Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis from l-quebrachitol of a series of 3-deoxygenated ether lipid-type phosphatidylinositol (PI) analogues is reported, that selectively block activation of Akt and downstream substrates without affecting activation of the upstream kinase, PDK-1, or other kinases downstream of ras such as MAPK in H157 and H1703 lung cancer cells that have high levels of constitutively active Akt. The 2-hydroxyl in these compounds was deleted or alkylated with the intent to preclude metabolic degradation of these compounds by PI-specific phospholipase C (PI-PLC). PI analogues with phosphate linkers are more effective than those with carbonate linkers. Specific inhibition of Akt by these compounds validates ligand design targeted to the PH domains of crucial signaling proteins, thus providing a unique class of possible cancer therapeutics.
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PMID:Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt. 1255 97

Platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (TP) catalyses the reversible phosphorolysis of thymidine to thymine and 2-deoxyribose-1-phosphate and is involved in the metabolism of fluoropyrimidines. It can also activate 5'-deoxyfluorouridine (5'DFUR) and possibly 5-fluorouracil (5FU) and Ftorafur (Ft), but inactivates trifluorothymidine (TFT). We studied the contribution of TP activity to the sensitivity for these fluoropyrimidines by modulating its activity and/or expression level in colon and lung cancer cells using a specific inhibitor of TP (TPI) or by overproduction of TP via stable transfection of human TP. Expression was analysed using competitive template-RT-PCR (CT-RT-PCR), Western blot and an activity assay. TP activity ranged from nondetectable to 70678 pmol h(-1) 10(-6) cells, in Colo320 and a TP overexpressing clone Colo320TP1, respectively. We found a good correlation between TP activity and mRNA expression (r=0.964, P&<0.01) in our cell panel. To determine the role of TP in the sensitivity to 5FU, 5'DFUR, Ft and TFT, cells were cultured with the various fluoropyrimidines with or without TPI and differences in IC(50)'s were established. TPI modified 5'DFUR, increasing the IC(50)'s 2.5- to 1396-fold in WiDR and Colo320TP1, respectively. 5-Fluorouracil could be modified by inhibiting TP but to a lesser extent than 5'DFUR: IC(50)'s increased 1.9- to 14.7-fold for WiDR and Colo320TP1, respectively. There was no effect on TFT or Ft. There appears to be a threshold level of TP activity to influence the 5'DFUR and 5FU sensitivity, which is higher for 5FU. Even high levels of TP overexpression only had a moderate effect on 5FU sensitivity.
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PMID:Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity. 1264 37

Raman spectroscopy is a vibrational spectroscopic technique that can be used to probe molecular changes associated with tissue malignancy. In this report, the effect of formalin fixation on human bronchial tissues was studied by near-infrared (NIR) Raman spectroscopy to determine if the variations of Raman spectra caused by formalin fixation would affect the potential diagnostic ability for lung cancer detection. A rapid dispersive-type NIR Raman system with an excitation wavelength of 785 nm was used for this study. Bronchial tissue samples were obtained from six patients with known or suspected malignancies of the lung. Raman spectra of fresh normal and tumor tissue were compared with spectra of formalin-fixed normal and tumor tissue. Changes of the ratios of Raman intensities at 1445 to 1655 cm(-1) and 1302 to 1265 cm(-1) versus formalin fixing times varying from 2 to 24 h were also examined. The major tissue Raman peaks at 1265, 1302, 1445, and 1655 cm(-1) were found in both fresh and fixed bronchial tissues. However, bronchial tissue preserved in formalin showed a progressive decrease in overall intensities of these Raman peaks. Raman contaminations due to formalin were also found in the 980-1100, and 1480-1650 cm(-1) ranges with notable formalin peaks (1041 and 1492 cm(-1)) appearing in the fixed normal and tumor tissues. The results showed that NIR Raman spectra of human bronchial tissues were significantly affected by formalin fixing and tissue hydration. Diagnostic markers at the 980-1100, and 1500-1650 cm(-1) regions derived from fixed tissues do not appear to be applicable for in vivo lung cancer detection. To yield valid Raman diagnostic information for in vivo applications, fresh tissue should be used. If only fixed tissue is available, thorough rinsing of specimens in phosphate-buffered saline (PBS) before spectral measurements may help reduce the formalin fixation artifacts on tissue Raman spectra.
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PMID:Effect of formalin fixation on the near-infrared Raman spectroscopy of normal and cancerous human bronchial tissues. 1288

We have previously observed the suppression of lung tumor growth in response to overexpression of melanoma differentiation-associated gene-7 (MDA-7)/interleukin-24 (IL-24; approved gene symbol IL24) in vitro and in vivo. MDA-7/IL-24 exerts its tumor-suppressive effects by multiple mechanisms, including the activation of the caspase cascade and the inhibition of angiogenesis. In this study, we used an adenoviral vector (Ad-mda7) to examine the effect of the ectopic production of MDA-7/IL-24 on cell migration and invasion by human non-small-cell lung carcinoma cells. Lung tumor cells (H1299 and A549) treated in vitro with Ad-mda7 migrated and invaded less than cells treated with phosphate-buffered saline (PBS) or Ad-Luc (vector control). MDA-7/IL-24 inhibited migration and invasion by down-regulating the production of phosphatidylinositol 3-kinase/protein kinase B, focal adhesion kinase, and matrix metalloproteinase-2 and -9 relative to PBS and Ad-Luc. Furthermore, tumor cells treated with Ad-mda7 ex vivo or with DOTAP:Chol-mda7 complex in vivo formed significantly fewer tumors in an experimental lung metastasis model. These results show that MDA-7/IL-24 inhibits invasion and migration by lung cancer cells by down-regulating proteins associated with these processes, resulting in reduced metastasis. Thus, Ad-mda7 should be considered a therapeutic agent that can inhibit primary tumor growth and prevent metastasis.
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PMID:Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. 1509 81

Human homologues of yeast Rad 6 (Hrad6B) encode ubiquitin-conjugating enzymes and complement the DNA repair and UV mutagenesis defects of Saccharomyces cerevisiae rad6 mutant. There is a larger subgroup with reduced DNA repair capacity that is likely to be at increased cancer risk. The authors investigated Hrad6B expression in lung cancer. An attempt was made to determine the influence of Hrad6B expression on clinicopathological features for patients with lung cancer who had undergone surgery. Expression of Hrad6B messenger RNA was evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 110 lung carcinomas and adjacent histological non-malignant lung samples from patients for whom follow-up data were available using LightCycler. The Hrad6B/glyceraldehydes-3-phosphate dehydrogenase (GAPDH) mRNA expression was significantly decreased in the lung cancer tissue (4.078+/-5.674) as compared with the non-malignant lung tissue (10.495+/-12.976, p<0.001). There was no relationship between Hrad6B/GAPDH expression and age, clinical stages, T-status, N-status, and pathological subtypes in lung cancer tissues. Hrad6B/GAPDH mRNA levels in males (3.521+/-4.280) and in females (6.420+/-8.167) were significantly different (p=0.0443) in lung cancer tissues, but not in non-malignant lung tissues. Heavy smokers had a slight non-significant tendency (p=0.0857) towards lower Hrad6B/GAPDH mRNA levels (3.453+/-4.743) in their lung cancer tissues as compared with light or non-smokers. Thus decreased Hrad6B mRNA expression might be a biomarker for decreased DNA repair capacity and the dysfunction of Hrad6B might play a role in the tobacco-related oncogenesis of lung cancer.
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PMID:Decreased Hrad6B expression in lung cancer. 1537 Jun 17

Autoantibodies against many proteins are common in sera from patients with various types of cancer. These antibodies are sometimes involved in the development of conditions associated with cancer, such as paraneoplastic neurologic disorders. We used a human brain cDNA expression library and serum from a paraneoplastic neurologic disorder patient to search for new autoantigens in the nervous system. Pyridoxal phosphatase was identified as a novel autoantigen. Expression studies showed that pyridoxal phosphatase was strongly expressed in various parts of the central nervous system. Sera contained antibodies against pyridoxal phosphatase in 22 of 243 (9.1%) patients with lung cancer and eight of 113 (7.1%) with other forms of cancer vs two of 88 (2.3%) healthy control subjects. In addition, 2-4% of patients with different autoimmune diseases had autoantibodies against pyridoxal phosphatase. None of the antipyridoxal phosphatase-positive patients were known to have a paraneoplastic neurologic disorder. Hence, autoantibodies against pyridoxal phosphatase correlate with cancer but not necessarily with the subset of patients with paraneoplastic neurological disorders although serum from such a patient was used to screen the cDNA library. This study showed that yet another enzyme involved in pyridoxal 5'-phosphate metabolism is an autoantigen. Thus, pyridoxal 5'-phosphate seems to be a common denominator for autoantigens involved in autoimmune diseases.
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PMID:Pyridoxal phosphatase is a novel cancer autoantigen in the central nervous system. 1545 47

Resistance to cisplatin is a common problem that limits its usefulness in cancer therapy. Molecular genetic studies in the model organism Dictyostelium discoideum have established that modulation of sphingosine kinase or sphingosine-1-phosphate (S-1-P) lyase, by disruption or overexpression, results in altered cellular sensitivity to this widely used drug. Parallel changes in sensitivity were observed for the related compound carboplatin but not for other chemotherapy drugs tested. Sensitivity to cisplatin could also be potentiated pharmacologically with dimethylsphingosine, a sphingosine kinase inhibitor. We now have validated these studies in cultured human cell lines. HEK293 or A549 lung cancer cells expressing human S-1-P lyase (hSPL) show an increase in sensitivity to cisplatin and carboplatin as predicted from the earlier model studies. The hSPL-overexpressing cells were also more sensitive to doxorubicin but not to vincristine or chlorambucil. Studies using inhibitors to specific mitogen-activated protein kinases (MAPK) show that the increased cisplatin sensitivity in the hSPL-overexpressing cells is mediated by p38 and to a lesser extent by c-Jun NH2-terminal kinase MAPKs. p38 is not involved in vincristine or chlorambucil cytotoxicity. Measurements of MAPK phosphorylation and enzyme activity as well as small interfering RNA inhibition studies show that the response to the drug is accompanied by up-regulation of p38 and c-Jun NH2-terminal kinase and the lack of extracellular signal-regulated kinase up-regulation. These studies confirm an earlier model proposing a mechanism for the drug specificity observed in the studies with D. discoideum and support the idea that the sphingosine kinases and S-1-P lyase are potential targets for improving the efficacy of cisplatin therapy for human tumors.
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PMID:Sphingosine-1-phosphate lyase regulates sensitivity of human cells to select chemotherapy drugs in a p38-dependent manner. 1588

Sphingosine kinase 1 (SK1) is a key enzyme critical to the sphingolipid metabolic pathway responsible for catalyzing the formation of the bioactive lipid sphingosine-1-phosphate. SK1-mediated production of sphingosine-1-phosphate has been shown to stimulate such biological processes as cell growth, differentiation, migration, angiogenesis, and inhibition of apoptosis. In this study, cell type-specific immunolocalization of SK1 was examined in the bronchus/terminal bronchiole of the lung. Strong immunopositive staining was evident at the apical surface of pseudostratified epithelial cells of the bronchus and underlying smooth muscle cells, submucosal serous glands, immature chondrocytes, type II alveolar cells, foamy macrophages, endothelial cells of blood vessels, and neural bundles. Immunohistochemical screening for SK1 expression was performed in 25 samples of normal/tumor patient matched non-small-cell lung cancer tissue and found that 25 of 25 tumor samples (carcinoid [5 samples], squamous [10 samples], and adenocarcinoma tumors [10 samples]), exhibited overwhelmingly positive immunostaining for SK1 as compared with patient-matched normal tissue. In addition, an approximately 2-fold elevation of SK1 mRNA expression was observed in lung cancer tissue versus normal tissue, as well as in several other solid tumors. Taken together, these findings define the localization of SK1 in lung and provide clues as to how SK1 may play a role in normal lung physiology and the pathophysiology of lung cancer.
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PMID:Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. 1592 63

Autotaxin (NPP2) is an extracellular protein that is upregulated in various malignancies, including breast and lung cancer. It potently stimulates cell proliferation, cell motility and angiogenesis, which is accounted for by its intrinsic lysophospholipase-D activity that generates the lipid mediators lysophosphatidic acid and sphingosine-1-phosphate. Based on its structural similarities with the better characterized nucleotide pyrophosphatase/phosphodiesterase NPP1, it has always been assumed that NPP2 is also synthesized as a type-II integral membrane protein and that extracellular NPP2 is generated from this membrane precursor. We show here, however, using domain swapping and mutagenesis experiments as well as N-terminal protein sequencing, that NPP2 is actually synthesized as a pre-pro-enzyme and that the proteolytically processed protein is secreted. Following the removal of a 27-residue signal peptide by the signal peptidase, NPP2 is subsequently cleaved by proprotein convertases (PCs). The removal of an N-terminal octapeptide by PCs is associated with an enhanced activity of NPP2 as a lysophospholipase D. These novel insights in the maturation of NPP2 have also implications for the development of NPP2 inhibitors as potential anti-cancer agents.
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PMID:Proteolytic maturation and activation of autotaxin (NPP2), a secreted metastasis-enhancing lysophospholipase D. 1598 67

The Cdc25 dual-specificity phosphatases are key regulators of cell cycle progression through activation of cyclin-dependent kinases (Cdk). Three homologs exist in humans: Cdc25A, Cdc25B, and Cdc25C. Cdc25A and Cdc25B have oncogenic properties and are overexpressed in some types of tumors. Compounds that inhibit Cdc25 dual-specificity phosphatase activity might thus be potent anticancer agents. We screened several hundred compounds in a library using an in vitro phosphatase assay, with colorimetric measurement of the conversion of p-nitrophenyl phosphate (pNPP) to p-nitrophenol by the catalytic domain of recombinant human Cdc25, and discovered TPY-835, which inhibits Cdc25A and Cdc25B activity (IC50 = 5.1 and 5.7 microM, respectively). TPY-835 had mixed inhibition kinetics for Cdc25A and Cdc25B. TPY-835 caused cell cycle arrest in the G1 phase in human lung cancer cells (A549 and SBC-5) but not cell cycle arrest in the G2/M phase. After treatment with TPY-835, the activation of Cdk2 was suppressed and phosphorylation of the retinoblastoma (Rb) protein was decreased in SBC-5 cells. In addition, TPY-835 induced an increase of the sub-G1 phase cell population after 48-72 h treatment. The growth inhibitory effects of TPY-835 against cisplatin (CDDP)-, camptothecin- and 5-FU-resistant cell lines are comparable to the growth inhibitory effect on their parental lines, thus indicating that TPY-835 did not show cross-resistance to these cell lines. These results suggest that TPY-835 is a promising candidate for constructing a novel class of antitumor agents that can control the cell cycle progression of cancer cells.
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PMID:A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity. 1612 47


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