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)

Although the deaminoneuraminic acid or KDN glycotope (2-keto-3-deoxy-D-glycero-D-galacto-nononic acid) is expressed in glycoconjugates that range in evolutionary diversity from bacteria to man, there is little information as to how this novel sugar is synthesized. Accordingly, biosynthetic studies were initiated in trout testis, an organ rich in KDN, to determine how this sialic acid is formed. These studies have shown that the pathway consists of the following three sequential reactions: 1) Man + ATP --> Man-6-P + ADP; 2) Man-6-P + PEP --> KDN-9-P + P(i); 3) KDN-9-P --> KDN + P(i). Reaction 1, catalyzed by a hexokinase, is the 6-O-phosphorylation of mannose to form D-mannose 6-phosphate (Man-6-P). Reaction 2, catalyzed by KDN-9-phosphate (KDN-9-P) synthetase, condenses Man-6-P and phosphoenolpyruvate (PEP) to form KDN-9-P. Reaction 3, catalyzed by a phosphatase, is the dephosphorylation of KDN-9-P to yield free KDN. It is not known if a kinase specific for Man (Reaction 1) and a phosphatase specific for KDN-9-P (Reaction 3) may exist in tissues actively synthesizing KDN. In this study, the KDN-9-P synthetase, an enzyme that has not been previously described, was identified as at least one key enzyme that is specific for the KDN biosynthetic pathway. This enzyme was purified 50-fold from rainbow trout testis and characterized. The molecular weight of the enzyme was estimated to be about 80,000, and activity was maximum at neutral pH in the presence of Mn(2+). N-Acetylneuraminic acid 9-phosphate (Neu5Ac-9-P) synthetase, which catalyzes the condensation of N-acetyl-D-mannosamine 6-phosphate and phosphoenol-pyruvate to produce Neu5Ac-9-P, was co-purified with the KDN-9-P synthetase. Substrate competition experiments revealed, however, that syntheses of KDN-9-P and Neu5Ac-9-P were catalyzed by two separate synthetase activities. The significance of these studies takes on added importance with the recent discovery that the level of free KDN is elevated in human fetal cord but not matched adult red blood cells and in ovarian cancer cells (Inoue, S., Lin, S-L., Chang, T., Wu, S-H., Yao, C-W., Chu, T-Y., Troy, F. A., II, and Inoue, Y. (1998) J. Biol. Chem. 273, 27199-27204). This unexpected finding emphasizes the need to understand more fully the role that free KDN and KDN-glycoconjugates may play in normal hematopoiesis and malignancy.
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PMID:Biosynthesis of KDN (2-keto-3-deoxy-D-glycero-D-galacto-nononic acid). Identification and characterization of a KDN-9-phosphate synthetase activity from trout testis. 1043 60

Mesothelin, a differentiation antigen, is a 40-kD glycosylphosphatidylinositol-linked cell-surface glycoprotein, that is present on the surface of normal mesothelium and is overexpressed in many patients with epithelial ovarian cancer and malignant mesotheliomas. Monoclonal antibody K1 is a murine immunoglobulin G1 that recognizes mesothelin. LysPE38QQR is a truncated form of Pseudomonas exotoxin that lacks the cell-binding domain, but retains the translocation and adenosine diphosphate-ribosylation domains. It has a single lysine residue near the amino terminus that is available for conjugation to antibodies. To prevent chemical conjugation of the antibody to lysine residues at the C-terminus of Pseudomonas exotoxin, the two lysine residues at positions 590 and 606 were mutated to glutamine, and the lysine residue at position 613 was mutated to arginine. Monoclonal antibody K1 was chemically conjugated with LysPE38QQR, by modifying the antibody with sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate and coupling it with SPDP N-succinimidyl 3-(2-pyridyldithio)propionate-modified LysPE38QQR. The resulting immunotoxin K1-LysPE38QQR was highly toxic to A431-K5 cells (a human epidermoid carcinoma cell line transfected with a mesothelin expression plasmid) with a half-maximal inhibitory concentration of 3-6 ng/mL. The immunotoxin had negligible activity against A431 cells, which do not express mesothelin (median inhibitory concentration > 100 ng/mL). This immunotoxin also caused complete regression of tumors in nude mice that received xenografts of mesothelin-positive human carcinomas. These results show that immunotoxins directed against mesothelin are a therapeutic option that merits further investigation for the treatment of ovarian cancer and malignant mesotheliomas.
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PMID:Anti-tumor activity of K1-LysPE38QQR, an immunotoxin targeting mesothelin, a cell-surface antigen overexpressed in ovarian cancer and malignant mesothelioma. 1091 57

The signaling pathway through which LHRH acts in endometrial and ovarian cancers is distinct from that in the anterior pituitary. The LHRH receptor interacts with the mitogenic signal transduction of growth factor receptors, resulting in down-regulation of expression of c-fos and proliferation. Only limited data are available on the cross-talk between LHRH receptor signaling and inhibition of mitogenic signal transduction. The present experiments were performed to analyze in endometrial and ovarian cancer cells: 1) whether mutations or splice variants of the LHRH receptor are responsible for differences in LHRH signaling, 2) the coupling of G protein subtypes to LHRH receptor, 3) the phosphotyrosine phosphatase (PTP) activation counteracting growth factor receptor tyrosine kinase activity. For these studies, the well characterized human Ishikawa and Hec-1A endometrial cancer cell lines and human EFO-21 and EFO-27 ovarian cancer cell lines were used, which express LHRH and its receptor. 1) Sequencing of the complementary DNA of the LHRH receptor from position 31 to position 1204, covering the complete coding region (position 56 to position 1042) showed that there are neither mutations nor splice variants of the LHRH receptor transcript in Ishikawa and Hec-1A endometrial cancer cells or in EFO-21 and EFO-27 ovarian cancer cells. 2) All analyzed cell lines except for the ovarian cancer cell line EFO-27 expressed both G proteins, alpha(i) and alpha(q), as shown by RT-PCR and Western blotting. In the EFO-27 cell line only G protein alpha(i), not G protein alpha(q), expression was found. Cross-linking experiments using disuccinimidyl suberate revealed that in the cell lines expressing G protein alpha(i) and G protein alpha(q), both G proteins coupled to the LHRH receptor. Inhibition of epidermal growth factor (EGF)-induced c-fos expression by LHRH, however, was mediated through pertussis toxin (PTX)-sensitive G protein alpha(i). Moreover, LHRH substantially antagonized the PTX-catalyzed ADP-ribosylation of G protein alpha(i). 3) Using a phosphotyrosine phosphatase assay based on molybdate-malachite green, treatment of quiescent EFO-21 and EFO-27 ovarian cancer cells and quiescent Ishikawa and Hec-1A endometrial cancer cells with 100 nM of the LHRH agonist triptorelin resulted in a 4-fold increase in PTP activity (P < 0.001). This effect was completely blocked by simultaneous treatment with PTX, supporting the concept of mediation through G protein alpha(i). As shown by quantitative Western blotting, EGF-induced tyrosine autophosphorylation of EGF receptors was reduced 45-63% after LHRH (100 nM) treatment (P < 0.001). This effect was completely blocked using the PTP inhibitor vanadate (P < 0.001). These results demonstrate that mutations or splice variants of the LHRH receptor in human endometrial and ovarian cancer cells are not responsible for the different signal transduction compared with that in pituitary gonadotrophs. We provide evidence that the tumor LHRH receptor couples to multiple G proteins, but the antiproliferative signal transduction is mediated through the PTX-sensitive G protein alpha(i). The tumor LHRH receptor activates a PTP counteracting EGF-induced tyrosine autophosphorylation of EGF receptor, resulting in down-regulation of mitogenic signal transduction and cell proliferation.
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PMID:Antiproliferative signaling of luteinizing hormone-releasing hormone in human endometrial and ovarian cancer cells through G protein alpha(I)-mediated activation of phosphotyrosine phosphatase. 1135 84

Because the efficacy of genetic prodrug activation therapy (GPAT) using herpes simplex virus thymidine kinase (tk)/ganciclovir (GCV) or Escherichia coli cytosine deaminase (cd)/5-fluorocytosine (5-FC) is not satisfied in early clinical trials and the mechanism of both the GPATs have been shown to lead to the activation of cell apoptotic pathway, we hypothesized that coexpression of procaspase-3, a central downstream executioner of apoptotic pathways, with cd-tk gene leads to enhanced cell death in ovarian cancer cells in vitro. Following transfection with the vectors encoding cd and tk, 5-FC and GCV treatments lead to greater cell death in procaspase-3-expressing clones of 3AO (3AO-caspase-3) than control cells (3AO-pcDNA3), as well as more rapid activation of caspase-3 and more rapid cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP). There is a greater degree of cell apoptotic rate in the procaspase-3-expressing clones than in control cells following the treatment with cd-tk/5-FC + GCV, and apoptosis is the main cell death form. None of these effects is seen following transfection with a control vector that does not encode tk and cd (pBTdel-279). The results strongly suggest that coexpression of procaspase-3 may lead to a significant enhancement of the efficacy of cd-tk/5-FC + GCV, and this strategy would be a novel and promising approach for the treatment of ovarian cancer.
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PMID:Procaspase-3 enhances the in vitro effect of cytosine deaminase-thymidine kinase disuicide gene therapy on human ovarian cancer. 1644 27

Epidemiologic studies show a correlation between increased consumption of fruits and vegetables with reduced risk of ovarian cancer. One major bioactive compound found in cruciferous vegetables, particularly broccoli, is sulforaphane, derived from the breakdown of glucoraphanin. We observed potent antiproliferative effects of sulforaphane on human ovarian cancer cell line SKOV3 (IC(50) 40 micromol/L) and mouse ovarian cancer cell lines C3 and T3 (IC(50) 25 micromol/L each) by cell viability assays. The loss of viability is reflected by a down-regulation of cell cycle transition regulators cyclin D1, cyclin-dependent kinase 4 (cdk4), and cdk6. The upstream mediators of sulforaphane effects on the cell cycle in ovarian cancer are still unknown. However, because the Akt signal transduction pathway is overactivated in ovarian cancer, we investigated the effects of sulforaphane on this prosurvival pathway. Both total Akt protein and active phosphorylated levels of Akt (Ser(473)) and phosphoinositide 3-kinase were significantly decreased in sulforaphane-treated SKOV3, C3, and T3 cells with a concomitant inhibition of Akt kinase activity by sulforaphane in SKOV3 and C3 cells. This inhibitory effect of sulforaphane leads to a potent induction of apoptosis in all three cell lines, along with the cleavage of poly(ADP)ribose polymerase. Our study is the first to report the antiproliferative effects of sulforaphane in ovarian cancer and identifying the Akt pathway as a target of sulforaphane, with implications for the inhibition of carcinogenesis by diet-based chemoprevention.
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PMID:Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells. 1723 92

ARLTS1 has been identified in chromosome 13q14 as a tumor suppressor gene of the adenosine diphosphate-ribosylation factor family with pro-apoptotic characteristics. The ARLTS1 mutation Trp149Stop and Cys148Arg have been shown to be associated with familial cancers, but limited information is available regarding the impact of ARLTS1 variants on familial ovarian cancer (OC). The aim of this study was to evaluate the ARLTS1 genetic variants associated with familial OC risk in China. We genotyped 85 OC patients with family ovarian/breast history, 80 sporadic OC patients, and 120 controls from general population by denaturing high-performance liquid chromatography screening analysis followed by direct sequencing of the conspicuous polymerase chain reaction products. ARLTS1 Cys148Arg revealed a significant association with an increased risk of familial OC compared with both sporadic cases and controls in a dose-dependent manner (P = 0.0031 and 0.012, respectively). In the clinical-pathological study, our results support previous data in demonstrating that familial OC was associated with younger age at diagnosis (49.7 years vs 53.3 years; P = 0.014), higher proportion of tumors of advanced stages (81.2% vs 67.5%; P = 0.033), and higher rates of serous adenocarcinomas (76.4% vs 53.8%; P = 0.028) compared with sporadic OC cases. To investigate the association between genetic variants of ARLTS1 and the clinical-pathological characteristics of familial OC, we identified a significantly higher proportion of serous adenocarcinoma (55/67, 82.1%) and higher rates of advanced stage tumors (88.1% vs 55.6%; P = 0.004) in ARLTS1 Cys148Arg carriers. We showed a significantly increased risk of familial OC for ARLTS1 Cys148Arg variant, which indicate that ARLTS1 may play a role in familial OC.
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PMID:Association of the ARLTS1 variants with familial ovarian cancer risk in China. 1950 54

Breast cancer is one of the most frequent tumors in women, and BRCA1 and BRCA2 genes play a major role in the hereditary susceptibility for this disease. Until the age of 70 women carrying a mutation in BRCA1 or BRCA2 gene have a 45-85% probability of developing breast cancer, and 11-62% probability of developing ovarian cancer. Mutation carrier's tumors contain nonfunctional BRCA1 or BRCA2 genes, which in healthy cells are involved in DNA repair. These tumors show an increased sensitivity to DNA damaging chemical agents and to PARP (poly(adenosine diphosphate-ribose) polymerase1) inhibitors. New targeted therapies already in use are directed toward tumors of mutation carriers. Successful treatment is most likely to be achieved through cooperation of a pathologist, oncologist and a genetic laboratory performing BRCA genes mutation screening.
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PMID:[Molecular basis of breast cancer related to BRCA 1 and BRCA2 genes: characteristics and targeting therapy]. 2035 58

The purpose of this study was to evaluate the anticancer potency and mechanism of a novel difluorodiarylidenyl piperidone (H-4073) and its N-hydroxypyrroline modification (HO-3867) in human ovarian cancer. Studies were done using established human ovarian cancer cell lines (A2870, A2780cDDP, OV-4, SKOV3, PA-1, and OVCAR3) as well as in a murine xenograft tumor (A2780) model. Both compounds were comparably and significantly cytotoxic to A2780 cells. However, HO-3867 showed a preferential toxicity toward ovarian cancer cells while sparing healthy cells. HO-3867 induced G(2)-M cell cycle arrest in A2780 cells by modulating cell cycle regulatory molecules p53, p21, p27, cyclin-dependent kinase 2, and cyclin, and promoted apoptosis by caspase-8 and caspase-3 activation. It also caused an increase in the expression of functional Fas/CD95 and decreases in signal transducers and activators of transcription 3 (STAT3; Tyr705) and JAK1 phosphorylation. There was a significant reduction in STAT3 downstream target protein levels including Bcl-xL, Bcl-2, survivin, and vascular endothelial growth factor, suggesting that HO-3867 exposure disrupted the JAK/STAT3 signaling pathway. In addition, HO-3867 significantly inhibited the growth of the ovarian xenografted tumors in a dosage-dependent manner without any apparent toxicity. Western blot analysis of the xenograft tumor tissues showed that HO-3867 inhibited pSTAT3 (Tyr705 and Ser727) and JAK1 and increased apoptotic markers cleaved caspase-3 and poly ADP ribose polymerase. HO-3867 exhibited significant cytotoxicity toward ovarian cancer cells by inhibition of the JAK/STAT3 signaling pathway. The study suggested that HO-3867 may be useful as a safe and effective anticancer agent for ovarian cancer therapy.
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PMID:Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts. 2044 15

To investigate the anticancer effects of the novel hydroxamic acid-derived histone deacetylase (HDAC) inhibitor MHY218, its efficacy was compared to that of suberoylanilide hydroxamic acid (SAHA) in human ovarian cancer cells. The anticancer effects of MHY218 on cell viability, cell cycle regulation and apoptosis were investigated. In addition, MHY218 or SAHA was administered for 28 days in a tumor carcinomatosis model with SKOV-3 cells. MHY218 significantly reduced the expression of HDAC4 and HDAC7 in SKOV-3 cells. Similarly, MHY218 also inhibited total HDAC, HDAC1, HDAC4 and HDAC7 enzyme activity in a concentration-dependent manner. The anticancer effect of MHY218 (IC50, 3.2 microM) was more potent than SAHA (IC50, 3.9 microM) in suppressing the SKOV-3 cell viability. Moreover, MHY218 markedly increased expression of p21WAF1/CIP1, which acts as a cell cycle inhibitor. Cell cycle analysis showed that the high dose (5 microM) of MHY218 significantly increased the proportion of cells in the G2/M phase. In particular, MHY218 and SAHA significantly increased the sub-G1 population and the number of TUNEL-positive apoptotic cells compared with those in the untreated control. These results were confirmed by analysis of poly-ADP ribose polymerase (PARP), where MHY218 and SAHA increased the level of an 85-kDa fragment resulting from PARP cleavage as well as caspase-3 activity. Likewise, MHY218-induced apoptosis through caspase-3 activation was confirmed by the increase in the release of cytochrome c and Bax/Bcl-2 ratio. In an in vivo tumor carcinomatosis model, the growth of transplanted SKOV-3 cells was inhibited by 71% after treatment with MHY218 (10 mg/kg), whereas SAHA (25 mg/kg) suppressed growth by 48%. These results indicate that MHY218 is a potent HDAC inhibitor that targets regulating multiple aspects of cancer cell death and might have preclinical value in ovarian cancer chemotherapy, warranting further investigation.
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PMID:Anticancer effects of the MHY218 novel hydroxamic acid-derived histone deacetylase inhibitor in human ovarian cancer cells. 2059 69

Data on the use of PET in women with genetic or familial high-risk for breast or ovarian cancer are scarce. Open issues include the complementary use of dedicated breast-PET scanners in patients at high-risk for breast cancer, the relation between pathological characteristics of cancer diagnosed in BRCA carriers and (18)F-fluorodeoxyglucose ((18)F-FDG)-avidity, and the predictive value of PET in patients at high-risk for ovarian cancer presenting with a pelvic mass or potential chemical markers. Therefore, the use of PET in high-risk patients with unproven malignant disease needs to be investigated in well designed clinical trials. Once breast or ovarian cancer is diagnosed, indications for (18)F-FDG-PET or PET-CT imaging are similar for high-risk patients and patients with sporadic cancer. However, PET can provide data that are beyond tumour detection per se. Future directions of PET in high-risk patients might include monitoring the response of BRCA carriers to new treatments such as poly-ADP ribose polymerase (PARP) inhibitors, personalisation of treatment, and the use of new PET tracers to investigate the tissue changes related to increased risk for breast and ovarian cancer.
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PMID:PET in women with high risk for breast or ovarian cancer. 2061 54


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