Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human epidermal growth factor receptor-2 (HER2) is a member of the epidermal growth factor receptor family, which produces factors that are considered to be important mediators of cell growth. Overexpression of HER2, which occurs in approximately 25% to 30% of human breast cancers, has fostered considerable interest in innovative therapeutic modalities designed to target tumor cells demonstrating such overexpression. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a humanized monoclonal antibody developed to target the HER2 receptor, is the most widely studied example of such a modality. In early clinical studies with trastuzumab, cardiomyopathy was observed with a clinical expression similar to that seen with the anthracyclines (ie, a potentially progressive decrease in cardiac systolic function). A number of possible explanations for this cardiotoxicity are explored in this report. The first is that trastuzumab has inherent toxicity. This consideration has some theoretical interest, since fetal myocardial cells exhibit HER2 receptors and the adult myocardium expresses HER3 receptors. A second possibility is that sequential stresses following doxorubicin administration contribute to cardiac dysfunction. A third explanation is that observational artifacts lead to an overestimation of trastuzumab cardiotoxicity. Approaches for additional study of the extent and severity of trastuzumab cardiotoxicity are briefly addressed.
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PMID:Cardiotoxicity in patients receiving transtuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact? 1048

Overexpression of the p185/HER2 protein is seen in 20%-25% of primary breast cancers and is associated with poor prognosis. Recent phase II and III clinical trials demonstrate that trastuzumab is active against breast tumors, both as a single agent and in combination with chemotherapy. In patients with HER2-overexpressing metastatic breast cancer, use of trastuzumab in combination with chemotherapy is associated with a 20% reduction in relative risk of death and an increase in median survival from 20.3 to 25.1 months compared to chemotherapy alone. Side effects include fever and chills and an unexpected increase in doxorubicin/trastuzumab-associated cardiomyopathy. Clinical development is now focused on trastuzumab in combination with chemotherapy regimens that do not contain an anthracycline. Trastuzumab in combination with docetaxel is synergistic in vitro. Data from ongoing clinical trials are consistent with this finding. Preliminary data from 3 phase II studies suggest a 44%-63% response rate when the combination is used first or second line in HER2-overexpressing metastatic breast cancer. The combination of docetaxel with trastuzumab is well tolerated and has not been associated with significant cardiotoxicity. Given in vitro evidence that platinum salts act synergistically with trastuzumab and docetaxel, and phase II data suggesting clinical efficacy and good tolerability, the combination of platinum salt plus trastuzumab and docetaxel is now being assessed in adjuvant trials
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PMID:Combining the anti-HER2 antibody trastuzumab with taxanes in breast cancer: results and trial considerations. 1197 Jul 40

Trastuzumab is a monoclonal antibody used for the treatment of metastatic breast carcinoma in women whose tumors overexpress the HER2 protein. Cardiotoxicity has been reported to occur with trastuzumab when administered alone and in combination with antineoplastic agents, particularly anthracyclines. The risk of cardiotoxicity with trastuzumab has been reported to be 4% with monotherapy and 27% when administered in combination with an anthracycline and cyclophosphamide, but to the author's knowledge severe outcomes, such as death or permanent disability, are uncommon. The majority of reported cardiac effects are mild to moderate, nonspecific, and medically manageable. Signs and symptoms are similar to those observed in patients who develop anthracycline-induced cardiomyopathy and include tachycardia, palpitations, and exertional dyspnea, which may progress to congestive heart failure. The pathogenesis and histologic changes responsible for trastuzumab-associated cardiotoxicity currently are under investigation. Unlike anthracycline-induced toxicity, trastuzumab-associated toxicity usually responds to standard treatment or the discontinuation of trastuzumab, and there is no evidence that the toxicity is dose related. Current methods for the early detection of cardiotoxicity in trastuzumab-treated patients are similar to those used in anthracycline-treated patients. Cardiac function is established at baseline and monitored regularly during treatment by physical examination and measurement of left ventricular ejection fraction. The majority of patients improve with proper treatment, and some are able to continue to receive trastuzumab.
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PMID:Trastuzumab-associated cardiotoxicity. 1223 30

The members of four generations of a family with Von Hippel-Lindau syndrome (VHL) have been followed by one of us (I.P.) for 30 years. The disease was proved in four members of this family, in three of them associated with pheochromocytoma. The grandmother (I-1) died at the age of 16 years two months after her first birth. The cause of death was not established. Her daughter (II-1) had 9 births with 5 children alive. Paresthesia and difficulties in walking followed by paraparesis and paraplegia were the first signs of the disease at the age of 58 years. The surgical treatment was performed because of an expansive lesion at the level of Th 3-4. Pathohistological examination was not done. It seems that a haemangioblastoma might be the cause of her disease. Diagnosis of pheochromocytoma was documented in a female patient (III-2) in 1972. Two years later she was successfully operated on. Pathohistological examination proved clinical diagnosis. She had also diabetes mellitus, cholelithiasis and cardiomyopathy. She died at the age of 56 years. A right-sided pheochromocytoma was diagnosed in a next female patient (III-4) at the age of 22 years. Her surgical treatment was successful. Retinal haemangioblastomatosis was established 7 years later in this patient. She was blind at the end of her life. Haemangioblastomatosis cerebelli was diagnosed soon, and she died at the age of 51 years. A 12- year old boy (IV-3) presented severe hypertension (36/24 kPa). Left-sided pheochromocytoma was removed in this patient one year later. Right-sided pheochromocytoma was operated on in the same patient at the age of 24 years. An elevated level of urinary dopamine was documented four years after the second operation. A malignant right-sided pheochromocytoma was operated on in the same patient 15 years later. At the same time metastases were found in the lower part of the right lung lobe. A 131-I-MIBG therapy could not be realized. He died at the age of 41. Pathohistological examinations proved the clinical diagnosis in this patient after all of three surgical treatments. MEN 2 syndrome was excluded by proper genetical analyses on the RET-protooncogen. Genetical analyses are in the course to identify the possible mutations of VHL-tumour-suppressor gene through the living members of the family. Multidisciplinary approach is mandatory in diagnosis, follow up and treatment of this specific group of patients. A collaboration among specialists of different fields of medicine (internal medicine, ophthalmology, neurology, radiology, urology, neurosurgery, biochemistry, pathology and genetics) is suggested.
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PMID:[The von Hippel-Lindau syndrome with pheochromocytoma]. 1258 97

The proto-oncogene ErbB2 (also known as c-neu or HER2 in humans) encodes a receptor tyrosine kinase that is frequently overexpressed in human tumors. It is the target of a novel and effective antibody-based therapy for malignant mammary tumors (trastuzumab/Herceptin). Biochemical and genetic experiments have shown that ErbB2 acts as a coreceptor for other members of the ErbB family of receptor tyrosine kinases. In particular, signals are transduced by ErbB2/ErbB4, ErbB2/ErbB3, and ErbB2/EGF receptor heteromers. ErbB2/4 and ErbB2/ErbB3 heteromers transmit neuregulin-1 signals in the developing and adult heart, and in the peripheral nervous system, respectively. Of particular medical relevance are recent findings that relied on tissue-specific mutation of ErbB2 in cardiomyocytes, which revealed an essential function of ErbB2 in normal heart physiology and demonstrated that loss of cardiac ErbB2 can cause dilated cardiomyopathy in adult mice. Thus, ErbB2 is important not only in development, but also for the correct functioning of the differentiated myocardium. The conditional ErbB2 mutant mice provide a model for the principal side effects--cardiomyopathy and heart failure--that can be observed in patients undergoing chemotherapy with Trastuzumab.
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PMID:ErbB2 pathways in heart and neural diseases. 1258 44

Beta-adrenergic receptor (beta-AR) blockade is now widely utilized therapeutically for heart failure, but its cellular mechanism of action is not clear. Mice with cardiac-specific overexpressed Gs alpha develop cardiomyopathy with age, which can be prevented by beta-AR blockade, making this model potentially useful for addressing this question. Our hypothesis was that distal mechanisms in beta-AR signaling, i.e. mitogen-activated protein kinases, were a potential mechanism. At 6-9 months, when cardiomyopathy began to develop in Gs alpha mice, there were significant increases in phospho-kinase levels of p38 MAP kinase (p38 MAPK), and p70(S6K) compared to wild type. In contrast, phospho-kinase levels of ERK and Akt were increased at 9-10 months, but phospho-kinase levels of c-Jun N-terminal kinase (JNK) increased only at 15-20 months (when cardiomyopathy was fully manifest). Treatment of 9-10 months old Gs alpha mice with propranolol for 5 weeks reverted the phospho-kinase levels of these kinases known to be involved in the growth and death of cardiac myocytes. Another novel observation of this study was that there were also decreases in total protein levels of p38 MAPK, p70(S6K), JNK, and Akt following beta-AR blockade. Thus, chronically enhanced beta-AR signaling elicits a differential pattern of altered mitogen-activated protein kinases, which was reversed with beta-AR blockade, raising the possibility that the beneficial effects of beta-AR blockade therapy in heart failure may be due in part to the inhibition of these pathways.
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PMID:Propranolol prevents enhanced stress signaling in Gs alpha cardiomyopathy: potential mechanism for beta-blockade in heart failure. 1487 58

Trypanosoma cruzi infection causes cardiomyopathy and vasculopathy. We examined the consequence of this infection for the mitogen-activated protein kinase (MAPK) pathways, which regulate cell proliferation in cultured human umbilical vein endothelial and vascular smooth muscle cells. Infection of these cells resulted in activation of extracellular signal-regulated kinases 1and 2 (ERK1/2) but not c-Jun N-terminal kinase or p38 MAPK. Treatment of these cells with the MAPK kinase inhibitor PD98059 prior to infection blocked the increase in phosphorylated ERK1/2 seen with infection. Heat-killed parasites did not activate ERK1/2, indicating that activation of ERK1/2 was dependent on infection of these cells by live parasites. Furthermore, transfection with dominant-negative Raf(301) or Ras(N17) constructs reduced the infection-associated levels of phospho-ERK1/2, indicating that the activation of ERK1/2 involved the Ras-Raf-ERK pathway. Infection also resulted in an increase in activator protein 1 (AP-1) activity, which was inhibited by transfection with a dominant-negative Raf(301) construct. T. cruzi-infected endothelial cells secreted endothelin-1 and interleukin-1beta, which activated ERK1/2 and induced cyclin D1 expression in uninfected smooth muscle cells. These data suggest a possible molecular paradigm for the pathogenesis of the vasculopathy and the cardiovascular remodeling associated with T. cruzi infection.
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PMID:Trypanosoma cruzi infection activates extracellular signal-regulated kinase in cultured endothelial and smooth muscle cells. 1532 23

We examined heart tissues of AIDS patients with or without HIV cardiomyopathy (HIVCM) by immunohistochemistry, in situ polymerase chain reaction, in situ riboprobe hybridization, and the TUNEL technique for apoptosis. In HIVCM tissues, only inflammatory cells, but not endothelial cells or cardiomyocytes, displayed HIV-1 DNA and RNA. However, macrophages, lymphocytes, and--in a patchy fashion--cardiomyocytes and endothelial cells exhibited virus envelope protein gp120. Macrophages infiltrated the myocardium in a perivascular fashion and expressed tumor necrosis factor family ligands; adjacent cardiomyocytes suffered apoptosis. In vitro HIV-1 strongly invaded neonatal rat ventricular myocytes (NRVMs) and coronary artery endothelial cells (CAECs) and induced microvilli but did not replicate. HIV-1, gp120, or Tat induced Erk 1/2 phosphorylation, activation of caspase-3, and apoptosis of NRVMs and CAECs; all of these were inhibited by a MAPK/ERK-kinase (MEK) inhibitor U0126. The pathogenesis of HIVCM involves HIV-1 replication in inflammatory cells and induction of cardiomyocyte apoptosis by (1) the extrinsic pathway through apoptotic ligands and (2) the intrinsic pathway through direct virus entry and gp120- and Tat-proapoptotic signaling.
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PMID:HIV-1 induces cardiomyopathyby cardiomyocyte invasion and gp120, Tat, and cytokine apoptotic signaling. 1537 27

Oleylethanolamide (OEA) is a natural fatty acid ethanolamide produced in the heart, but its biological actions in myocardium have not yet been defined. This study was carried out to determine whether OEA could be used to prevent the development of heart failure or improve evolving heart failure. We studied in vivo and in vitro actions of OEA in cardiac muscle. In an animal model of doxorubicin cardiomyopathy, OEA showed robust effects and attenuated the progression of systolic/diastolic dysfunction and ventricular remodeling. During evolving doxorubicin cardiomyopathy, a therapeutic course of OEA treatment partially restored myocardial function. The preventive and therapeutic effects of OEA were associated with significant improvement of survival. To investigate the mechanism of OEA action in cardiac muscle, we have carried out in vitro experiments in cultured cardiomyocytes. The results showed that OEA, through activation of Ras-Raf-1-Mek-Erk signaling, inhibited doxorubicin-induced apoptosis. Additional experiments showed that OEA activation of the Erk pathway involved activation of Neu/ErbB2 receptor, which suggests OEA actions in cardiac muscle might require activation of Neu/ErbB2. In summary, OEA improved ventricular remodeling and augmented cardiac function in doxorubicin cardiomyopathy, possibly involving activation of Neu/ErbB2 and Ras-Erk signaling. These findings suggest OEA is a novel cardioprotective compound that may be used to develop new strategies for the management of cardiomyopathy.
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PMID:Oleylethanolamide activates Ras-Erk pathway and improves myocardial function in doxorubicin-induced heart failure. 1626 55

Evidence suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the beta(1)-adrenergic receptor (beta(1)-EC(II)) is mediated via a biologically active anti-beta(1)-EC(II) antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the beta(1)-EC(II) autoantibody is a partial beta(1)-agonist, we speculate that the cardiomyopathy is produced by the beta(1)-receptor-mediated stimulation of the CaMKII-p38 MAPK-ATF6 signaling pathway and endoplasmic reticulum (ER) stress, and that excess norepinephrine (NE) exaggerates the cardiomyopathy. Rabbits were randomized to receive beta(1)-EC(II) immunization, sham immunization, NE pellet, or beta(1)-EC(II) immunization plus NE pellet for 6 mo. Heart function was measured by echocardiography and catheterization. Myocyte apoptosis was determined by terminal deoxytransferase-mediated dUTP nick-end labeling and caspase-3 activity, whereas CaMKII, MAPK family (JNK, p38, ERK), and ER stress signals (ATF6, GRP78, CHOP, caspase-12) were measured by Western blot, immunohistochemistry, and kinase activity assay. beta(1)-EC(II) immunization produced progressive LV dilation, systolic dysfunction, and myocyte apoptosis. These changes were associated with activation of GRP78 and CHOP and increased cleavage of caspase-12, as well as increased CaMKII activity, increased phosphorylation of p38 MAPK, and nucleus translocation of cleaved ATF6. NE pellet produced additive effects. In addition, KN-93 and SB 203580 abolished the induction of ER stress and cell apoptosis produced by the beta(1)-EC(II) antibody in cultured neonatal cardiomyocytes. Thus ER stress occurs in autoimmune cardiomyopathy induced by beta(1)-EC(II) peptide, and this is enhanced by increased NE and caused by activation of the beta(1)-adrenergic receptor-coupled CaMKII, p38 MAPK, and ATF6 pathway.
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PMID:Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine. 1754 81


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