Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 26S proteasome is a multicatalytic threonine protease complex that is responsible for intracellular protein turnover in eukaryotic cells. This complex degrades and processes proteins required for regulation of various cellular functions. Bortezomib is a novel proteasome inhibitor approved for therapy of multiple myeloma. Inhibition of ubiquitin-proteasome-mediated protein degradation by bortezomib leads to accumulation of its diverse substrates, including cyclins, transcriptional factors, tumor suppressor proteins, and protooncogenes. The sequelae of such profound perturbation of cellular function include cell cycle arrest and activation of apoptotic programs. As the development of this agent continues, there is interest in evaluating its interaction with other anticancer agents. This review provides an overview of selected interactions between bortezomib and other anticancer agents preclinically and in early clinical trials.
Clin Lung Cancer 2005 Oct
PMID:Sequencing bortezomib with chemotherapy and targeted agents. 1625 Sep 28

Mutations of the PPP2R1B gene, which encodes the Abeta scaffolding subunit of serine/threonine protein phosphatase 2A (PP2A), have been identified in several types of cancer including lung and breast carcinoma. One of these mutations results in an alteration of glycine 90 to aspartic acid (G90D), which has been found in both tumor and genomic DNA, raising the possibility that it is associated with an increased risk for cancer. A novel microarray-based technology was used to screen for this single-nucleotide polymorphism in 387 cancer patients and 329 control individuals. These data were used for case-control and family-based comparisons in order to study the association of this polymorphism with susceptibility to lung carcinoma, breast carcinoma, and acute lymphoblastic leukemia. The frequency of the G90D polymorphism in breast cancer patients was significantly higher in cases (3%) than in controls (0.3%). The wild-type Abeta subunit interacted with the B56gamma (PPP2R5C), PR72 (PPP2R3A), and PR48 subunits of PP2A but did not interact with the B55alpha (PPP2R2A), B56alpha (PPP2R5A), or B56beta (PPP2R5B) regulatory subunits in an in vitro binding assay. The G90D alteration inhibited the interaction of Abeta with the B56gamma subunit but had no effect on binding to the PR72 subunit. These results provide evidence that the G90D alteration of the Abeta subunit of PP2A is associated with a low frequency of breast carcinoma and that the role of this alteration in transformation is likely to involve decreased interaction with the B56gamma regulatory subunit.
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PMID:The glycine 90 to aspartate alteration in the Abeta subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function. 1627 21

ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 micromol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 = 2, 4, and 7 nmol/L for PDGFR-beta, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50 = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED50 = 1.5-5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC50 corrected for plasma protein binding = 0.08 microg/mL, >or=7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer.
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PMID:Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. 1664 71

Mutations of the epidermal growth factor receptor (EGFR) gene have been reported in non-small-cell lung cancer (NSCLC), especially in patients with adenocarcinoma and never smokers. Some common somatic mutations in EGFR, including deletion mutations in exon 19 and leucine-to-arginine substitution at amino acid position 858 (L858R) in exon 21, have been examined for their ability to predict sensitivity to gefitinib or erlotinib, which are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs). On the other hand, reports have shown that the threonine-to-methionine substitution at amino acid position 790 (T790M) in exon 20 is related to gefitinib resistance. Some studies have indicated that high copy numbers of the EGFR gene may be a more effective molecular predictor to responsiveness and prolonged survival in patients treated with EGFR-TKIs. Here, we describe two NSCLC patients with the L858R mutation who did not respond to gefitinib. Case 1 harbored both the T790M and L858R mutations, and fluorescence in situ hybridization showed EGFR gene amplification. Case 2 harbored both the L858R and aspartic acid-to-tyrosine substitution at amino acid position 761 in exon 19 of EGFR mutations and had a high polysomy status for EGFR. In these two cases, tumors showed resistance to gefitinib treatment despite the presence of EGFR L858R mutation and increased copy number. Our findings encourage further molecular analysis to elucidate the relationship between the EGFR status, including mutations and amplifications, and the responsiveness of NSCLC to gefitinib.
Lung Cancer 2006 Jul
PMID:Double mutation and gene copy number of EGFR in gefitinib refractory non-small-cell lung cancer. 1673 Aug 55

It has been reported that the threonine-to-methionine substitution at amino acid position 790 (T790M) of the epidermal growth factor receptor (EGFR) gene is correlated with acquired resistance to gefitinib. We previously reported that there was some population that harbored the EGFR T790M mutation as a minor clone of tumor cells prior to drug treatment, may be causing resistance to gefitinib during treatment. This fact also suggests that the detection of the EGFR T790M mutation prior to treatment may predict the development of resistance. We also showed that pleural fluid is a useful specimen for detection of EGFR mutation using sensitive assays. In this study, we reported a female patient who was treated with gefitinib because an EGFR L858R mutation was found in her pleural fluid. Our patient showed partial response to gefitinib, but she had progressive disease only 4 months after the start of treatment. Furthermore, the EGFR T790M mutation was detected in the pleural fluid before gefitinib treatment by the mutant-enriched PCR assay. Our findings confirmed that the EGFR T790M mutation was occasionally present as a minor population in tumor cells before treatment and caused resistance after gefitinib administration. The detection of a small fraction of T790M-positive alleles may be useful to predict the clinical course of the gefitinib-treated non-small-cell lung cancer patients.
Lung Cancer 2007 Jun
PMID:EGFR mutation status in pleural fluid predicts tumor responsiveness and resistance to gefitinib. 1733 35

PPARgamma ligands inhibit the proliferation of non-small cell lung carcinoma (NSCLC) cells in vitro. The mechanisms responsible for this effect remain incompletely elucidated, but PPARgamma ligands appear to inhibit the mammalian target of rapamycin (mTOR) pathway. We set out to test the hypothesis that PPARgamma ligands activate tuberous sclerosis complex-2 (TSC2), a tumor suppressor gene that inhibits mTOR signaling. We found that the PPARgamma ligand rosiglitazone stimulated the phosphorylation of TSC2 at serine-1254, but not threonine-1462. However, an antagonist of PPARgamma and PPARgamma siRNA did not inhibit these effects. Rosiglitazone also increased the phosphorylation of p38 MAPK, but inhibitors of p38 MAPK and its downstream signal MK2 had no effect on rosiglitazone-induced activation of TSC2. Activation of TSC2 resulted in downregulation of phosphorylated p70S6K, a downstream target of mTOR. A TSC2 siRNA induced p70S6K phosphorylation at baseline and inhibited p70S6K downregulation by rosiglitazone. When compared to a control siRNA in a thymidine incorporation assay, the TSC2 siRNA reduced the growth inhibitory effect of rosiglitazone by fifty percent. These observations suggest that rosiglitazone inhibits NSCLC growth partially through phosphorylation of TSC2 via PPARgamma-independent pathways.
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PMID:Rosiglitazone, an Agonist of PPARgamma, Inhibits Non-Small Cell Carcinoma Cell Proliferation In Part through Activation of Tumor Sclerosis Complex-2. 1759 35

Development of acquired resistance to gefitinib after an initial good response is common. Recently, it was reported that this acquired resistance is related to a secondary mutation associated with a substitution of threonine by methionine at codon 790 (T790M) of the epidermal growth factor receptor (EGFR) gene. In this report, we present a "never smoking" woman with advanced lung cancer who showed acquired resistance to gefitinib, and analysis of autopsy samples revealed no evidence of EGFR mutations in either exons 18-21 or codon 790, and positive immunostaining for breast cancer resistance protein (BCRP). We describe, for the first time, a case in which expression of BCRP was associated with acquired resistance to gefitinib, independent of EGFR mutations.
Lung Cancer 2007 Nov
PMID:Breast cancer resistance protein (BCRP) affected acquired resistance to gefitinib in a "never-smoked" female patient with advanced non-small cell lung cancer. 1761 5

Previous studies demonstrated that ING4 as a novel member of ING (inhibitor of growth) family has potential effect on tumor inhibition via multiple pathways. However, adenovirus-mediated ING4 expression in inhibition of human tumors has not been reported. To explore its therapeutic effect on human lung carcinoma, we constructed a recombinant adenoviral vector Ad-ING4 expressing the humanized ING4 gene derived from murine ING4 with two amino acid modifications at residue 66 (Arg to Lys) and 156 (Ala to Thr) by site-directed mutagenesis. We demonstrated that Ad-ING4-mediated transfection of A549 human lung carcinoma cells induced cell apoptosis, altered cell cycle with S phase reduction and G2/M phase arrest, suppressed cell invasiveness, and down-regulated IL-6, IL-8, MMP-2, and MMP-9 expression of transfected tumor cells. In athymic mice bearing A549 lung tumors, intratumoral injections of Ad-ING4 suppressed the tumor growth and reduced the tumor microvessel formation. Therefore, Ad-ING4 may be useful in gene therapy of human lung carcinoma.
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PMID:Adenovirus-mediated ING4 expression suppresses lung carcinoma cell growth via induction of cell cycle alteration and apoptosis and inhibition of tumor invasion and angiogenesis. 1878 75

Matrix metalloproteinase-1 (MMP-1) is an inflammation-inducible neutral protease that mediates extracellular matrix remodeling and promotes tumor invasion. In this study, we examined the activation of MMP-1 gene expression in A549 lung carcinoma cells stimulated with the inflammatory cytokine interleukin-1beta (IL-1beta). We found that MMP-1 mRNA levels were maximal following 16 hours of IL-1beta stimulation and that this correlated with the expression of the transcription factor CCAAT enhancer-binding protein-beta (CEBPB). Knockdown of CEBPB expression with short hairpin RNA abrogated the expression of MMP-1, MMP-3, and MMP-10 in IL-1beta-stimulated A549 cells. An established CEBP element in the MMP-1 promoter was found to be required for basal and IL-1beta-induced transcription. Electrophoresis mobility shift assays showed that CEBPB binds to this promoter element maximally 16 hours after IL-1beta stimulation. DNA affinity chromatography studies showed that the LAP1, LAP2, and LIP isoforms of CEBPB bind to the IL-1beta-responsive CEBPB site in the MMP-1 promoter. Exogenous expression of the LAP1 and LAP2 isoforms stimulated the MMP-1 promoter, whereas LIP had no effect. Phosphorylation of CEBPB at Thr(235) peaked at 16 hours in IL-1beta-stimulated cells. The MEK inhibitor U0126 inhibited this phosphorylation and reduced MMP-1 gene induction. These studies establish CEBPB as an important mediator of metalloproteinase gene activation during inflammatory responses in lung cancer cells and highlight the different regulatory roles of CEBPB isoforms.
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PMID:CCAAT enhancer binding protein-beta regulates matrix metalloproteinase-1 expression in interleukin-1beta-stimulated A549 lung carcinoma cells. 1972 73

Fasudil, an inhibitor of Rho kinase, is known to suppress tumorigenicity and cancer metastasis. However, the underlying molecular mechanisms of how fasudil suppresses cell metastasis have not been fully elucidated. The purpose of this study was to determine the effects of fasudil on migration and cancer growth and to evaluate Rho kinase activity in the 95-D lung carcinoma cell line. The cytotoxic effect of drugs on 95-D cells was measured by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Treatment with fasudil inhibited the growth of 95-D cells in a dose-dependent manner, and the IC50 of fasudil was approximately 0.79 mg/ml (95% confidence limits (CL): 0.58-1.11 mg/ml). The total amounts of active MMP2 and MMP9 per microgram of protein when treated with 0.75 mg/ml fasudil and using the gelatinase assay were decreased compared with the control group by about 22.7% (P<0.05) and 65.9% (P<0.01) respectively. Although ABCC1, ABCC3, ABCA3, and ABCC5 were over-expressed at the mRNA level, ABCE1 was the only transporter responsible for resistance in this study. We also found that myosin phosphatase targeting subunit 1 (MYPT1) phosphorylation at Thr-696, which provided direct evidence of Rho kinase activity, was reduced by 29.4% in response to fasudil compared with the control group (P<0.05). Taken together, our findings show that fasudil prevents cancer metastasis by inhibiting the Rho/Rho kinase pathway and that the ABCE1 gene was involved in the migration of 95-D cells.
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PMID:The Rho kinase inhibitor fasudil inhibits the migratory behaviour of 95-D lung carcinoma cells. 1987 5


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