BACKGROUND: Endotoxin, the component of outermembrane of gram negative organism, plays an important role in the initiation and amplification of inflammatory reaction by its effects on inflammatory cells. Until recently, there have been continuing efforts to delinate the mechanisms of the signal trasduction pathway of endotoxin stimuli on inflammatory cells. By uncovering the mechanisms of signal transduction pathway of endotoxin stimuli, we can expect to have tools to control the excessive inflammatory responses which sometimes may be fatal to the involved host. It was generally accepted that endotoxin exerts its inflammatory effects through inflammatory cytokines that are produced by endotoxin-stimulated inflammatory cells and there were some reports on the importance of protein kinase C and protein tyrosine kinase activation in the production of inflammatory cytokines by endotoxin. So we evaluated the effect of pretreatment of protein kinase C inhibitors (H7, Staurosporin) and protein tyrosine kinase inhibitors(Herbimycin, Genistein) on the endotoxin-stimulated cytokines(IL-8 & TNF-alpha) mRNA expression. METHOD: Peripheral blood monocytes were isolated from healthy volunteers by Ficoll-Hypaque density gradient method and purified by adhesion to 60mm Petri dishes. Endotoxin(LPS 100ng/ml) was added to each dishes except one control dish, and each endotoxin-stimulated dishes was preincubated with H7, Staurosporin(protein kinase C inhibitor), Herbimycin or Genistein(protein tyrosine kinase inhibitor) respectively except one dish. Four hours later the endotoxin stimulation, total RNA was extracted and Northern blot analysis for IL-8 mRNA and TNF-alpha mRNA was done. RESULT: Endotoxin stimulation increased the expression of IL-8 mRNA and TNF-alpha mRNA expression in human peripheral blood monocyte as expected and the stimulatory effect of endotoxin on TNF-alpha mRNA expression was inhibited by protein kinase C inhibitors(H7, Staurosporin) and protein tyrosine kinase inhibitors (Herbimycin, Genistein). The inhibitory effect of each drugs was increased with increasing concentration. The stimulatory effect of endotoxin on IL-8 mRNA was also inhibited by H7 and protein tyrosine kinase inhibitors (Herbimycin, Genistein) dose-dependently but not by Staurosporin. CONCLUSION: Protein kinase C and protein tyrosine kinase are involved in the endotoxin induced signal transduction pathway in human peripheral blood monocyte.
Blotting, Northern ; Cytokines ; Healthy Volunteers ; Humans ; Interleukin-8 ; Monocytes* ; Phosphotransferases ; Protein Kinase C* ; Protein Kinases* ; Protein-Tyrosine Kinases* ; RNA ; RNA, Messenger ; Signal Transduction* ; Tumor Necrosis Factor-alpha

Nuclear factor kappaB (NF- kappaB) activation is modulated by various protein kinases. Activation of NF- kappaB is known to be important in the regulation of cell viability. The present study investigated the effect of inhibitors of protein tyrosine kinase (PTK), protein kinase C (PKC) and protein kinase A (PKA) on NF- kappaB activity and the viability of bovine cerebral endothelial cells (BCECs). In serum-deprivation-induced BCEC death, low doses of TNF alpha showed a protective effect. TNF alpha induced NF- kappaB activation within 4 h in serum-deprivation. PTK inhibitors (herbimycin A and genistein) and PKC inhibitor (calphostin C) prevented NF- kappaB activation stimulated by TNF alpha. Likewise, these inhibitors prevented the protective effect of TNF alpha. In contrast to TNF alpha-stimulated NF- kappaB activity, basal NF- kappaB activity of BCECs in media containing serum was suppressed only by calphostin C, but not by herbimycin A. As well BCEC death was also induced only by calphostin C in serum-condition. H 89, a PKA inhibitor, did not affect the basal and TNF alpha-stimulated NF- kappaB activities and the protective effect of TNF alpha on cell death. These data suggest that modulation of NF- kappaB activation could be a possible mechanism for regulating cell viability by protein kinases in BCECs.
Cell Death* ; Cell Survival ; Cyclic AMP-Dependent Protein Kinases ; Endothelial Cells* ; Protein Kinase C ; Protein Kinases* ; Protein-Tyrosine Kinases

Over the past decade, several kinase inhibitors have been approved based on their clinical benefit in cancer patients. Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. To date, several major mechanisms of acquired resistance, such as secondary mutation of the epidermal growth factor receptor (EGFR) gene, amplification of the MET gene and overexpression of hepatocyte growth factor, have been reported. This review describes the recent findings on the mechanisms of primary and acquired resistance to EGFR tyrosine kinase inhibitors and acquired resistance to anaplastic lymphoma kinase inhibitors, primarily focusing on non-small cell lung carcinoma.
Drug Resistance* ; Epidermal Growth Factor* ; Hepatocyte Growth Factor ; Humans ; Lung ; Lymphoma* ; Phosphotransferases* ; Protein Kinase Inhibitors ; Protein-Tyrosine Kinases ; Receptor Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor*

ZD1839 (Iressa(R)) is a new anticancer agent, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathway implicated in the proliferation and survival of cancer cells and other host-dependent process promoting cancer growth. But this agent can induce cutaneous side effects including acneiform eruption, dry skin, and hair abnormality, which is related with the interruption of normal epidermal and hair follicular kinetics. We report a case of hair change and acneiform eruption induced by ZD1839 (Iressa(R)).
Acneiform Eruptions* ; Hair* ; Kinetics ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor ; Signal Transduction ; Skin

epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase inhibitors, new therapeutic strategies are needed to improve clinical outcomes. Immunotherapy through the use of immune checkpoint inhibitors has provided one of the most important breakthroughs in the management of solid tumors, including lung cancers, and has shown promising results in numerous clinical trials. This review will present the current status of immunotherapy for lung cancer and future perspectives on these treatments.]]>
Immunotherapy ; Lung Neoplasms ; Lung ; Lymphoma ; Phosphotransferases ; Prognosis ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor

BACKGROUND: Statins are used to treat hypercholesterolemia; however, major cardiovascular events are decreased only 30% by statin treatment. Treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been reported to decrease serum glucose levels and improved insulin sensitivity in mice and humans, but there was no study in serum cholesterol levels. This study examined the effect of gefitinib, an EGFR tyrosine kinase inhibitor, on cholesterol metabolism in humans. METHODS: We retrospectively reviewed the medical records of 299 patients with primary lung cancer treated with gefitinib for ≥1 month and 72 patients with other treatments. Serum cholesterol, serum triglycerides, and body mass index were measured before and after treatment. The changes in serum cholesterol, serum triglycerides, and body mass index were compared between the gefitinib treatment group and the control group and were also analyzed according to the presence or absence of EGFR mutations. RESULTS: Serum cholesterol levels decreased significantly from 178.9 to 164.4 mg/dL after 1-month of gefitinib treatment. A total of 54 of the 299 patients underwent examination for the presence of the EGFR mutations. Serum cholesterol was significantly decreased in the group with the activating EGFR mutation (Δ=21.3 mg/dL) compared to that of those without the EGFR mutation (Δ=-3.1 mg/dL) after treatment with gefitinib. In contrast, there was no significantly difference between the two groups in control patients. CONCLUSION: Treatment with gefitinib decreased serum cholesterol in lung cancer patients, particularly in those with activating mutations in EGFR. These data suggest that EGFR tyrosine kinase inhibitors provide a novel and attractive strategy for the treatment of hypercholesterolemia.
Animals ; Blood Glucose ; Body Mass Index ; Cholesterol ; Epidermal Growth Factor ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Hypercholesterolemia ; Insulin Resistance ; Lung Neoplasms ; Lung ; Medical Records ; Metabolism ; Mice ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor ; Retrospective Studies ; Triglycerides

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib show good response and survival benefit in EGFR-mutant lung cancer, acquired resistance inevitably develops which limits the median response duration to around 1 year. Secondary T790M gatekeeper mutation is the most common mechanism representing approximately 50% of resistance. The suggested strategies for overcoming T790M including irreversible EGFR-TKIs, mutant-selective EGFR-TKIs, EGFR dual targeting and HSP90 inhibitors should be further investigated for clinical application. Bypass signals through MET or AXL also contribute to resistance, which lead to development of MET or AXL inhibitors. Other mechanisms such as small cell transformation, epithelial-to-mesenchymal transition, PI3KCA mutation, ERK/HER2 amplification and miRNAs are other suggested candidates awaiting validation. As many resistant mechanisms have been recognized, it is important to obtain tissue samples after resistance to provide appropriate treatment. In this review, recent advances in the understanding of resistance and novel ways of overcoming it are discussed.
Drug Resistance ; Epidermal Growth Factor ; Lung ; Lung Neoplasms ; MicroRNAs ; Protein-Tyrosine Kinases ; Quinazolines ; Receptor, Epidermal Growth Factor ; Erlotinib Hydrochloride

Since the first description of non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation as a distinct clinical entity, studies have proved EGFR tyrosine kinase inhibitors (TKIs) as a first choice of treatment. The median response duration of TKIs as a first-line treatment for EGFR mutant tumors ranges from 11 to 14 months. However, acquired resistance to EGFR-TKIs is inevitable due to various mechanisms, such as T790M, c-Met amplification, activation of alternative pathways (IGF-1, HGF, PI3CA, AXL), transformation to mesenchymal cell or small cell features, and tumor heterogeneity. Until development of a successful treatment strategy to overcome such acquired resistance, few options are currently available. Here we provide a summary of the therapeutic options after failure of first line EGFR-TKI treatment for NSCLC.
Carcinoma, Non-Small-Cell Lung ; Drug Resistance ; Epidermal Growth Factor ; Lung ; Population Characteristics ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor

The emergence of new therapeutic agents for non-small cell lung cancer (NSCLC) implies that histologic subtyping and molecular predictive testing are now essential for therapeutic decisions. Histologic subtype predicts the efficacy and toxicity of some treatment agents, as do genetic alterations, which can be important predictive factors in treatment selection. Molecular markers, such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement, are the best predictors of response to specific tyrosine kinase inhibitor treatment agents. As the majority of patients with NSCLC present with unresectable disease, it is therefore crucial to optimize the use of tissue samples for diagnostic and predictive examinations, particularly for small biopsy and cytology specimens. Therefore, each institution needs to develop a diagnostic approach requiring close communication between the pulmonologist, radiologist, pathologist, and oncologist in order to preserve sufficient biopsy materials for molecular analysis as well as to ensure rapid diagnosis. Currently, personalized medicine in NSCLC is based on the histologic subtype and molecular status. This review summarizes strategies for tissue acquisition, histologic subtyping and molecular analysis for predictive testing in NSCLC.
Biopsy* ; Carcinoma, Non-Small-Cell Lung* ; Diagnosis ; Humans ; Precision Medicine ; Lymphoma ; Phosphotransferases ; Protein-Tyrosine Kinases ; Receptor Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor

ABBREVIATIONS: Akt/PKB protein kinase B, ALI acute lung injury, ARDS acute respiratory distress syndrome, CREB C-AMP response element binding protein, ERK extracelluar signal-related kinase, fMLP fMet-Leu-Phe, G-CSF granulocyte colony-stimulating factor, IL interleukin, ILK integrin-linked kinase, JNK Jun N-terminal kinase, LPS lipopolysaccharide, MAP mitogen-activated protein, MEK MAP/ERK kinase, MIP-2 macrophage inflammatory protein-2, MMP matrix metalloproteinase, MPO myeloperoxidase, NADPH nicotinamide adenine dinucleotide phosphate, NE neutrophil elastase, NF-kappaB nuclear factor-kappa B, NOS nitric oxide synthase, p38 MAPK p38 mitogen activated protein kinase, PAF platelet activating factor, PAKs p21-activated kinases, PMN polymorphonuclear leukocytes, PI3-K phosphatidylinositol 3-kinase, PyK proline-rich tyrosine kinase, ROS reactive oxygen species, TNF-alpha tumor necrosis factor-alpha.
Abbreviations ; Acute Lung Injury* ; Carrier Proteins ; Granulocyte Colony-Stimulating Factor ; Interleukins ; Leukocyte Elastase ; Macrophages ; N-Formylmethionine Leucyl-Phenylalanine ; NADP ; Neutrophil Activation* ; Neutrophils* ; NF-kappa B ; Nitric Oxide Synthase ; p21-Activated Kinases ; p38 Mitogen-Activated Protein Kinases ; Peroxidase ; Phosphatidylinositol 3-Kinase ; Phosphotransferases ; Platelet Activating Factor ; Protein Kinases ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins c-akt ; Reactive Oxygen Species ; Respiratory Distress Syndrome, Adult ; Response Elements ; Signal Transduction ; Tumor Necrosis Factor-alpha