Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SCH58500 (ACN53) is a replication-deficient, type 5 adenovirus (Ad) expressing human wild-type p53 tumor suppressor. It is currently undergoing clinical trials as a cancer therapeutic. Many SCH58500 clinical trials incorporate an arm comparing traditional chemotherapy against chemotherapy combined with SCH58500. Paclitaxel was chosen for combination therapy in the preclinical study reported here due to its extensive use as a first-line therapy in ovarian cancer, its synergy with SCH58500 in preclinical cancer models, and its activation of p53-independent apoptosis, which might result in a "lowered threshold" for tumor cell death. SCID mice bearing human tumor xenografts were dosed with intratumoral vehicle, control Ad vector, or SCH58500, with or without paclitaxel. Real-time quantitative reverse transcriptase polymerase chain reaction assays were developed and validated to quantitate expression of p53, the p53 downstream effector gene p21, and the apoptosis-related genes, bax, bcl-2, and survivin. Protein expression was confirmed using immunohistochemical assays for p53 and p21. Only tumors injected with SCH58500 had detectable levels of exogenous p53 DNA and mRNA. After SCH58500 treatment, 3-11-fold elevations of p21 expression were observed in tumor xenografts containing nonfunctional p53 (MDA-MB-468, MDA-MB-231, MIAPaCa2, DU-145, and SK-OV-3), but no change in p21 mRNA in wild-type p53 PA-1 tumors. Immunohistochemical assays confirmed induction of p21 protein in MDAMB-468 and SK-OV-3 cells, but not in PA-1 cells. Ad vector alone or paclitaxel alone had no effect on p21 mRNA levels in most tumors. However, paclitaxel suppressed p21 expression induced by SCH58500 4-fold in DU-145 and SK-OV-3 tumors. Paclitaxel also affected expression of the housekeeping gene gapdh. There was no consistent pattern to the changes in bax, bcl-2, or survivin after SCH58500 treatment with or without paclitaxel between tumor types, although there were consistent responses within individual tumor lines. The mRNA ratios for bax/bcl-2 and bax/survivin were also not informative across tumor types. Of the genes examined, only p21 gave a predictable response 24 hours after p53 gene therapy and therefore, p21 expression may be useful for confirming SCH58500 activity in human tumor biopsies.
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PMID:Development and validation of sensitive assays to quantitate gene expression after p53 gene therapy and paclitaxel chemotherapy using in vivo dosing in tumor xenograft models. 1112 89

Se-methylselenocysteine (Se-MSC) is a potent chemopreventive agent in many test systems and has been shown to inhibit tumor promotion and induce apoptosis, but its mechanism of action is still not well understood. The present study was designed to assess the mechanism of Se-MSC on the induction of apoptosis in SKOV-3 ovarian cancer cells. Se-MSC displayed strong inhibitory effects on cell proliferation and viability of SKOV-3 cells in dose and time dependent manners and induced apoptosis. Investigation of the mechanism of Se-MSC-induced apoptosis revealed that treatment with Se-MSC produced morphological features of apoptosis and DNA fragmentation. This was associated with caspase-3 activation and cleavage of poly(ADP-ribose) polymerase and phospholipase C-gamma1 proteins. However, SKOV-3 cells treated with Se-MSC did not demonstrate cytochrome c accumulation in the cytosol during apoptosis induction. Pretreatment of cells with the caspase inhibitors (z-VAD-fmk and DEVD-CHO) prevented Se-MSC-induced apoptosis. These results suggested that Se-MSC induces apoptosis through cytochrome c-independent caspase-3 activation in SKOV-3 cells. In late stage of apoptosis, p18kDa fragment of Bax was generated with the down-regulation of the expressions of survivin, X-linked inhibitor of apoptosis protein, and human inhibitor of apoptosis protein 1 following Se-MSC treatment, suggesting that the modulation of Bax and IAP (inhibitors of apoptosis) family proteins play some role in Se-MSC-mediated apoptosis. Pre-treatments of z-VAD-fmk and the calpain inhibitor, calpeptin inhibited Bax cleavage. These results suggested that Bax cleavage is mediated by calpain, and calpain activation may be a caspase-dependent one. Taken together, the chemopreventive effects of Se-MSC may be related in part to the caspase-3 activation, the down-regulation of IAP family proteins, and Bax cleavage mediated by caspase-dependent calpain activation.
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PMID:Se-methylselenocysteine induces apoptosis through caspase activation and Bax cleavage mediated by calpain in SKOV-3 ovarian cancer cells. 1217 27

The naturally occurring cyclic tetrapeptide chlamydocin is a very potent inhibitor of cell proliferation. Here we show that chlamydocin is a highly potent histone deacetylase (HDAC) inhibitor, inhibiting HDAC activity in vitro with an IC(50) of 1.3 nM. Like other HDAC inhibitors, chlamydocin induces the accumulation of hyperacetylated histones H3 and H4 in A2780 ovarian cancer cells, increases the expression of p21(cip1/waf1), and causes an accumulation of cells in G(2)/M phase of the cell cycle. In addition, chlamydocin induces apoptosis by activating caspase-3, which in turn leads to the cleavage of p21(cip1/waf1) into a 15-kDa breakdown product and drives cells from growth arrest into apoptosis. Concomitant with the activation of caspase-3 and cleavage of p21(cip1/waf1), chlamydocin decreases the protein level of survivin, a member of the inhibitor of apoptosis protein family that is selectively expressed in tumors. Although our data indicate a potential link between degradation of survivin and activation of the apoptotic pathway induced by HDAC inhibitors, stable overexpression of survivin does not suppress the activation of caspase-3 or cleavage of p21(cip1/waf1) induced by chlamydocin treatment. The decrease of survivin protein level is mediated by degradation via proteasomes since it can be inhibited by specific proteasome inhibitors. Taken together, our results show that induction of apoptosis by chlamydocin involves caspase-dependent cleavage of p21(cip1/waf1), which is strikingly associated with proteasome-mediated degradation of survivin.
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PMID:Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degradation of survivin. 1253 46

Increased survivin expression is a negative prognostic marker in many tumours, including ovarian cancer. We show here that ovarian carcinoma cells upregulate survivin transcription in response to increased expression of the proapoptotic protein procaspase 3. We have utilized this observation in a combination gene therapy strategy using adenoviral constructs expressing the dominant-negative mutant survivin T34A (Ad Survivin T34A) and procaspase 3 (Ad Caspase 3) in ovarian carcinoma cell lines. Transfection of ovarian carcinoma cells with Ad Survivin T34A induces apoptosis via a caspase 9-mediated pathway that is not affected by cell cycle block prior to G2/M. Ad Survivin T34A-induced apoptosis can be significantly enhanced by cotransfection with Ad Caspase 3, and the combination of Ad Survivin T34A and Ad Caspase 3 leads to a significant increase in survival in a murine intraperitoneal ovarian carcinoma model with some long-term survivors. This suggests that inhibiting endogenous survivin activity while also delivering high levels of procaspase 3 allow proteolytic cleavage and activation of the terminal caspase cascade leading to tumour cell death.
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PMID:Procaspase 3 expression in ovarian carcinoma cells increases survivin transcription which can be countered with a dominant-negative mutant, survivin T34A; a combination gene therapy strategy. 1278 62

Geranylgeranyltransferase I inhibitors (GGTIs) represent a new class of anticancer drugs. However, the mechanism by which GGTIs inhibit tumor cell growth is still unclear. Here, we demonstrate that GGTI-298 and GGTI-2166 induce apoptosis in both cisplatin-sensitive and -resistant human ovarian epithelial cancer cells by inhibition of PI3K/AKT and survivin pathways. Following GGTI-298 or GGTI-2166 treatment, kinase levels of PI3K and AKT were decreased and survivin expression was significantly reduced. Ectopic expression of constitutively active AKT2 and/or survivin significantly rescue human cancer cells from GGTI-298-induced apoptosis. Previous studies have shown that Akt mediates growth factor-induced survivin, whereas p53 inhibits survivin expression. However, constitutively active AKT2 failed to rescue the GGTIs downregulation of survivin. Further, GGTIs suppress survivin expression and induce programmed cell death in both wild-type p53 and p53-deficient ovarian cancer cell lines. These data indicate that GGTI-298 and GGTI-2166 induce apoptosis by targeting PI3K/AKT and survivin parallel pathways independent of p53. Owing to the fact that upregulation of Akt and survivin as well as inactivation of p53 are frequently associated with chemoresistance, GGTIs could be valuable agents to overcome antitumor drug resistance.
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PMID:Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis. 1473 5

Taxol is one of the most successful drugs for the treatment of cancer because of its ability to target tubulin, block cell cycle progression at mitosis, and induce apoptosis. Despite the success of Taxol, the development of drug resistance hampers its clinical applicability. Herein we report that beta-tubulin mutant, Taxol-resistant ovarian cancer cells exhibit defective mitotic response to Taxol, even at high concentrations that are sufficient to trigger apoptosis. This mitotic response-defective phenotype is independent of p53 status. We have found that survivin, the mitosis regulator and inhibitor of apoptosis protein, is deregulated in these Taxol-resistant cancer cells; Taxol fails to induce survivin levels and survivin phosphorylation in these cells, in contrast to their parental drug-sensitive counterparts. Exogenous expression of wild-type survivin is able to restore the mitotic response of the resistant cells to Taxol treatment. On the other hand, exogenous expression of dominant-negative survivin abrogates the Taxol-induced mitotic response in drug-sensitive cancer cells. We have also found that overexpression of the mitotic kinase Cdk1, which phosphorylates survivin, is unable to restore the Taxol-induced mitotic response in the resistant cells. Our results show the importance of survivin for the mitotic response in the context of Taxol resistance and provide novel insights into the mechanisms of mitotic arrest and apoptosis induced by microtubule-targeting agents.
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PMID:Survivin deregulation in beta-tubulin mutant ovarian cancer cells underlies their compromised mitotic response to taxol. 1557 81

We investigated the association of survivin expression with prognosis and other apoptosis-related biological factors in 110 primary ovarian cancer patients admitted to the Division of Gynecologic Oncology, Catholic University of Rome. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections by using polyclonal antibody ab469 for survivin, and mouse monoclonal antibodies (clone 124 and DO-7), for bcl-2 and p53, respectively. Cytoplasmic survivin immunoreaction was observed in 84.5% cases, while nuclear survivin immunostaining was observed in 29.1% cases. We failed to find any relationship between cytoplasmic survivin positivity rate and any of the parameters examined. Serous tumours showed a lower percentage of nuclear survivin positivity with respect to other histotypes (20.5 vs 48.6%, respectively; P-value=0.004). The percentage of nuclear survivin positivity was higher in cases subjected to primary tumour cytoreduction (43.5%), with respect to patients subjected to exploratory laparotomy (20%) (P=0.024). Bcl-2 and p53 were, respectively, expressed in 27.3 and 60.0% of the cases and their expression was not correlated with survivin status. During the follow-up period, progression and death of disease were observed in 68 (61.8%) and 53 (48.2%) cases, respectively. There was no difference in time to progression and overall survival according to survivin status in ovarian cancer patients. In conclusion, in our experience, the immunohistochemical assessment of survivin status does not seem to be helpful in the prognostic characterisation of ovarian cancer. A more in depth investigation of the complex physiology of divergent survivin variants is needed in order to clarify the biological and the clinical role of differentially located survivin isoforms.
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PMID:Survivin expression in ovarian cancer and its correlation with clinico-pathological, surgical and apoptosis-related parameters. 1565 41

Survivin, an anti-apoptosis gene that is abnormally overexpressed in a variety of human tumors, may play an important role in the carcinogenesis and drug resistance of cancer. This study was designed to explore the effects of liposome-survivin antisense oligonucleotide (Lip-ASODN) on the growth and apoptosis of human ovarian cancer cell lines, A2780 and SKOV3. To investigate the use of survivin as a therapeutic target on ovarian cancer, we carried out transfections with Lip-ASODN to induce apoptosis in ovarian cancer cell lines, A2780 and SKOV3. The expression of survivin mRNA and relative protein were evaluated separately by quantitative real-time RT-PCR and Western blot analysis. Cell proliferation inhibition was determined by methyl thiazolyl tetrazolium (MTT) assay, and the induced cell apoptosis was examined using flow cytometry (FCM) after Lip-ASODN transfection. Our results showed that the overexpression of survivin led to infinite carcino-proliferation, and survivin expression in the survivin-positive ovarian cancer cell line A2780 and SKOV3 cells was significantly and gradually reduced when transfected with Lip-ASODN at concentrations of 200, 400 and 600 nM by degrees. Lip-ASODN transfection induced greater apoptosis rates in the human ovarian cancer cell lines A2780 and SKOV3 (p<0.05). The growth inhibition and apoptotic rates of tumor cells change when treated with different concentrations of Lip-ASODN. The cell growth inhibition peak rate was reached when increasing Lip-ASODN concentration to 600 nM. Furthermore, time course evaluation showed that survivin protein expression was inhibited by Lip-ASODN within 12 h after transfection. We concluded that down-regulation of survivin by a targeted antisense oligonucleotide appears to be an effective gene therapy approach in the treatment of ovarian cancer.
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PMID:Induction of apoptosis in human ovarian epithelial cancer cells by antisurvivin oligonucleotides. 1594 1

Cyclin-dependent kinases (CDK) play a crucial role in the control of the cell cycle. Aberrations in the control of cell cycle progression occur in the majority of human malignancies; hence, CDKs are promising targets for anticancer therapy. Here, we define the cellular effects of the novel CDK inhibitor NU6140, alone or in association with paclitaxel, with respect to inhibition of cell proliferation and cell cycle progression and induction of apoptosis in HeLa cervical carcinoma cells and in comparison with purvalanol A. Both CDK inhibitors induced a concentration-dependent cell cycle arrest at the G(2)-M phase and an increase in the apoptotic rate, with a concomitant down-regulation of the antiapoptotic protein survivin, a member of the inhibitors of apoptosis protein family. Notably, the addition of NU6140 to paclitaxel-treated cells resulted in markedly increased cytotoxic effect and apoptotic response in comparison with the paclitaxel-purvalanol A combination (86 +/- 11% and 37 +/- 8%, respectively). Similarly, the extent of caspase-9 and caspase-3 activation in paclitaxel-NU6140-treated cells was approximately 4-fold higher than after the paclitaxel-purvalanol A combination. Moreover, an almost complete abrogation of the expression of the active, Thr(34)-phosphorylated form of survivin was observed in cells exposed to the paclitaxel-NU6140 combination. A synergistic effect of the paclitaxel-NU6140 combination, as a consequence of survivin inhibition and increased activation of caspase-9 and caspase-3, was also observed in OAW42/e ovarian cancer line but not in the derived OAW42/Surv subline ectopically expressing survivin. Results from this study indicate that NU6140 significantly potentiates the apoptotic effect of paclitaxel, with inhibition of survivin expression/phosphorylation as the potential mechanism.
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PMID:Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation. 1617 24

We have determined the methylation frequencies of 24 CpG islands of genes associated with DNA damage responses or with ovarian cancer in 106 stage III/IV epithelial ovarian tumors. We have analyzed this data for whether there is evidence of a CpG island methylator phenotype or associations of CpG island methylation with response to chemotherapy in advanced ovarian cancer. Frequent methylation was observed for OPCML, DCR1, RASSF1A, HIC1, BRCA1, and MINT25 (33.3%, 30.7%, 26.4%, 17.3%, 12.3%, and 12.0%, respectively), whereas no methylation was observed for APAF-1, DAPK, FANCF, FAS, P14, P21, P73, SOCS-3, and SURVIVIN. The remaining genes showed only a low frequency of methylation, <10%. Unsupervised gene shaving identified a nonrandom pattern of methylation for OPCML, DCR1, RASSF1A, MINT25, HIC1, and SFRP1, supporting the concept of concordant methylation of these genes in ovarian cancer. Methylation of at least one of the group of genes involved in DNA repair/drug detoxification (BRCA1, GSTP1, and MGMT) was associated with improved response to chemotherapy (P = 0.013). We have examined the frequency of a polymorphism in the DNA methyltransferase gene DNMT3b6, which has been previously reported to affect gene transcription and cancer risk. The genetic polymorphism in the DNMT3b6 gene promoter (at position -149) is not significantly associated with the concordant methylation observed, but is weakly associated with the overall frequency of methylation at the genes examined (P = 0.04, n = 56). This supports the hypothesis that genetic factors affecting function of DNMT genes may underlie the propensity of tumors to acquire aberrant CpG island methylation.
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PMID:CpG island methylation of DNA damage response genes in advanced ovarian cancer. 1620 69


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