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)

Gefitinib (Iressa, ZD1839), a quinazoline tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR), is approved for patients with advanced non-small cell lung cancer (NSCLC) in several countries including Japan. However, the mechanism of drug sensitivity to gefitinib is not fully understood. In this study, we examined the molecular basis of sensitivity to gefitinib using nine human lung cancer cell lines derived from NSCLC. PC9 was the most sensitive to gefitinib of the nine NSCLC cell lines when assayed either by colony formation or MTS assays. The various cell lines expressed different levels of EGFR, HER2, HER3, and HER4, but there was no correlation between levels of EGFR and/or HER2 expression and drug sensitivity. Phosphorylation of EGFR, protein kinase B/AKT (Akt), and extracellular signal-regulated kinase (ERK) 1/2 was inhibited by much lower concentration of gefitinib in PC9 cells than in the other eight cell lines under exponential growing conditions. About 80% of cell surface EGFR in PC-9 was internalized within 10 min, whereas only about 30-50% of the cell surface EGFR was internalized in more drug-resistant cell lines in 15-60 min. The present study is the first to demonstrate that sensitivity to growth inhibition by gefitinib in NSCLC cell lines under basal growth condition is associated with dependence on Akt and ERK1/2 activation in response to EGFR signaling for survival and proliferation and also that drug sensitivity may be related to the extent of EGF-induced down-regulation of cell surface EGFR.
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PMID:Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. 1507 90

To study the effects of cyclooxygenase 2 selective inhibitor Nimesulide (NIM) combined with Cisplatin (DDP) on human lung cancer and the possible mechanisms, the proliferation and apoptosis of human lung cancer cell line A549 were evaluated by MTT reduction assay and flow cytometry respectively. The inhibitory effect on neoplasia in vivo was tested on nude mice subcutaneously implanted tumor. Our results showed that NIM and DDP could inhibit A549 cell proliferation in a concentration-dependent pattern; this action was enhanced when NIM (25 micromol/L) was given in combination with DDP and they worked in a synergistic or additive pattern as DDP concentration > or = 1 microg/ml. NIM and DDP could induce A549 cells apoptosis and the action was augmented when used in combination (P<0.01). NIM and DDP could inhibit the growth of subcutaneously implanted tumors on nude mice (P<0.05, P<0.01) and the inhibitory rate of NIM combined with DDP was significantly higher than that of NIM or DDP group (P<0.01, P<0.01). It is concluded that combined use of NIM and DDP has significant synergistic antitumor effects on lung cancer cell line A549 and in animals in vivo. The synergy may be achieved by growth inhibition and apoptosis induction.
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PMID:The effects of nimesulide combined with cisplatin on lung cancer. 1531 58

CT120, a novel membrane-associated gene implicated in lung carcinogenesis, was previously identified from chromosome 17p13.3 locus, a hot mutation spot involved in human malignancies. In the present study, we further determined that CT120 ectopic expression could promote cell proliferation activity of NIH3T3 cells using MTS assay, and monitored the downstream effects of CT120 in NIH3T3 cells with Atlas mouse cDNA expression arrays. Among 588 known genes, 133 genes were found to be upregulated or downregulated by CT120. Two major signaling pathways involved in cell proliferation, cell survival and anti-apoptosis were overexpressed and activated in response to CT120: One is the Raf/MEK/Erk signal cascades and the other is the PI3K/Akt signal cascades, suggesting that CT120 might contribute, at least in part, to the constitutively activation of Erk and Akt in human lung cancer cells. In addition, some tumor metastasis associated genes cathepsin B, cathepsin D, cathepsin L, MMP-2/TIMP-2 were also upregulated by CT120, upon which CT120 might be involved in tumor invasiveness and metastasis. In addition, CT120 might play an important role in tumor progression through modulating the expression of some candidate "Lung Tumor Progression" genes including B-Raf, Rab-2, BAX, BAG-1, YB-1, and Cdc42.
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PMID:Altered gene expression profiles of NIH3T3 cells regulated by human lung cancer associated gene CT120. 1562 16

The expressions of thymidylate synthase (TS) and intracellular metabolic enzymes have been reported to be associated with the sensitivity and/or resistance to 5-fluorouracil (5-FU). However, since the role of these enzymes in the mechanism of resistance to 5-FU has not been fully examined in lung cancer, in the present study we measured the expression levels of TS, dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase (OPRT) genes in lung cancer cell lines by real-time PCR, and the sensitivity to 5-FU using the MTS assay. The expression of DPD was significantly correlated with the concentration of 5-FU for 50% cell survival in 15 non-small-cell lung cancer (NSCLC) cell lines (p<0.05), but the expressions of TS, TP, and OPRT were not. Treatment with 5-chloro-2,4-dihydroxypyridine, an inhibitor of DPD, altered the sensitivity to 5-FU in DPD-expressing RERF-LC-MT cells, indicating that modulation of DPD activity could increase the 5-FU sensitivity in lung cancer. In contrast, TS expression was dramatically higher in a 5-FU-resistant small-cell lung cancer cell line than in the parent cell line, whereas the expressions of DPD, TP, and OPRT genes were not markedly different. In order to examine the effect of other cytotoxic agents on TS and DPD expression, we compared the expressions of both genes between cisplatin-, paclitaxel-, gemcitabine-, or 7-ethyl-10-hydroxycamptothecin-resistant lung cancer cells and their respective parent cells, but found no differences between any pair of resistant subline and the corresponding parent cell line. Our results indicate that degradation of 5-FU due to DPD is an important determinant in 5-FU sensitivity, while induction of TS contributes to acquired resistance against 5-FU in lung cancer. Therefore, the expression levels of TS and DPD genes may be useful indicators of 5-FU activity in lung cancer.
Lung Cancer 2005 Sep
PMID:The role of thymidylate synthase and dihydropyrimidine dehydrogenase in resistance to 5-fluorouracil in human lung cancer cells. 1599 11

Lung cancer remains one of the most common causes of cancer-related death worldwide. Approximately 80% is histologically non-small cell lung carcinoma (NSCLC) and in about 70% of patients it is an unresectable type. Clinical studies indicated that application of platinum derivatives caused good results and combinations of platinum with other agents could improve median survivals. In view of the central problem of sufficient efficiency of drugs in chemotherapy, efforts have focused on the development of alternative platinum-based analogues that can be more effective in cancer treatment. cis-bis(3-aminoflavone)dichloroplatinum(II) (cis-Pt(II) complex of 3-aminoflavone) represents a novel class of platinum-based potential antitumour agents. In order to evaluate the degree of apoptosis, acridine orange/ethidium bromide and Hoechst 33258/propidum iodide double staining as well as RT-PCR (P53 and BAX expression evaluation) were used in lung cancer cell line A549 after treatment with this compound in comparison with cis-diamminedichloroplatinum(II) (cis-DDP). Apoptotic cells at early and late stages and also necrotic ones were observed after usage of cis-Pt(II) complex of 3-aminoflavone and the percentage of these cells outnumbered the values obtained after cis-DDP application. The former compound induced a higher percentage of P53 and BAX expression in A549 cells in comparison with the latter one. Results indicate the beneficial properties of cis-Pt(II) complex of 3-aminoflavone as a potential antitumor drug.
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PMID:Enhanced P53 and BAX gene expression and apoptosis in A549 cells by cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP. 1601 88

Polyoxometalates are negatively charged inorganic compounds which contain metal ions such as tungsten, molybdenum, vanadium etc. and which make clusters with the surrounding oxygen atoms. [NH3Pri]6[Mo7O24].3H2O (PM-8) was found to be a significant antitumor polyoxomolybdates. It had already been reported that the PM-8 suppressed the growth of Co-4 human colon cancer, MX-1 human breast cancer and OAT human lung cancer xenografted in nude mice. However, the mechanism of the antitumor activity has not been clarified. In this study, the antitumor activity of one of the metal oxide clusters (polyoxometalates), hexabis(isopropylammonium) heptamolybdate trihydrate, [NH3Pri]6[Mo7O24].3H2O (PM-8) were shown in an MTS assay. DNA ladder formation and detection of apoptotic bodies in nuclei were revealed that antitumor activity of PM-8 in MKN45 cells was due to apoptosis. It is concluded that the observation of significant tumor growth suppression of PM-8 in MKN45-bearing mice results from the induction of apoptosis. PM-8 shows promise as a novel anti-cancer agent.
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PMID:Antitumor activity of polyoxomolybdate, [NH3Pri]6[Mo7O24].3H2O, against, human gastric cancer model. 1686 May 28

Bcl-XL is overexpressed in a variety of human tumors and is involved in tumorigenesis and chemoresistance. This study investigated the inhibitory effect of the hairpin Bcl-XL small interfering RNA (siRNA) on the expression of the Bcl-XL gene in the cisplatin (DDP)-resistant human lung adenocarcinoma cell line A549/DDP, and the effect of Bcl-XL siRNA on drug sensitization in A549/DDP cells. Bcl-XL siRNA and negative siRNA plasmids were constructed and stably transfected into A549/DDP cells. Reverse transcription-polymerase chain reaction and Western blot analysis were used to detect the target gene expression. Spontaneous apoptosis of cells was detected by acridine orange and ethidium bromide staining. Drug sensitivity of the cells to DDP was analyzed with dimethylthiazol-diphenyltetrazolium bromide (MTT) and flow cytometry. Expression levels of Bcl-XL mRNA and protein in siRNA stable transfectants were clearly reduced as compared with negative siRNA transfectants and untreated cells. MTT results indicated that Bcl-XL transfectants had a higher cell inhibition rate than the negative vector or untreated cells after treatment with 0.2-200 micarog/ml DDP. Flow cytometry revealed increased apoptosis in Bcl-XL siRNA cells. After the addition of 20 microg/ml DDP, siRNA targeting of the Bcl-XL gene specifically down-regulated gene expression in A549/DDP cells, increased spontaneous apoptosis, and sensitized cells to DDP. The results showed that Bcl-XL siRNA contributed to an increase of DDP-induced cell death in non-small-cell lung cancer and sensitized cells to DDP, leading to increased the effectiveness of the drug in treating non-small-cell lung cancer.
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PMID:Bcl-XL small interfering RNA sensitizes cisplatin-resistant human lung adenocarcinoma cells. 1749 31

The effects of RNA interference-mediated insulin-like growth factor 1 receptor (IGF1R) gene silencing in response to cisplatin (DDP) in the lung cancer cell line A549 in vivo and in vitro were investigated using two plasmids expressing short hairpin RNA (shRNA) to IGF1R. A549 cells were transfected with plasmids expressing each shRNA and then treated with DDP. Semi-quantitative reverse transcription-PCR and Western blot analysis were used to detect the expression of IGF1R. MTT assay, flow cytometry and tumor growth assay in athymic nude mice were used to assess the chemosensitivity to DDP following IGF1R knockdown. Our data showed that the transfection of A549 cells with shRNA resulted in specific silencing of IGF1R by 78.9% at the mRNA level and by 89.8% at the protein level. Down-regulation of IGF1R significantly enhanced cell sensitivity to DDP, decreased the IC50 of DDP in A549 cells at 24 h, 48 h and 72 h, and retained 77.5% of A549 cells in the G0/G1 phase. Furthermore, shRNA-mediated silencing of IGF1R in combination with DDP treatment enhanced the suppression of tumor growth in both size and weight by more than 60% and increased apoptosis by more than 75% when compared with the controls in vivo. Suppression of IGF1R gene expression by shRNA enhances the chemosensitivity of A549 cells to DDP both in vitro and in vivo, indicating the therapeutic potential of RNA interference as a method for gene therapy in treating lung cancer.
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PMID:Knockdown of insulin-like growth factor 1 receptor enhances chemosensitivity to cisplatin in human lung adenocarcinoma A549 cells. 1853 48

To investigate the immunologic characteristics and cytotoxicity of the RetroNectin-activated cytokine-induced killer cells (CIK) against drug-resistant lung cancer cell lines DDP-A549 (DDP: Cisplatin). Peripheral blood mononuclear cells (PBMC) were collected from healthy donors and divided into two groups: group I and group II. Seeded samples of group I into culture flask precoated with RetroNectin and CD3MAb to induce the CIK cells while seeded the group II into culture flask precoated with CD3MAb. In both groups, IFN-gamma was put into the flask on the same day and then IL-2 on the second day. The proliferation of CIK cells was tested by cytometirc analysis. The cytotoxicity activity of CIK cells was determined by MTT assays. The phenotype changes of CIK cells were identified by flow cytometric analysis. Scanning electron microscope (SEM) and transmission electron microscope (TEM) were used to view the cytotoxicity against DDP-A549 of CIK cells and the changes of DDP-A549. The total CIK cells significantly increased by 524.77 fold in cell proliferation number due to the activation to CIK cells of RetroNectin. The expression rate of CD3+CD56+ cells was (31.40 +/- 1.91)%. The cytotoxicity of CIK cells showed statistically significance between DDP-A549 and the sensitive strains of parental generation A549 (P < 0.01). There was no significant difference of CIK cells' cytotoxicity between two groups when the effector: target ratio was fixed (P > 0.05). RetroNectin can significantly improve the proliferation activity of CIK cells. There was no evident influence to the cytotoxicity of CIK cells. CIK cells may be used as the immuotherapy to lung adenocarcinoma owing to its significant inhibition to the proliferation of DDP-A549.
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PMID:[Proliferation and cytotoxicity of RetroNectin-activated cytokine-induced killer cells against cisplatin-resistant lung carcinoma cell]. 1899 38

Cetuximab, an antibody against epidermal growth factor receptor, has been approved for the treatment of colorectal carcinoma and head and neck squamous cell carcinoma. There is increasing evidence that cetuximab can reverse the resistance to irinotecan (CPT-11) and oxaliplatin. Since cisplatin (DDP) is a widely used chemotherapeutics this study examined whether cetuximab could reverse the resistance to DDP. Combined treatment with DDP and cetuximab resulted in an increase in the cytotoxicity of DDP in a DDP-sensitive lung cancer cell line (A549), but not in a DDP-resistant derivative (A549/DDP). Meantime, DDP activated the EGFR pathway in A549 cells but not in A549/DDP cells in a ligand-independent fashion. After the expression of excision repair cross-complementation group 1 (ERCC-1) protein was inhibited by small interfering RNA (siRNA), the potential of cetuximab to enhance DDP-mediated cytotoxicity was restored in A549/DDP cells. These data suggested that ERCC-1 was involved in the resistance of cetuximab combined with DDP as overexpression of ERCC-1 prohibits the activation of EGFR pathway, which would facilitate the preselection of lung cancer patients for the treatment of cetuximab combined with DDP.
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PMID:The overexpression of ERCC-1 is involved in the resistance of lung cancer cells to cetuximab combined with DDP. 2000 41


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