Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous attempts to delineate the consequences of Galpha (q) activation in cardiomyocytes relied largely on molecular strategies in cultures or transgenic mice. Modest levels of wild-type Galpha(q) overexpression induce stable cardiac hypertrophy, whereas intense Galpha(q) stimulation induces cardiomyocyte apoptosis. The precise mechanism(s) whereby traditional targets of Galpha (q) subunits that induce hypertrophy also trigger cardiomyocyte apoptosis is not obvious and is explored with recombinant Pasteurella multocida toxin (rPMT, a Galpha(q) agonist). Cells cultured with rPMT display cardiomyocyte enlargement, sarcomeric organization, and increased atrial natriuretic factor expression in association with activation of phospholipase C, novel protein kinase C (PKC) isoforms, extracellular signal-regulated protein kinase (ERK), and (to a lesser extent) JNK/p38-MAPK. rPMT stimulates the ERK cascade via epidermal growth factor (EGF) receptor transactivation in cardiac fibroblasts, but EGF receptor transactivation plays no role in ERK activation in cardiomyocytes. Surprisingly, rPMT (or novel PKC isoform activation by PMA) decreases basal Akt phosphorylation; rPMT prevents Akt phosphorylation by EGF or IGF-1 and functionally augments cardiomyocyte apoptosis in response to H2O2. These results identify a Galpha(q)-PKC pathway that represses basal Akt phosphorylation and impairs Akt stimulation by survival factors. Because inhibition of Akt enhances cardiomyocyte susceptibility to apoptosis, this pathway is predicted to contribute to the transition from hypertrophy to cardiac decompensation and could be targeted for therapy in heart failure.
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PMID:Dual actions of the Galpha(q) agonist Pasteurella multocida toxin to promote cardiomyocyte hypertrophy and enhance apoptosis susceptibility. 1198 85

C-erbB-2 (HER2/neu) protein overexpression or amplification has been noted in some solid tumors a molecular target for tumor suppression. C-erbB-2 protein is localized on the membrane surface and is classified in the EGFR family. Trastuzumab is a humanized monoclonal antibody which binds to the extracellular domain of the c-erbB-2 protein in breast cancer cells. Good responders to trastuzumab may be ICH 2 + and FISH positive breast tumors, and ICH 3 + cancer. The response rate is approximately 15% with single administration of trastuzumab. Combination therapy with paclitaxel for the treatment of patients with metastatic cancer may bring more than 60% response and improve time to disease progression. Congestive heart failure associated with trastuzumab may be severe, and combination therapy which includes anthracyclines increases the incidence and severity of cardiac dysfunction. Other toxicities include infusion reaction.
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PMID:[Clinical implications of trastuzumab]. 1293 63

Trastuzumab (Herceptin) is a humanized monoclonal antibody recognizing the human epidermal growth factor receptor-2 (HER-2/neu). This receptor is overexpressed in 20-30% of invasive breast carcinomas. HER-2/neu normally regulates cell growth and survival, and overexpression leads to increased signaling and thus to malignant transformation and growth. HER-2/neu overexpression used to confer a worse prognosis, as these tumors respond poorly to a variety of chemo- and hormonal therapies. The invention of targeted therapies against the HER-2/neu receptor changed this picture. Trastuzumab binds to HER-2/neu close to the cell membrane and inhibits signal transduction, as well as leading to receptor degradation and immune-mediated attack against the tumor cells. It was shown to be effective and safe in several clinical trials, and approved for use in humans. The most important adverse effect is cardiotoxicity, leading to a risk of congestive heart failure in some patients, especially those pretreated with anthracyclines. As this risk is low, adjuvant trastuzumab therapy was investigated and showed very positive results. The addition of trastuzumab to adjuvant chemotherapy consistently resulted in significant increases of both disease-free and overall survival. Therefore, trastuzumab should nowadays be applied to all eligible patients, i.e. patients whose tumor over-expresses HER-2/neu with a immunostaining intensity of 3+ or shows HER-2/neu gene amplification as demonstrated by fluorescence in situ hybridization (FISH), and who do not have other contraindications. This article highlights the results of pertinent clinical trials and discusses current knowledge on the optimal use of trastuzumab.
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PMID:[Use of trastuzumab in the therapy of breast cancer]. 1862 14

Anticancer drugs continue to cause significant reductions in left ventricular ejection fraction resulting in congestive heart failure. The best-known cardiotoxic agents are anthracyclines (ANTHs) such as doxorubicin (DOX). For several decades cardiotoxicity was almost exclusively associated with ANTHs, for which cumulative dose-related cardiac damage was the use-limiting step. Human epidermal growth factor (EGF) receptor 2 (HER2; ErbB2) has been identified as an important target for breast cancer. Trastuzumab (TRZ), a humanized anti-HER2 monoclonal antibody, is currently recommended as first-line treatment for patients with metastatic HER2(+) tumors. The use of TRZ may be limited by the development of drug intolerance, such as cardiac dysfunction. Cardiotoxicity has been attributed to free-iron-based, radical-induced oxidative stress. Many approaches have been promoted to minimize these serious side effects, but they are still clinically problematic. A new approach to personalized medicine for cancer that involves molecular screening for clinically relevant genomic alterations and genotype-targeted treatments is emerging.
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PMID:Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. 2589 46