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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidant-induced apoptosis involves oxidation of many different and essential molecules including phospholipids. As a result of this non-specific oxidation, any signaling role of a particular phospholipid-class of molecules is difficult to elucidate. To determine whether preferential oxidation of phosphatidylserine (PS) is an early event in apoptotic signaling related to PS externalization and is independent of direct oxidant exposure, we chose a genetic-based induction of apoptosis. Apoptosis was induced in the lung cancer cell line NCI-H226 by decreasing the amount of Bcl-2 protein expression by preventing the translation of bcl-2 mRNA using an antisense bcl-2 oligonucleotide. Peroxidation of phospholipids was assayed using a fluorescent technique based on metabolic integration of an oxidation-sensitive and fluorescent fatty acid, cis-parinaric acid (PnA), into cellular phospholipids and subsequent HPLC separation of cis-PnA-labeled phospholipids. We found a decrease in Bcl-2 was associated with a selective oxidation of PS in a sub-population of the cells with externalized PS. No significant difference in oxidation of cis-PnA-labeled phospholipids was observed in cells treated with medium alone or a nonsense oligonucleotide. Treatment with either nonsensc or antisense bcl-2 oligonucleotides was not associated with changes in the pattern of individual phospholipid classes as determined by HPTLC. These metabolic and topographical changes in PS arrangement in plasma membrane appear to be early responses to antisense bcl-2 exposure that trigger a PS-dependent apoptotic signaling pathway. This observed externalization of PS may facilitate the 'labeling' of apoptotic cells for recognition by macrophage scavenger receptors and subsequent phagocytic clearance.
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PMID:Depletion of Bcl-2 by an antisense oligonucleotide induces apoptosis accompanied by oxidation and externalization of phosphatidylserine in NCI-H226 lung carcinoma cells. 1216 25

Arsenic trioxide (As(2)O(3)) has been found to induce apoptosis in leukemia cell lines and clinical remissions in patients with acute promyelocytic leukemia. In this study, we investigated the cytotoxic effect and mechanisms of action of As(2)O(3) in human tumor cell lines. As(2)O(3) caused inhibition of cell growth (IC(50) range, 3-14 microM) in a variety of human solid tumor cell lines, including four human non-small-cell lung cancer cell lines (H460, H322, H520, H661), two ovarian cancer cell lines (SK-OV-03, A2780), cervical cancer HeLa, and breast carcinoma MCF-7, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry analysis showed that As(2)O(3) treatment resulted in a time-dependent accumulation of cells in the G(2)/M phase. We observed, using Wright-Giemsa and 4',6-diamidine-2-phenylindole-dihydrochloride staining, that As(2)O(3) blocked the cell cycle in mitosis. In vitro examination revealed that As(2)O(3) markedly promoted tubulin polymerization without affecting GTP binding to beta-tubulin. Immunocytochemical and EM studies of treated MCF-7 cells showed that As(2)O(3) treatment caused changes in the cellular microtubule network and formation of polymerized microtubules. Similar to most anti-tubulin agents, As(2)O(3) treatment induced up-regulation of the cyclin B1 levels and activation of p34(cdc2)/cyclinB1 kinase, as well as Bcl-2 phosphorylation. Furthermore, activation of caspase-3 and -7 and cleavage of poly(ADP-ribose) polymerase and beta-catenin occurred only in As(2)O(3)-induced mitotic cells, not in interphase cells, suggesting that As(2)O(3)-induced mitotic arrest may be a requirement for the activation of apoptotic pathways. In addition, As(2)O(3) exhibited similar inhibitory effects against parental MCF-7, P-glycoprotein-overexpressing MCF-7/doxorubicin cells, and multidrug resistance protein (MRP)-expressing MCF-7/etoposide cells (resistance indices, 2.3 and 1.9, respectively). Similarly, As(2)O(3) had similar inhibitory effect against parental ovarian carcinoma A2780 cells and tubulin mutation paclitaxel-resistant cell lines PTx10 and PTx22 (resistance indices, 0.86 and 0.93, respectively), suggesting that its effect on tubulin polymerization and G(2)/M phase arrest is distinct from that of paclitaxel. Taken together, our data demonstrate that As(2)O(3) has a paclitaxel-like effect, markedly promotes tubulin polymerization, arrests cell cycle at mitosis, and induces apoptosis. In addition, As(2)O(3) is a poor substrate for transport by P-glycoprotein and MRP, and non-cross-resistant with paclitaxel resistant cell lines due to tubulin mutation, suggesting that As(2)O(3) may be useful for treatment of human solid tumors, particularly in patients with paclitaxel resistance.
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PMID:Arsenic trioxide produces polymerization of microtubules and mitotic arrest before apoptosis in human tumor cell lines. 1218 29

Prognosis of patients with non small cell lung cancer (NSCLC) remains difficult to assess, even after adjustment for pathological stage. Prognostic value of numerous biological markers has been evaluated, with conflicting results. Data of 86 patients with NSCLC treated by surgery were collected with clinical characteristics, histopathological data including tumor differentiation and status of blood and lymphatic vessel invasion and evaluation by immunohistochemistry of Rb, Bcl-2 and Ki-67 expression. Prognostic values for overall survival (OS) and event-free survival (EFS) were analyzed by the log tank test and the multivariable Cox model. Using univariable analyses, pT, pN, poor differentiation or large cell subtype were associated with a poor OS, while lymphatic and/or blood vessel invasion were associated with a short EFS. None of the molecular markers had a significant prognostic value for either outcome. In multivariable analyses, only stage remained of prognostic value for OS. Interestingly, the presence of blood vascular invasion in the tumor was significantly predictive for subsequent metastatic occurrence in stages I and II. This feature might, therefore, be relevant for administration of adjuvant therapy in completely resected NSCLC.
Lung Cancer 2002 Nov
PMID:Blood vessel invasion in resected non small cell lung carcinomas is predictive of metastatic occurrence. 1239 29

Lung cancer continues to be the leading cause of cancer-related death in the United States. Therefore, new agents targeting prevention and treatment of lung cancer are urgently needed. In the present study, we demonstrate that a novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) is a potent inducer of apoptosis in human non-small cell lung carcinoma (NSCLC) cells. The concentrations required for a 50% decrease in cell survival (IC50) ranged from 0.1 to 0.3 microM. CDDO-Me induced rapid apoptosis and triggered a series of effects associated with apoptosis including a rapid release of cytochrome c from mitochondria, activation of procaspase-9, -7, -6, and -3, and cleavage of poly(ADP-ribose) polymerase and lamin A/C. Moreover, the caspase-3 inhibitor Z-DEVD-FMK and the pan caspase inhibitor Z-VAD-FMK suppressed CDDO-Me-induced apoptosis. These results indicate that CDDO-Me induced apoptosis in human NSCLC cells via a cytochrome c-triggered caspase activation pathway. CDDO-Me did not alter the level of Bcl-2 and Bcl-xL proteins, and no correlation was found between cell sensitivity to CDDO-Me and basal Bcl-2 expression level. Furthermore, overexpression of Bcl-2 did not protect cells from CDDO-Me-induced apoptosis. These results suggest that CDDO-Me induces apoptosis in NSCLC cells irrespective of Bcl-2 expression level. In addition, no correlation was found between cell sensitivity to CDDO-Me and p53 status, suggesting that CDDO-Me induce a p53-independent apoptosis. Our results demonstrate that CDDO-Me may be a good candidate for additional evaluation as a potential therapeutic agent for human lung cancers and possibly other types of cancer.
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PMID:Identification of a novel synthetic triterpenoid, methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, that potently induces caspase-mediated apoptosis in human lung cancer cells. 1246 12

Bcl-2 in cancer cells was shown to be a potent indicator of 5-FU efficacy, but the protein in normal tissue cells appeared not to be a marker of 5-FU toxicity probably due to the functional alteration of Bcl-2 associated with cell senescence. Transfection analysis of Bcl-2-S and Bcl-2-AS into A549 lung cancer cells revealed that Bcl-2 suppressed cell death induced by 5-FU, and the gene expression level of Bcl-2 was closely correlated with the IC50 for 5-FU in 21 fresh human gastric tumor specimens. Such correlation could not be observed in a neonatal human foreskin fibroblast strain, MJ90 (HCA2), and 21 human normal tissues adjacent to tumors. Transfection analysis of Bcl-2-S and Bcl-2-AS into MJ90 cells showed that Bcl-2 correlated with the resistance to 5-FU in the transfectants at PDL60 as in A549 cells, but increased Bcl-2 in the PDL72 senescent transfectant did not cause an increase of the resistance to 5-FU. Cell aging was observed in MJ90 cells and Bcl-2 in the cells was found to decrease with the cell senescence. The senescent cells, however, were more resistant to 5-FU than the younger PDL60 cells having proliferation activity.
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PMID:Bcl-2 in cancer and normal tissue cells as a prediction marker of response to 5-fluorouracil. 1246 2

Early detection of lung cancer requires none or few invasive techniques. Distal lung cancer (40% of the cases in most European countries) can be sensitively detected by spiral computed tomography. Theoretically, in 60% of cases, the proximal lesions (main to segmental bronchi, accessible by bronchoscopy) should be able to be detected by sputum cytology. Unfortunately, this very specific technique has a low sensitivity and is time consuming. Fluorescent bronchoscopy increases the detection rate of early or micro-invasive lesions and may be proposed in highly selected populations, but not as a screening test. Biomarkers in blood and sputum have not yet been clinically validated. However, the amount of data generated from studies first on resected tumours, then on early bronchial lesions and more recently on blood and sputum offer a wide field for investigation. Lung carcinogenesis is a multistep process characterised by the accumulation of successive molecular genetic and epigenetic abnormalities, resulting in selection of clonal cells with uncontrolled growth capacities throughout the whole respiratory tract (field cancerisation). Molecular lesions far precede morphological transformation of preneoplastic bronchial lesions (dysplasia) or alveolar lesions (atypical alveolar hyperplasia). Genetic and epigenetic abnormalities in the genes involved in cell cycle, senescence, apoptosis, repair, differentiation and cell migration control may be detected on bronchial biopsies, on respiratory cells from the sputum and even in the circulating deoxyribonucleic acid (DNA). The key genes involved include those in the P53-retinoblastoma (Rb) pathways. The balance between cyclin-dependent kinases and their inhibitors regulates the level of Rb phosphorylation and its function at G1-S transition; P53 plays at least two functions (cell cycle and apoptosis control). The balance of bax-bcl2 is important in the control of apoptosis as well as loss of fragile histidine triad expression. O(6)-methylguanine-DNA methyltransferase seems to be important in DNA repair control, the RARbeta receptor in differentiation, and cadherin H and E and different metalloproteases genes in cell migration. The demonstration of hyperexpression or silencing of these genes needs different validated techniques: immunohistochemistry on biopsies or cytological preparations, molecular biology techniques for mutations, loss of heterozygosity and aberrant methylation abnormalities. Automation and miniaturisation of these techniques will allow early detection and may be widely applied once clinically validated.
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PMID:Early detection of lung cancer: role of biomarkers. 1257

Surgical series of non-small cell lung cancer (NSCLC) pathologic samples have shown that the expression of the proteins bcl-2 and bax, which regulate cell death, may have prognostic implications. Laboratory data also suggests that these proteins may impact chemotherapy response. In order to determine the rate of bcl-2 and bax expression in advanced NSCLC and assess the impact on chemotherapy response and patient survival, we performed immunohistochemistry on biopsy samples from patients enrolled in a phase I/II trial of vinorelbine plus docetaxel. We chose to study the pathology of patients in this specific trial because both docetaxel and vinorelbine phosphorylate bcl-2 and we hypothesized that this mechanism may affect clinical outcome. The goal of this study was to determine the feasibility of this analysis, and to observe any differences in response rate or survival based on bcl-2 or bax staining results. Unstained slides from paraffin blocks were obtained for 31 patients (55%) on the phase I/II trial. The patient characteristics for this subgroup did not differ significantly from the entire cohort of patients on the trials. Bcl-2 staining was positive in 5/31 samples (16%, 95% CI 3-29%) and bax was positive in 19/28 samples (68%, 95% CI 51-85%). Bcl-2 and bax staining did not correlate with response (p = 0.65 and 1.00 respectively, Fisher's exact test), or survival (by Kaplan-Meier curves). In conclusion, bcl-2 and bax expression was similar in this population with advanced NSCLC to previously reported results for early stage disease, but did not predict response to vinorelbine plus docetaxel in this series.
Lung Cancer 2003 Feb
PMID:Bcl-2 and bax expression in advanced non-small cell lung cancer: lack of correlation with chemotherapy response or survival in patients treated with docetaxel plus vinorelbine. 1258 65

The chronological changes in intracellular Ca(2+)concentrations ([Ca(2+)](i)) were analysed during heat-induced apoptosis in human lung cancer cell lines LK-2 (squamous cell carcinoma) and LU65A (large cell carcinoma). In LK-2 cells, increased [Ca(2+)](i) levels were maintained at levels between 250-350 nm 9 h after heat-shock. Treatment with BAPTA, an intracellular Ca(2+) chelator, prior to heat-shock, decreased the frequency of heat-induced apoptosis in LK-2, while thapsigargin, a selective endoplasmic reticulum Ca(2+)-ATPase inhibitor, did not change the number of apoptotic cells, regardless of the presence or absence of Ca(2+)-supplemented medium. In LU65A cells, treatment with BAPTA or thapsigargin did not alter the apoptotic rates. Western blotting demonstrated that, although expression of Bax and Bcl-2 were not changed by heat-shock, p53 expression was elevated in LK-2, but not LU65A cells. Immunohistochemistry showed that p53 was localized predominantly in the cytoplasms of LK-2 cells, suggesting that p53 protein is not functional in LK-2. Heat-shock also elevated activities of caspase-3, -8 and -9 in both cell lines. It is concluded that a temporal increase in [Ca(2+)](i) is the important initiating factor in hyperthermia-induced apoptosis in LK-2 cells and that, in these two lung cancer cell lines, apoptosis may occur through 'cross-talk' between p53-independent mitochondrial and death receptor pathways.
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PMID:Elevated levels of intracellular Ca2+ and apoptosis in human lung cancer cells given heat-shock. 1262 40

The p53 mutant 143Ala is a human temperature-sensitive mutant with two conformational states. To definitively determine whether the Fas signal transduction pathway and the function of the pathway are dependent on p53 status, we have established stable transfectants of p53 mutant 143Ala in two human cancer cell lines: H1299 (lung cancer line) and PC-3 (prostate cancer line), the native state of which contains null p53 status and can grow at 37 degrees C and 32.5 degrees C. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell cycle analysis showed inhibition of the growth of cells overexpressing p53 mutant 143Ala in the wild-type p53 form at 32.5 degrees C because of induction of G0/G1 arrest. Transfected cells had increased protein expression of p21, Fas, and MDM2 at the wild-type p53 conformation at 32.5 degrees C, but not in the mutant p53 form at 37 degrees C. However, there was no change in protein expression of FADD, FAP-1, Bcl-2, or Bax at 32.5 or 37 degrees C. Assays for apoptosis demonstrated that anti-Fas antibody CH-11 and FasL induced apoptosis only in cells that overexpress p53 mutant 143Ala at 32.5 degrees C with the wild-type p53 form. Both caspase-3 and caspase-8 activities were increased by anti-Fas antibody CH-11 only in cells at 32.5 degrees C with wild-type p53. Our results demonstrated that Fas-mediated apoptosis in H1299 and PC-3 cells expressing p53 mutant 143Ala occurred only with the wild-type p53 phenotype. These results support the hypothesis that Fas-mediated apoptosis is dependent, at least partially, on the presence of a functional wild-type p53 state. This model may be a useful tool for dissecting the specific interactions between wild-type p53 and the Fas signal transduction pathway in human cancer cells.
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PMID:Fas-mediated apoptosis is dependent on wild-type p53 status in human cancer cells expressing a temperature-sensitive p53 mutant alanine-143. 1267 Sep

Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer especially in India and displays resistance to anticancer treatment. In our earlier study we had isolated a cDNA clone from rat thymocytes induced to undergo apoptosis, which was found to encode S29 ribosomal protein [Biochem. Biophys. Res. Commun. 277 (2000) 476]. In the present study an attempt has been made to find out whether enhanced expression of S29 cDNA can kill NSCLC H520 cells. We found that S29 induced apoptosis and augmented the effect of anticancer drugs. Expressions of several molecular determinants of apoptosis were analyzed in order to understand the mechanism of apoptosis induced by S29. We observed downregulation of the expression of inhibitors of apoptosis proteins (IAPs) Bcl-2, Bcl-X(L), and survivin and upregulation of pro-apoptotic p53 and Bax as assessed by Western blotting. Mitochondrial release of cytochrome c and activation of initiator caspase-8 and -9 and effector caspase-3, followed by cleavage of nuclear substrate poly(ADP-ribose) polymerase, were also observed. Permeability transition as determined by changes in DeltaPsi(m) was not a requirement for cytochrome c release. There was a marginal increase in the release of apoptosis inducing factor (AIF) and reduction of NF-kappaB dependent transcriptional activity. There was non-involvement of calcium and the telomerase activity, a proliferation marker.
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PMID:S29 ribosomal protein induces apoptosis in H520 cells and sensitizes them to chemotherapy. 1270 79


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