Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have demonstrated that ionizing radiation activate existing cellular response pathways involving protein kinases. These pathways mediate the cytotoxic and cytoprotective responses of cell death and cell survival, respectively. Cytoprotective responses involve dominantly mitogen-activated protein kinase (MAPK) through radiation-induced activation of EGF receptors and may stimulate cell proliferation if radiation-induced damage is successfully repaired. Similarly, overexpression of EGF receptor family members or their activation by ligands expressed at normal levels may also confer radioresistance. Recent encouraging results indicate that EGF receptor inhibitors such as antibodies or small molecule tyrosine-kinase inhibitors may be effective radiosensitizers in tumors. Within the antibody class of EGF receptor inhibitors are monoclonal antibodies such as cetuximab and trastuzumab. These agents have a common target of the extracellular domain of the EGF receptor. Striking synergistic antitumor effects on human epidermoid and on adenocarcinoma cancer-cell xenografts have been observed when cetuximab treatment is combined with radiotherapy. Promising results have also been obtained from the first clinical trial with cetuximab and radiotherapy in squamous-cell carcinoma of the head and neck. Trastuzumab has been poorly studied in combination with radiotherapy but showed an increased radiosensitivity of HER2-overexpressing breast cancer cells as measured by in vitro colony-forming assays. The mechanism of radiosensitization appears to involve DNA repair. There are well over a dozen agents in the small molecule tyrosine-kinase inhibitor category but the preclinical studies in combination with radiotherapy exist only for ZD1839 and CI1033. Preliminary studies confirm the capacity of ZD1839 and radiotherapy to produce a highly significant increase in tumor growth inhibition when compared to treatment with either modality alone. Another member of the quinazoline class of small molecule tyrosine-kinase inhibitors (CI1033) has recently been examined for its impact in conjunction with radiation in a series of HER-overexpressing breast cancer cell lines. This molecule inhibits tyrosine-kinase activity in all four members of the HER family, and preclinical studies showed a synergistic interaction of CI1033 with ionizing radiation. Finally, EGF receptor family member inhibitors may themselves be effective radiosensitizers and their use in future clinical investigations are based on a solid radiobiological rational.
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PMID:[Radiotherapy and inhibitors of epidermal growth factor receptor: preclinical findings and preliminary clinical trials]. 1476 41

The majority of cancer cells derived from epithelial tissue express Lewis-Y (LeY) type difucosylated oligosaccharides on their plasma membrane. This results in the modification of cell surface receptors by the LeY antigen. We used the epidermal growth factor (EGF) receptor family members ErbB1 and ErbB2 as model systems to investigate whether the sugar moiety can be exploited to block signaling by growth factor receptors in human tumor cells (i.e., SKBR-3 and A431, derived from a breast cancer and a vulval carcinoma, respectively). The monoclonal anti-LeY antibody ABL364 and its humanized version IGN311 immunoprecipitated ErbB1 and ErbB2 from detergent lysates of A431 and SKBR-3, respectively. ABL364 and IGN311 blocked EGF- and heregulin-stimulated phosphorylation of mitogen-activated protein kinase [MAPK = extracellular signal-regulated kinase 1/2] in SKBR-3 and A431 cells. The effect was comparable in magnitude with that of trastuzumab (Herceptin) and apparently noncompetitive with respect to EGF. Stimulation of MAPK by ErbB was dynamin dependent and contingent on receptor internalization. ABL364 and IGN311 changed the intracellular localization of fluorescent EGF-containing endosomes and accelerated recycling of intracellular [(125)I]EGF to the plasma membrane. Taken together, these observations show that antibodies directed against carbohydrate side chains of ErbB receptors are capable of inhibiting ErbB-mediated signaling. The ability of these antibodies to reroute receptor trafficking provides a mechanistic explanation for their inhibitory action.
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PMID:Antibodies directed against Lewis-Y antigen inhibit signaling of Lewis-Y modified ErbB receptors. 1487 42

We have examined overexpression of the human epidermal growth factor receptor 2 (HER2) to determine if it modifies the anti-proliferative effect of transforming growth factor (TGF)-beta against MCF-10A human mammary epithelial cells. Exogenous TGF-beta inhibited cell proliferation and induced Smad-dependent transcriptional reporter activity in both MCF-10A/HER2 and MCF-10A/vector control cells. Ligand-induced reporter activity was 7-fold higher in HER2-overexpressing cells. In wound closure and transwell assays, TGF-beta induced motility of HER2-transduced, but not control cells. The HER2-blocking antibody trastuzumab (Herceptin) prevented TGF-beta-induced cell motility. Expression of a constitutively active TGF-beta type I receptor (ALK5(T204D)) induced motility of MCF-10A/HER2 but not MCF-10A/vector cells. TGF-beta-induced motility was blocked by coincubation with either the phosphatidylinositol 3-kinase inhibitor LY294002, the mitogen-activated protein kinase (MAPK) inhibitor U0126, the p38 MAPK inhibitor SB202190, and an integrin beta(1) blocking antibody. Rac1 activity was higher in HER2-overexpressing cells, where both Rac1 and Pak1 proteins were constitutively associated with HER2. Both exogenous TGF-beta and transduction with constitutively active ALK5 enhanced this association. TGF-beta induced actin stress fibers as well as lamellipodia within the leading edge of wounds. Herceptin blocked basal and TGF-beta-stimulated Rac1 activity but did not repress TGF-beta-stimulated transcriptional reporter activity. These data suggest that 1) overexpression of HER2 in nontumorigenic mammary epithelial is permissive for the ability of TGF-beta to induce cell motility and Rac1 activity, and 2) HER2 and TGF-beta signaling cooperate in the induction of cellular events associated with tumor progression.
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PMID:Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. 1504 65

Trastuzumab (herceptin) and pertuzumab (Omnitarg, 2C4) are recombinant humanized monoclonal antibodies that target different extracellular regions of the HER-2 tyrosine kinase receptor. We explored combination effects of these agents in the HER-2-overexpressing BT474 breast cancer cell line. Trastuzumab and 2C4 synergistically inhibited the survival of BT474 cells, in part, because of increased apoptosis. Trastuzumab increased 2C4-mediated disruption of HER-2 dimerization with the epidermal growth factor receptor and HER-3. Combination drug treatment reduced levels of total and phosphorylated HER-2 protein and blocked receptor signaling through Akt but did not affect mitogen-activated protein kinase. These results suggest that combining HER-2-targeting agents may be a more effective therapeutic strategy in breast cancer rather than treating with a single HER-2 monoclonal antibody.
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PMID:The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. 1505 83

rViscumin is a recombinant mistletoe lectin under clinical investigation as new anti-cancer drug. The relationship between oncogene, e.g., HER-2/neu (c-erbB2) receptor activation and tumor cell chemosensitivity, is of considerable importance to better predict the response to chemotherapy. Here, we analyze the cellular and molecular effects of HER-2 expression on rViscumin chemotoxicity in SKOV-3 cells. We show that selective depletion of HER-2 by ribozyme-targeting markedly decreases cellular sensitivity towards rViscumin. These findings are confirmed by treatment with the well-established inhibitory HER-2 antibody trastuzumab (Herceptin). Using clonal ribozyme-transfected cell lines, we establish a 'HER-2 gene dose' dependence of rViscumin cytotoxicity, which is due to differential induction of apoptosis and is not mediated by cell cycle alterations or altered cellular rViscumin binding/internalization. We further demonstrate an rViscumin-mediated, HER-2-dependent down-regulation of bcl-2 and the dose-dependent activation of members of the MAPK family, p42/44, SAPK/JNK, and p38, but not of caspases-3 and -7.
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PMID:Cytotoxicity of the novel anti-cancer drug rViscumin depends on HER-2 levels in SKOV-3 cells. 1535 91

Current treatment options for ovarian cancer, which is one of the most widespread gynecological malignancies, are limited, mainly because patients with advanced-stage disease often develop resistance to chemotherapeutics. In breast cancer cells, several studies suggest that overexpression of the human epidermal growth factor receptor-2 (HER-2) leads to increased resistance against certain, but not all cytotoxic drugs. In ovarian carcinoma, conflicting data on the correlation of HER-2 expression and tumor cell sensitivity exist. In this paper, we explore the role of HER-2 expression and signaling levels pertaining to paclitaxel (Taxol) chemoresistance by applying three different and independent strategies in SKOV-3 ovarian carcinoma cells. Firstly, we show that treatment with the HER-2 inhibitory antibody trastuzumab (Herceptin), which is well established in tumor therapy, results in markedly increased, rather than decreased, cellular paclitaxel resistance. Next, we present two newly developed low molecular weight inhibitors of HER-2 tyrosine kinase activity, D-69491 and D-70166. With both drugs, the decrease in cellular paclitaxel sensitivity upon HER-2 inhibition is confirmed. Finally, for more detailed analysis we stably downregulate HER-2 expression by ribozyme-targeting. Using clonal ribozyme-transfected SKOV-3 cells with different residual HER-2 levels, we establish a 'HER-2 gene dose effect' of paclitaxel cytotoxicity. We show that this effect is due to differential induction of apoptosis and differential cell cycle inhibition by paclitaxel. Finally, paclitaxel- or HER-2-mediated alterations in the phosphorylation of MAP kinases p42/44, Stress-activated protein kinase/Jun-terminal kinase (SAPK/JNK), and p38, and effects on the activation of caspase-3, caspase-7, and bcl-2 are discussed. We conclude that paclitaxel cytotoxicity in SKOV-3 cells is 'HER-2 dose-dependent' and identify cell proliferation as one underlying cellular event of this effect.
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PMID:Inhibition of HER-2 by three independent targeting strategies increases paclitaxel resistance of SKOV-3 ovarian carcinoma cells. 1570 Jan 18

We examined the effects of Herceptin, a bioengineered monoclonal antibody directed against Her-2/neu oncogene on skeletal metastasis using a xenograft model of breast cancer. Treatment of Her-2 overexpressing human breast cancer cells BT-474 with Herceptin caused a dose-dependent decrease in cell proliferation. In in vivo studies, BT-474 cells (1 x 10(5)) were injected into the left ventricle of female BALB/c nu/nu mice. Intraperitoneal (i.p.) infusion of Herceptin (1 mg/kg twice a week for 5 weeks) from the day of tumor cell inoculation or at the time of radiologically detectable skeletal metastasis either slowed the development or prevented the progression of skeletal metastasis as compared to control groups of animals receiving nonspecific IgG. Bone histological analysis of long bones showed the ability of Herceptin to reduce the ratio of tumor volume to bone volume as well as mitotic index, effects that were more pronounced when Herceptin treatment was initiated from the day of tumor cell inoculation. While immunohistochemical analysis of long bones showed no difference in the production of Her-2, phosphorylated (P) Her-2 and MAPK, a significantly lower level of P-MAPK was seen in bones of Herceptin treated animals. These studies demonstrate the ability of Herceptin to inhibit the development and abrogate the progression of skeletal metastases associated with breast cancer by blocking the HER-2-mediated signaling pathways.
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PMID:Effect of Herceptin on the development and progression of skeletal metastases in a xenograft model of human breast cancer. 1609 54

Extensive interactions between estrogen receptor alpha (ERalpha) and HER2 signaling pathways have been described. Using BT-474 human breast cancer cells, we have previously shown that the combination of tamoxifen (TAM) and Herceptin results in strong synergistic growth inhibition, enhancement of G(0)-G(1) cell cycle accumulation, inhibition of HER2 activity and a cytostatic effect without cell death. To further examine the underlying mechanism of synergy, we investigated the effect of this drug combination on ERalpha function and growth factor downstream signaling. TAM caused a small increase in ERalpha levels while Herceptin had no effect, and both drugs caused an increase in the level of Ser118-phosphorylated ERalpha. However, both TAM and Herceptin individually inhibited ERalpha transcriptional activity, although the combination did not have a greater effect than either single agent. Herceptin inhibited MAPK and Akt activity, while TAM had no effect on these either as a single agent or when added to Herceptin. Using a BALB/c athymic BT-474 in vivo xenograft model, the drug combination (Herceptin 0.3 mg/kg i.p. twice weekly, TAM 1.0 mg/mouse i.p. three times per week) showed a greater inhibition of tumor growth compared to either single agent. Tumor extracts and fixed sections were examined at the end of the treatment period for treatment-specific alterations: we noted a paradoxical proliferation-inducing effect of TAM that was reversed by the addition of Herceptin. Our results indicate that combined targeting of both peptide growth factor receptors and ERalpha represents a promising breast cancer treatment strategy.
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PMID:In vitro and in vivo effects of combination of Trastuzumab (Herceptin) and Tamoxifen in breast cancer. 1615 96

Although first-line chemotherapy induces complete clinical remission in many cases of epithelial ovarian cancer, relapse usually occurs 18-28 months from diagnosis owing to micrometastases. The present study aimed to evaluate the effect of trastuzumab on disease-free and overall survival in a specially designed murine model of ovarian cancer (OVCAR-3), which mimicked the natural history of human micrometastatic disease. Trastuzumab can cure the mice if started soon after induction chemotherapy. It can modestly inhibit the proliferation through mitogen-activated protein kinase signal transduction and clearly inhibit AKT phosphorylation, which is involved in survival pathway. As OVCAR-3 cell lines show no HER2 amplification or overexpression, these results warrant further studies to assess the efficacy of trastuzumab in the early stage of relapse in cancer models other than those overexpressing HER2.
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PMID:Selective inhibition of HER2 inhibits AKT signal transduction and prolongs disease-free survival in a micrometastasis model of ovarian carcinoma. 1621 25

An important recent advance in anticancer therapy was the development of molecular-targeting drugs, such as the epidermal growth-factor receptor (EGFR)-targeting drug ZD1839 (Iressa) and the HER2-trageting anti-HER2 monoclonal antibody trastuzumab (Herceptin). ZD1839 and trastuzumab are reported to improve the therapeutic efficacy of treatment for non-small-cell lung cancer (NSCLC) and breast cancer, respectively, although the effectiveness of either drug alone is not satisfactory. NSCLC cells often express both EGFR and HER2. We therefore investigated whether a combination of ZD1839 and trastuzumab had an additive or synergistic antitumor effect. In culture ZD1839 inhibited the growth of four NSCLC cell lines (A549, NCI-H23, NCI-H727, and NCI-H661) that expressed various levels of EGFR, HER2, HER3, and HER4. A significant cytotoxic effect was observed when ZD1839 was combined with trastuzumab in A549 cells. However, this combination had no apparent effect in NCI-H23 cells. Significant G(1)-phase arrest, increased p27 expression and decreased cyclin E or D1 levels were detected in A549 cells treated with ZD1839 and trastuzumab. No significant effects were detected in NCI-H23 cells examined. The combination treatment significantly inhibited the phosphorylation of EGFR, HER2, retinoblastoma, extracellular signal-regulated kinase-1/2, and protein kinase B/Akt in A549 cells, but not in NCI-H23 cells. Our results indicated that increased levels of constitutive EGFR/HER2 heterodimers were formed in A549 cells in the presence of ZD1839, whereas no heterodimer formation was detected in NCI-H23 cells. We therefore suggest that combination treatment with ZD1839 and trastuzumab might have improved therapeutic efficacy against NSCLC cells expressing both EGFR and HER2.
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PMID:Cooperative cell-growth inhibition by combination treatment with ZD1839 (Iressa) and trastuzumab (Herceptin) in non-small-cell lung cancer. 1625 59


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