, E6(AS) induced loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into the cytoplasm, and subsequent activation of caspase-9 and caspase-3. These results indicate that HPV 16 E6(AS) induces apoptosis in CaSki cells via upregulation of p53 and release of cytochrome c into cytoplasm, consequently activating procaspase-9 and procaspase-3.
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PMID:HPV E6 antisense induces apoptosis in CaSki cells via suppression of E6 splicing. 1208 99

Arsenic trioxide (As(2)O(3)) has been found to induce apoptosis in leukemia cell lines and clinical remissions in patients with acute promyelocytic leukemia. In this study, we investigated the cytotoxic effect and mechanisms of action of As(2)O(3) in human tumor cell lines. As(2)O(3) caused inhibition of cell growth (IC(50) range, 3-14 microM) in a variety of human solid tumor cell lines, including four human non-small-cell lung cancer cell lines (H460, H322, H520, H661), two ovarian cancer cell lines (SK-OV-03, A2780), cervical cancer HeLa, and breast carcinoma MCF-7, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry analysis showed that As(2)O(3) treatment resulted in a time-dependent accumulation of cells in the G(2)/M phase. We observed, using Wright-Giemsa and 4',6-diamidine-2-phenylindole-dihydrochloride staining, that As(2)O(3) blocked the cell cycle in mitosis. In vitro examination revealed that As(2)O(3) markedly promoted tubulin polymerization without affecting GTP binding to beta-tubulin. Immunocytochemical and EM studies of treated MCF-7 cells showed that As(2)O(3) treatment caused changes in the cellular microtubule network and formation of polymerized microtubules. Similar to most anti-tubulin agents, As(2)O(3) treatment induced up-regulation of the cyclin B1 levels and activation of p34(cdc2)/cyclinB1 kinase, as well as Bcl-2 phosphorylation. Furthermore, activation of caspase-3 and -7 and cleavage of poly(ADP-ribose) polymerase and beta-catenin occurred only in As(2)O(3)-induced mitotic cells, not in interphase cells, suggesting that As(2)O(3)-induced mitotic arrest may be a requirement for the activation of apoptotic pathways. In addition, As(2)O(3) exhibited similar inhibitory effects against parental MCF-7, P-glycoprotein-overexpressing MCF-7/doxorubicin cells, and multidrug resistance protein (MRP)-expressing MCF-7/etoposide cells (resistance indices, 2.3 and 1.9, respectively). Similarly, As(2)O(3) had similar inhibitory effect against parental ovarian carcinoma A2780 cells and tubulin mutation paclitaxel-resistant cell lines PTx10 and PTx22 (resistance indices, 0.86 and 0.93, respectively), suggesting that its effect on tubulin polymerization and G(2)/M phase arrest is distinct from that of paclitaxel. Taken together, our data demonstrate that As(2)O(3) has a paclitaxel-like effect, markedly promotes tubulin polymerization, arrests cell cycle at mitosis, and induces apoptosis. In addition, As(2)O(3) is a poor substrate for transport by P-glycoprotein and MRP, and non-cross-resistant with paclitaxel resistant cell lines due to tubulin mutation, suggesting that As(2)O(3) may be useful for treatment of human solid tumors, particularly in patients with paclitaxel resistance.
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PMID:Arsenic trioxide produces polymerization of microtubules and mitotic arrest before apoptosis in human tumor cell lines. 1218 29


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