Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Src tyrosine kinase has been found to be overexpressed and activated in a high proportion of ovarian cancers and ovarian cancer cell lines. Furthermore, Src activation is associated with activation of growth and survival signaling pathways. The present study was conducted in order to determine the effects of Src inhibition on ovarian cancer cell survival in response to chemotherapeutic agents. Inhibition of Src, either pharmacologically or through expression of a Src dominant-negative fusion construct, enhanced the cytotoxicity of two different classes of chemotherapeutics: paclitaxel and cisplatinum, in both mouse and human ovarian cancer cells. Interestingly, Src inhibition also restored sensitivity to drug-resistant ovarian cancer cells. The increased cytotoxicity in response to Src inhibition was associated with a large increase in processing and activation of caspase-3. The activation of caspase-3 seems to be independent of cytochrome c release and caspase-9 activation. The present study indicates that Src tyrosine kinase may provide an important target for small molecule inhibition in ovarian cancer.
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PMID:Src inhibition enhances paclitaxel cytotoxicity in ovarian cancer cells by caspase-9-independent activation of caspase-3. 1571 93

Human Kruppel-like factor 2 (KLF2) is a Cys(2)/His(2) zinc-finger-containing transcriptional factor, which is involved in multiple cellular pathways. Utilizing gene expression profiling to identify aberrantly expressed genes in ovarian cancer, we found that KLF2 was significantly and specifically downregulated in ovarian tumors. After reintroducing KLF2 into ovarian cancer cell lines, we observed decreased cell growth and increased sensitivity to DNA damage-induced apoptosis. Analysis of genes that could be potential targets of KLF2 revealed that KLF2 negatively regulated WEE1 expression. WEE1 encodes a tyrosine kinase that regulates the G2/M cell cycle transition. Expression of KLF2 markedly repressed the transcription of WEE1 by directly binding to an SP1/CPBP motif located between -252 bp and the start codon of the WEE1 promoter. Both activation and zinc-finger domains of KLF2 were required for this suppression of Wee1 expression. In addition, we demonstrated that Wee1 expression prevents cancer cells from undergoing apoptosis in response to DNA damage; however, this resistance was abolished by coexpression of KLF2, which inhibits WEE1 transcription. Thus, the level of WEE1 is regulated by KLF2 and enhanced KLF2 expression sensitizes cells to DNA damage-induced apoptosis.
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PMID:Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis. 1573 66

Most women with epithelial ovarian cancer are diagnosed with advanced disease. Despite surgery and initial tumor reduction by standard chemotherapy, the tumors frequently recur and the patients eventually die of their disease. New drugs that inhibit tyrosine kinase receptors (TKRs) are being investigated for treatment and this study was undertaken to determine the expression and mutational state for 3 TKRs (c-kit, platelet-derived growth factor receptor [PDGFR] alpha, and PDGFR beta) in ovarian cancer. Tissue arrays containing 84 epithelial ovarian tumors were studied by immunohistochemistry with antibodies specific for c-kit, PDGFR alpha, and PDGFR beta. Immunoreactivity was detected in 78% of the tumor to at least one TKR. PDGFR alpha was expressed in the largest percentage of ovarian tumors (58%) whereas 29% expressed PDGFR beta. Two commercial antibodies against c-kit were studied and 33% of the tumors stained with one but only 6% were interpreted as positive with the second antibody. Activation of TKRs may occur through mutations but, by sequence analysis, no mutations were detected in 6 ovarian tumors with elevated immunoreactivity for each of the TKRs (c-kit, PDGFR alpha, and PDGFR beta). Tyrosine kinase receptors could also be activated through autocrine or paracrine stimulation of receptor by its ligand. Of 43 (35%) tumors tested for both c-kit receptor and its ligand (stem cell factor), 15 expressed both proteins indicating the possibility that this autocrine stimulation feedback loop is a factor in the growth of some ovarian cancers. This study demonstrates that PDGFR alpha, PDGFR beta, and c-kit are expressed in a high percentage of epithelial ovarian cancers suggesting that tyrosine kinase inhibitors may be useful in the treatment of these tumors.
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PMID:Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian cancers. 1579 68

The overexpression of the epidermal growth factor receptor (EGFR) is associated with a poor prognosis in ovarian cancer. The dominant-negative EGFR (EGFR-DNR) is a truncated receptor that lacks the tyrosine kinase domain and is devoid of signaling capability. This study tested the effects of a EGFR-DNR approach in ovarian cancer cells. NuTu-19, a rat ovarian cancer cell line was rendered resistant to cisplatin. Both NuTu-19 and resistant cells were infected with a retroviral vector containing the EGFR-DNR. NuTu-19 and NuTu-DNR (NuTu-19 cells expressing the EGFR-DNR) were injected into Fisher 344 immunocompetent rats. Western blot analyses were used to assess signal transduction pathways. All rats injected with NuTu-DNR cells remained healthy following tumor injection. In contrast, 100% of the rats injected with the NuTu-19 and NuTu-Sham (NuTu-19 cells expressing an empty vector) died of disease progression at the end of 15 weeks (P = 0.00009). On Western blot analysis, both NuTu-19 and NuTu-Sham cells showed a strong activation of mitogen-activated protein kinase (MAPK) after exposure to EGF. Cisplatin-resistant cell lines showed an enhanced EGF stimulatory effect via the MAPK pathway compared with parental cells. The EGFR-DNR significantly reduced the ability of EGF to induce cell signaling through the MAPK pathway. Lastly, the EGFR-DNR can partially reverse cisplatin resistance in drug-resistant cells. The EGFR-DNR approach suggests that EGFR confers a growth advantage to NuTu-19 cells in vivo. Thus, EGFR blockade may ultimately prove to be a useful therapeutic tool in the treatment of cisplatin-sensitive and cisplatin-resistant ovarian cancers.
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PMID:Suppression of ovarian cancer cell tumorigenicity and evasion of Cisplatin resistance using a truncated epidermal growth factor receptor in a rat model. 1583 56

Specific and reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib are clinically active in advanced or metastatic NSCLC and both are approved in various countries for the treatment of patients that failed prior chemotherapy. Erlotinib has also prolonged survival in pancreatic cancer patients when added to gemcitabine and regulatory approval in this disease is being sought. Additional promising activity has been seen in other tumor types, such as ovarian cancer or head and neck malignancies, and phase III trials in these malignancies are ongoing or planned. Despite these successes, these agents have exhibited anecdotal or modest activity when used as single agents in unselected patients with various other tumor types. We have learned that the clinical development of these agents is far from simple and we need to better understand biological and clinical criteria for patient selection and how to best use the different available agents. The recent discovery of EGFR mutations and the potential identification of other markers that might predict patient response could help to optimize the use of these agents in the future. Irreversible EGFR inhibitors, dual EGF/HER2 and pan-ErbB receptor inhibitors may have greater antitumor activity although the tolerance of these compounds compared to specific EGFR TKIs needs further characterization. HER2 specific TKIs are also in development. Lapatinib, a dual EGFR/HER2 TK inhibitors, is particularly promising in breast cancer. Newer agents, such as BMS-599626, have recently entered into the clinic. In addition to the use of these agents as single agents, many clinical studies are addressing the role of combining them with hormonal agents, biological agents or chemotherapy.
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PMID:Small molecules with EGFR-TK inhibitor activity. 1585 87

Ovarian cancer (OC) is the leading cause of death in gynecologic diseases in which there is evidence for a complex chemokine network. Chemokines are a family of proteins that play an important role in tumor progression influencing cell proliferation, angiogenic/angiostatic processes, cell migration and metastasis, and, finally, regulating the immune cells recruitment into the tumor mass. We previously demonstrated that astrocytes and glioblastoma cells express both the chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1), and that SDF-1alpha treatment induced cell proliferation, supporting the hypothesis that chemokines may play an important role in tumor cells' growth in vitro. In the present study, we report that CXCR4 and SDF-1 are expressed in OC cell lines. We demonstrate that SDF-1alpha induces a dose-dependent proliferation in OC cells, by the specific interaction with CXCR4 and a biphasic activation of ERK1/2 and Akt kinases. Our results further indicate that CXCR4 activation induces EGF receptor (EGFR) phosphorylation that in turn was linked to the downstream intracellular kinases activation, ERK1/2 and Akt. In addition, we provide evidence for cytoplasmic tyrosine kinase (c-Src) involvement in the SDF-1/CXCR4-EGFR transactivation. These results suggest a possible important "cross-talk" between SDF-1/CXCR4 and EGFR intracellular pathways that may link signals of cell proliferation in ovarian cancer.
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PMID:Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation. 1592 80

Src tyrosine kinase has been found to be overexpressed in both mouse and human ovarian cancer cells as well as in human primary ovarian cancers. Furthermore, Src inhibition sensitizes ovarian cancer cells to chemotherapeutic agents such as paclitaxel and cisplatin. Interestingly, Src inhibition has also been shown to resensitize paclitaxel-resistant cells to the cytotoxic effects of paclitaxel. The current study was undertaken in an effort to determine the mechanism by which Src resensitizes drug-resistant ovarian cancer cells. The paclitaxel-resistant human (CaOV3TaxR) and mouse (ID8TaxR) ovarian cancer cell lines express large amounts of the multidrug resistance-1 (MDR-1) protein compared with the paclitaxel-sensitive parent cell lines. Src inhibition had no effect on MDR-1 protein expression. Furthermore, Src inhibition did not affect MDR-1 function as determined by rhodamine 123 and paclitaxel uptake or retention. Coinhibition of both Src and MDR-1 synergistically enhanced paclitaxel-induced cytotoxicity in paclitaxel-resistant ovarian cancer cell lines. Inhibition of Src enhanced microtubule stabilization in paclitaxel-resistant ovarian cancer cells treated with paclitaxel without affecting expression of beta-tubulin isotypes and resulted in multipolar spindle formation and apoptosis. These results show that Src inhibition restores paclitaxel sensitivity to paclitaxel-resistant ovarian cancer cells by an MDR-independent mechanism, possibly by decreasing the critical intracellular concentration at which paclitaxel induces tubulin stabilization and bundling. Src tyrosine kinase may provide a viable target for therapeutic intervention in drug-resistant ovarian cancer.
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PMID:SRC tyrosine kinase and multidrug resistance protein-1 inhibitions act independently but cooperatively to restore paclitaxel sensitivity to paclitaxel-resistant ovarian cancer cells. 1628 28

The erbB-2 gene encodes tyrosine kinase receptor p185(neu). Overexpression of erbB-2 plays a key role in tumorigenesis and the progression of tumors such as breast cancer and ovarian cancer. Our investigation suggests that the anti-inflammatory agent N-(4-ethoxyphenol)-2-hydroxy-acid amide (SUCI02) reversibly represses tyrosine phosphorylation of erbB-2 in a dose-dependent manner, with half maximal inhibition occurring at a concentration of 21.05 micromol/L without reduced erbB-2 receptor expression. Activation of mitogen-activated protein kinase and protein kinase B, downstream molecules of the erbB-2-mediated signal transduction pathway, was inhibited following exposure to SUCI02. In contrast, tyrosine phosphorylation of epidermal growth factor receptor (EGFR) was relatively unaffected by SUCI02. Proliferation of erbB-2-overexpressing BT474 cells was inhibited to a greater extent than proliferation of EGFR-overexpressing A431 cells following exposure to SUCI02. SUCI02 induced cell cycle arrest in G(1) phase with upregulation of p27 and downregulation of pRb phosphorylation. Systemic administration of SUCI02 in nude mice resulted in inhibition of erbB-2 tyrosine kinase phosphorylation of subcutaneous human breast cancer BT474 xenografts. We conclude that SUCI02 inhibits erbB-2 tyrosine kinase phosphorylation in vitro and in vivo, shuts down the erbB-2 downstream pathway and induces cell cycle arrest in G(1) phase. These results suggest that SUCI02 is a potential novel anticancer agent that deserves further investigation. (Cancer Sci 2006; 97: 84-89).
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PMID:SUCI02 inhibits the erbB-2 tyrosine kinase receptor signaling pathway and arrests the cell cycle in G1 phase in breast cancer cells. 1636 26

The Ras gene family has been implicated in the development of many human epithelial cancers. Mutations in K-ras or its downstream mediator BRAF have been detected in about two thirds of low-grade serous carcinomas and borderline serous tumors; mutations in K-ras are also often present in benign and invasive mucinous ovarian cancers. Although the oncogenic allele H-ras(V12) is present in only approximately 6% of ovarian cancers, physiologically activated H-ras protein is commonly detected in human ovarian cancer, presumably because of an increase in upstream signals from tyrosine kinase growth factor receptors such as Her-2/neu, despite the lack of a Ras mutation. The mechanisms by which ras oncogenes transform human epithelial cells are not clear. The methods described here are what we use to culture human ovarian surface epithelial cells, to immortalize those cells, and to transform the immortalized cells with oncogenic H-ras or K-ras. These Ras-transformed human ovarian surface epithelial cells form tumors in nude mice and recapitulate many features of human ovarian cancer, thus providing an excellent model system for studying the initiation and progression of human ovarian cancer.
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PMID:Use of Ras-transformed human ovarian surface epithelial cells as a model for studying ovarian cancer. 1675 60

Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma.
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PMID:Antiangiogenic and antitumor effects of SRC inhibition in ovarian carcinoma. 1695 Nov 77


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