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

Small-cell lung cancer accounts for up to one-fifth of all lung cancers diagnosed. While the response rates to chemotherapy are high, ultimately the majority of patients will relapse and die from their disease. Long-term outcomes are poor. A number of new agents and novel strategies for the treatment of small-cell lung cancer are under evaluation, and this review outlines the current most promising agents and pivotal trials. Oblimersen, an antisense oligonuclide to the oncogene bcl-2, has been safely combined with chemotherapy. The proteosome inhibitor bortezomib has not demonstrated single-agent activity in phase II trials but is now being evaluated with proapoptotic triggers. A number of anti-angiogenic strategies have been evaluated in small-cell lung cancer. The vascular endothelial growth factor (VEGF) antibody bevacizumab and a number of VEGF receptor tyrosine kinase inhibitors are in the early phases of clinical trials. Results from trials have not demonstrated any survival advantage with the addition of matrix metalloproteinase inhibitors. A phase III trial has reported improvements in median survival with the addition of thalidomide to chemotherapy, but toxicity has been problematic. Immunotherapy with p53 vaccines and BEC2 antibodies have shown some promise and require further evaluation to determine whether humoral responses can predict for response. Trials with the immunoconjugate BB-10901 and temirolimus are ongoing.
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PMID:Novel therapies for the treatment of small-cell lung cancer: a time for cautious optimism? 1710 Apr 4

Selaginella tamariscina is a traditional Chinese herb for the therapy of chronic trachitis and has been approved some anti-tumor activity. However, the anti-metastasis effects of Selaginella tamariscina in the lung cancer have not been understood clearly. The objectives of study were to investigate the effects of the Selaginella tamariscina extracts (STE) on the invasion and motility of highly metastatic A549 and Lewis lung carcinoma (LLC) cells. To further investigate the precise involvement of STE in tumor metastasis, A549 and LLC cells were treated with STE at various concentrations (0-100 microg/mL) for a specified period. The results from zymography showed that a STE treatment decreased (p<0.05) the expressions of matrix metalloproteinase (MMP)-2, -9 and urokinase plasminogen activator (u-PA) in a dose-dependent manner in the A549 and LLC cell. Meanwhile, their endogenous inhibitors, which are tissue inhibitor of metalloproteinase-2 (TIMP-2) and plasminogen activator inhibitor-1 (PAI-1), were increased in the A549 cell. Furthermore, the inhibitory effect of STE on the growth and metastasis of LLC cells in vivo was also proven. These results demonstrated that STE could be a candidate antimetastatic agent against lung cancer.
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PMID:Antimetastatic activities of Selaginella tamariscina (Beauv.) on lung cancer cells in vitro and in vivo. 1711 37

Insulin-like growth factor binding protein-3 (IGFBP-3), a major IGF-binding protein in human serum, regulates the growth of non-small cell lung cancer (NSCLC) cells through IGF-dependent and IGF-independent mechanisms. However, the role of IGFBP-3 in lung cancer metastasis is not well known. In the present study, we showed that noncytotoxic doses of adenoviral or recombinant IGFBP-3 significantly decreased the migration and invasion of H1299 and A549 NSCLC cells. Furthermore, treatment of human lung fibroblasts with recombinant IGFBP-3 suppressed their ability to stimulate the invasion of H1299 cells. Overexpression of IGFBP-3 markedly reduced lung metastasis of A549 cells in an experimental animal model system and prolonged the survival time of the animals. Urokinase-type plasminogen activator (uPA) inhibitor treatment or uPA small interfering RNA transfection of A549 and H1299 cells resulted in a significant decrease in invasion. Corresponding ELISA, Western blot, gelatin zymogram, and semiquantitative reverse transcription-PCR analyses revealed that IGFBP-3 reduced the expression of uPA mRNA through IGF-independent mechanisms. The specific role of uPA in anti-invasive activity of IGFBP-3 was further confirmed in NSCLC cells, in which uPA expression/activity was suppressed by the transfection with synthetic small interfering RNA or by the treatment with uPA inhibitor or induced by the infection with an adenoviral vector. IGFBP-3 also decreased the expression/activity of matrix metalloproteinase-2 through IGF-dependent but uPA-independent pathways. Taken together, our data suggest that IGFPB-3 effectively block uPA- and matrix metalloproteinase-2-stimulated invasion pathways, ultimately reducing lung cancer cell metastasis. Our findings indicate that IGFBP-3 may be a promising anti-invasive and antimetastatic therapeutic agent in lung cancer.
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PMID:Antimetastatic activity of insulin-like growth factor binding protein-3 in lung cancer is mediated by insulin-like growth factor-independent urokinase-type plasminogen activator inhibition. 1712 15

HIV-1 protease inhibitor (PI), nelfinavir (NFV) induced growth arrest and apoptosis of NCI-H460 and -H520, A549, EBC-1 and ABC-1 non-small-cell lung cancer (NSCLC) cells in association with upregulation of p21waf1, p27kip1 and p53, and downregulation of Bcl-2 and matrix metalloproteinase (MMP)-2 proteins. We found that NFV blocked Akt signalling in these cells as measured by Akt kinase assay with glycogen synthase kinase-3alpha/beta (GSK-3alpha/beta) as a substrate. To explore the role of Akt signalling in NFV-mediated growth inhibition of NSCLC cells, we blocked this signal pathway by transfection of Akt small interfering RNA (siRNA) in these cells; transient transfection of Akt siRNA in NCI-H460 cells decreased the level of Bcl-2 protein and slowed their proliferation compared to the nonspecific siRNA-transfected cells. Conversely, forced-expression of Akt partially reversed NFV-mediated growth inhibition of these cells, suggesting that Akt may be a molecular target of NFV in NSCLC cells. Also, we found that inhibition of Akt signalling by NFV enhanced the ability of docetaxel to inhibit the growth of NCI-H460 and -H520 cells, as measured by MTT assay. Importantly, NFV slowed the proliferation and induced apoptosis of NCI-H460 cells present as tumour xenografts in nude mice without adverse systemic effects. Taken together, this family of compounds might be useful for the treatment of individuals with NSCLC.
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PMID:NFV, an HIV-1 protease inhibitor, induces growth arrest, reduced Akt signalling, apoptosis and docetaxel sensitisation in NSCLC cell lines. 1713 72

The high incidence of lung cancer and ineffective toxic action of current mono and doublet chemotherapy approaches result in poor patient survival. Further, matrix metalloproteinases (MMPs) are implicated in neoplastic invasion and metastasis. Based on this, the authors investigated the effect of a dietary micronutrient mixture (NM) containing lysine, proline, arginine, ascorbic acid, and green tea extract on the tumor growth of human lung carcinoma cell A-549 xenografts in athymic nude mice. Additionally, the authors tested the in vitro antitumor effect of NM on lung carcinoma A-549 cells by measuring cell proliferation by MTT assay, MMP-2 and -9 secretion by gelatinase zymography, and cell invasion through Matrigel. Nutrient supplementation strongly suppressed the growth of tumors without adverse effects in nude mice; tumor weight was reduced by 44% (P = .0001) and tumor burden was reduced by 47% (P < .0001) with supplementation. Zymography demonstrated in vitro secretion of MMP-2 by uninduced human lung carcinoma cells and both MMP-2 and -9 by phorbol 12-mysristate 13-acetate (PMA) (200 ng/mL)-treated cells. NM inhibited the secretion of both MMPs in a dose-dependent fashion, with virtual total inhibition at 500 microg/mL concentration. The invasion of human lung carcinoma cells through Matrigel was significantly reduced at 100 microg/mL (64%) and totally inhibited at 500 microg/mL concentration of NM (P = .01). Suppression of lung tumor growth in nude mice and inhibition of MMP secretion and Matrigel invasion suggest NM may act as an anticancer agent and as such warrants further investigation.
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PMID:In vivo and in vitro antitumor effect of a unique nutrient mixture on lung cancer cell line A-549. 1716 51

Flavanones richly exist in citrus and have been well characterized to have various bioactive properties. However, the anti-metastasis properties of flavanones remain unclear. The anti-metastatic effects of six flavanones including flavanone, 2'-OH flavanone, 4'-OH flavanone, 6-OH flavanone, naringin, and naringenin were investigated in lung cancer cells. Despite little influence on cell viability, flavanone and 2'-OH flavanone markedly inhibited the invasion, motility, and cell-matrix adhesion of A549 cells. This was associated with a reduced expression of matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen activator (u-PA) in treated cells. Treatment with flavanone and 2'-OH flavanone also potently attenuated the phosphorylations of extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38(MAPK), as well as the activations of NF-kappaB and AP-1. The reduced expressions of MMP-2 and u-PA, as well as inhibition of cell invasion were obtained in the cultures treated with U0126 (ERK 1/2 inhibitor) and SB203580 (p38(MAPK) inhibitor). Thus, the inhibitory effects of flavanone and 2'-OH flavanone on the expression of MMP-2 and u-PA may be at least partly through inactivation of ERK 1/2 and p38(MAPK) signaling pathways. Finally, oral administration of flavanone and 2'-OH flavanone were evidenced by its inhibition on the metastasis of A549 cells and Lewis lung carcinoma (LLC) cells in vivo. In conclusion, flavanone and 2'-OH flavanone perturb the invasion and metastasis of lung cancer cells, thereby constituting an adjuvant treatment for metastasis control.
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PMID:Flavanone and 2'-OH flavanone inhibit metastasis of lung cancer cells via down-regulation of proteinases activities and MAPK pathway. 1737 16

The brain is frequently affected by the spread of lung cancer, and haematogenous metastasis is a common route to brain metastasis. We therefore developed an isogenic brain metastasis model of lung cancer to use the Lewis lung carcinoma cell line and analysed dynamics of neoplastic cells after extravasation. Histological analysis revealed two characteristic patterns: metastatic foci exhibiting an angiocentric pattern were designated 'perivascular proliferations'; neoplastic cells infiltrating the brain parenchyma were designated 'invasive proliferations'. Electron microscopic observation of perivascular proliferations showed that neoplastic cells were confined to the perivascular space. In invasive proliferations, however, fragments of collagen fibre were observed in the gaps between neoplastic cells, indicating that the neoplastic cells had disintegrated the pia-glial membrane. We analysed the expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 by using both immunohistochemical analysis and real-time polymerase chain reaction analysis. MMP-2 expression was significantly higher in invasive proliferations. MMP-9 expression was significantly higher in day 7, but there was no significant difference in day 11. The pia-glial membrane and perivascular space are the barriers that neoplastic cells must overcome to infiltrate the brain. In conclusion, our findings suggest that brain metastasis requires two distinct processes.
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PMID:A double three-step theory of brain metastasis in mice: the role of the pia mater and matrix metalloproteinases. 1749 10

The type 1 insulin-like growth factor receptor (IGF-1R), which is over-expressed or activated in many human cancers, including lung cancer, mediates cancer cell proliferation and metastasis. Several studies indicate that blocking IGF-1R expression can inhibit tumor cell proliferation and metastasis. In this study, inhibition of the endogenous IGF-1R by recombinant adenoviruses encoding short hairpin RNAs against IGF-1R was found to significantly suppress IGF-1R expression, arrest the cell cycle, enhance the apoptotic response, and inhibit proliferation, adhesion, invasion and migration in A549 cells. Moreover, silencing IGF-1R decreases the expression of invasive-related genes including matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-plasminogen activator (u-PA), and the phosphorylation of Akt and ERK1/2. These results suggest that the silencing of IGF-1R has the potential to be an effective cancer gene therapy strategy for human lung cancer.
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PMID:Silencing of the type 1 insulin-like growth factor receptor increases the sensitivity to apoptosis and inhibits invasion in human lung adenocarcinoma A549 cells. 1758 22

We showed previously that treatment of human airway smooth muscle cells and lung fibroblasts with lysophosphatidic acid (LPA) increases the binding of epidermal growth factor (EGF) to EGF receptors (EGFRs). The purpose of this study was to determine whether LPA also regulates EGFR binding in airway epithelial cells. Airway epithelial cells were incubated in the absence or presence of 10 microM LPA for increasing times, and binding of 125I-EGF to intact cells on ice was measured. Exposure to LPA for only 15 min caused a 30 to 70% decrease in EGFR binding in a dose-dependent manner, depending on the cell line. This decrease in binding was sustained to at least 18 h in BEAS-2B and primary human bronchial epithelial cells. In contrast, the LPA-induced decrease in binding reversed rapidly in two lung cancer epithelial cell lines, H292 and A549, returning to control levels within 3 h. LPA increased phosphorylation of the EGFR in BEAS-2B cells, and this phosphorylation was inhibited by both 4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline (AG1478; EGFR tyrosine kinase inhibitor) and N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide (GM6001; matrix metalloproteinase inhibitor) but not by CRM197 (heparin-binding EGF inhibitor). AG-1478 and GM6001 also inhibited the LPA-induced decrease in EGFR binding but only by 50%, suggesting only partial involvement of EGFR transactivation in the decrease in EGFR binding. In summary, LPA stimulates a decrease in EGFR binding in airway epithelial cells that is sustained in normal cells but that rapidly reverses in cancer cells. LPA-induced transactivation of EGFRs occurs and contributes to the decrease in EGFR binding, but additional pathway(s) may also be involved.
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PMID:Lysophosphatidic acid decreases epidermal growth factor receptor binding in airway epithelial cells. 1764 Sep 53

It has been reported that an endogenous matrix metalloproteinase (MMP) inhibitor, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), is able to inhibit tumour angiogenesis, invasion, and metastasis through inhibition of MMP-2, MMP-9, and membrane type-1 (MT1)-MMP (MMP-14) secretion and activity. In this study, using quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR), we have analysed RECK expression levels in resected non-small-cell lung cancer (NSCLC) tissue and compared these data with the clinicopathological features of these patients to investigate the role of RECK in NSCLC. We have also analysed the expression of MMP-2, MMP-9, and MMP-14 and compared the data with those for RECK expression. Tissue samples of primary lung cancers were obtained from a total of 83 patients [46 with adenocarcinomas (ADC) and 37 with squamous cell carcinomas (SCC)] who underwent curative resection. The samples were taken from 83 tumours and 20 matched normal lung tissue samples as controls. Expressions of RECK in ADC and SCC were significantly lower than in the control. In ADC tissue, the expression of RECK was higher in stage IA than in stage IB-IIIA. There was no such a correlation in SCC. In ADC, univariate analysis for relapse-free survival using Cox regression analysis identified low RECK expression (p=0.036), low MMP-14 expression (p=0.038), and tumour T2 (p=0.034) as significant negative prognostic predictors. However, in SCC, none of the clinicopathological factors assessed, including RECK expression, had prognostic value. In conclusion, our study suggests that suppression of RECK expression is involved in the progression of ADC of the lung and that RECK expression in resected ADC of the lung is a favorable predictor of patients' prognosis.
Lung Cancer 2007 Dec
PMID:Low expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) indicates a shorter survival after resection in patients with adenocarcinoma of the lung. 1771 26


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