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

Cinnamic acid, a naturally occurring aromatic fatty acid of low toxicity, has a long history of human exposure. We now show that cinnamic acid induces cytostasis and a reversal of malignant properties of human tumor cells in vitro. The concentration causing a 50% reduction of cell proliferation (IC50) ranged from 1 to 4.5 mM in glioblastoma, melanoma, prostate and lung carcinoma cells. Using melanoma cells as a model, we found that cinnamic acid induces cell differentiation as evidenced by morphological changes and increased melanin production. Moreover, treated cells had reduced invasive capacity associated with modulation of expression of genes implicated in tumor metastasis (collagenase type IV, and tissue inhibitor metalloproteinase 2) and immunogenicity (HLA-A3, class-I major histocompatibility antigen). Further molecular analysis indicated that the anti-tumor activity of cinnamic acid may be due in part to the inhibition of protein isoprenylation known to block mitogenic signal transduction. The results presented here identify cinnamic acid as a new member of the aromatic fatty acid class of differentiation-inducers with potential use in cancer intervention.
 ...
PMID:Cinnamic acid: a natural product with potential use in cancer intervention. 762 77

We investigated the effect of Tiazofurin (TR-2-beta-D-furanosylthiazole-4-carbamide) on tumour cell invasion using metastatic 3LL-HH murine lung carcinoma and HT168-M1 human melanoma as experimental models. TR pretreatment of 3LL-HH cells, in a dose range of 15-60 microM, caused inhibition of cell proliferation, adhesion to plastic and extracellular matrix proteins. The TR-induced altered matrix interactions of 3LL-HH cells were reflected in decreased migration through matrix-covered filters. Analysis of the expression of certain invasion markers indicated that TR suppressed the expression of alpha v beta 3 integrin and MMP2 metalloproteinase. Biochemical studies indicated that 24 h 60 microM TR treatment of 3LL-HH cells inhibited glycosylation of a wide range of glycoproteins with the most pronounced effect on proteoglycans. TR pretreatment of 3LL-HH tumour cells resulted in the loss of lung colonisation potential in vivo. Furthermore, in vivo TR treatment inhibited the formation of liver metastases of 3LL-HH murine carcinoma. TR treatment also induced inhibition of integrin and MMP2 expression, migration and liver colonisation of the human melanoma HT168-M1 cell line. Since the TR concentration which inhibited various cellular functions was much lower for cell adhesion and lung colonisation than for cell proliferation, we suggest that the predominant effect of TR is the inhibition of metastasis in these model systems. We also suggest that both the effect of TR on tumour cell proliferation and on extracellular matrix interaction contribute to its remarkable antimetastatic potential in vivo.
 ...
PMID:The antimetabolite Tiazofurin (TR) inhibits glycoconjugate biosynthesis and invasiveness of tumour cells. 869 25

Increased levels of matrix metalloproteinases are associated with tissue degradation and remodeling during tumor invasion and wound healing. In both processes, there is evidence that cell interactions between fibroblasts and tumor cells or keratinocytes lead to increases in metalloproteinase production. We have previously isolated and purified a tumor cell surface protein, EMMPRIN (extracellular matrix metalloproteinase inducer), which stimulates production of interstitial collagenase, gelatinase A, and stromelysin-1 by fibroblasts, and we have obtained cDNA clones that encode the EMMPRIN protein from LX-1 human lung carcinoma cells. In this study we report immunolocalization of EMMPRIN around the surface of human keratinocytes in vitro and in vivo, and isolation of cDNAs that encode the entire open reading frame for EMMPRIN from a human keratinocyte library. Comparison of the EMMPRIN cDNAs from normal human keratinocytes and LX-1 human tumor cells by nucleotide sequence analysis, expression of the recombinant proteins, and in vitro translation using the cDNAs from the two sources indicate that they express very similar forms of EMMPRIN. Native EMMPRIN isolated directly from extracts of keratinocytes, however, is slightly smaller in size and is present at a lower concentration compared with that from LX-1 tumor cells. These results establish the presence of EMMPRIN in the normal epidermis and raise the possibility of its involvement in regulation of matrix remodeling at the epidermal-dermal interface.
 ...
PMID:Human keratinocytes express EMMPRIN, an extracellular matrix metalloproteinase inducer. 875 67

Because adjuvant chemotherapy has resulted in only modest prolongation of survival for patients with lung cancer, investigators have turned to the evaluation of alternative treatment strategies for this patient population. Immunotherapy with Bacillus Calmette Guerin, Corynebacterium parvum, and levamisole has been evaluated in several prospective randomized trials, and no study has shown a statistically significant difference in overall survival. Interferon has been evaluated in three trials of adjuvant therapy after response to chemotherapy for small cell lung cancer. Different interferon preparations were used, but none of the trials showed a significant prolongation of survival. The retinoids have been evaluated as adjuvant treatment after complete resection of stage IN-SCLC. One trial showed a reduction in second primary tumors, and in particular, tumors to tobacco smoking in patients treated with retinyl palmitate. A second trial using 13-cis retinoic acid is ongoing in North America. In the last decade, several inhibitors of angiogenesis have been identified, and they are now beginning to be evaluated in the clinical setting. The National Cancer Institute of Canada Clinical Trials Group and the European Organization for Research and Treatment of Cancer have initiated a study of adjuvant marimastat, a metalloproteinase inhibitor, for patients who have responded to induction chemotherapy for small cell lung cancer. This is the first adjuvant antiangiogenesis factor trial to be initiated for any tumor type. Other investigational agents which are currently undergoing Phase I and Phase II testing include monoclonal antibodies which may inhibit tumour cell growth by binding to growth factors, or which may be conjugated to toxins or chemotherapeutic agents which result in tumour cell death. In the last decade, we have witnessed an explosion in our knowledge and understanding of the regulation of normal and neoplastic cell growth at the molecular level. It remains only speculative at this time as to whether manipulation of abnormal genes in malignant cells will be clinically possible, and whether treatment of this sort may be applied in an adjuvant setting.
Lung Cancer 1997 Jun
PMID:Alternatives to chemotherapy and radiotherapy as adjuvant treatment for lung cancer. 921 9

Numerous inhibitors of angiogenesis are currently under study in lung cancer. Four trials of adjuvant interferon after chemotherapy for small cell lung cancer (SCLC) were negative. Several metalloproteinase inhibitors (MMPIs) are now in study in SCLC and non-small cell lung cancer (NSCLC). Two large randomized trials have closed recently in which Marimastat 10 mg bid was compared to placebo in responding patients with SCLC. Two randomized studies of Prinomastat versus placebo with combination chemotherapy in advanced NSCLC have also completed accrual. The results of these trials are not yet available, but should be reported in mid-2001. A Phase III trial of BMS-275291, a broad-spectrum MMPI in combination with paclitaxel and carboplatin is open for patients with advanced NSCLC. Neovastat, a standardized shark cartilage extract is under study in inoperable Stage III NSCLC. VEG-F gene expression is increased in many tumors including NSCLC, and may act as a paracrine mediator of growth. A randomized Phase II trial of paclitaxel and carboplatin with or without a recombinant humanized anti-VEG-F has been undertaken in NSCLC. Modestly better response and survival were seen with anti-VEG-F and a large Phase III trial is planned. Numerous receptor tyrosine kinases (TK) have been found to be directly or indirectly involved in angiogenesis including Flk-1, Flt-l, Tie-1 and Tie-2. SU5416 is a small molecular TK inhibitor and potent inhibitor of VEG-F-mediated Flk-1 receptor signaling. Another TK inhibitor SU6668 blocks VEG-F, bFGF and PDGF receptor signaling. It is orally available, and it may be evaluated in lung cancer trials in the near future. ZD4190 is an inhibitor of KDR/Flk-1 that may be evaluated in SCLC. Thalidomide has recently been shown in pre-clinical models to be anti-angiogenic. A randomized trial of paclitaxel/carboplatin and radiation with or without thalidomide is open for patients with Stage IIIB NSCLC in the United States. Numerous other anti-angiogenesis agents are in early clinical trials, but have not been evaluated in lung cancer yet.
Lung Cancer 2001 Dec
PMID:Angiogenesis inhibitors in the treatment of lung cancer. 1174 Sep 99

For the metastasis and invasion of cancer cells, destruction of extracellular matrix is essential. In this process, collagen is broken down by some matrix metalloproteinases. Matrix metalloproteinase 2 (MMP2) is able to cleave type IV collagen, and membrane-type-1-matrix metalloproteinase (MT1-MMP) induces activation of proMMP2. We investigated the expressions of MT1-MMP and MMP2 and their relation to both clinicopathologic parameters and clinical outcome in non-small cell lung carcinomas (NSCLC). Eighty-nine specimens of NSCLC were examined using in situ hybridization and immunohistochemistry. Each metalloproteinase was expressed within the cytoplasm of tumor cells with or without stromal cells in NSCLC. Tumors in which tumor cells strongly stained for MT1-MMP mRNA or protein made up more than 50% of the tumor area were found in 44 and 26% of cases, respectively. The corresponding values for MMP-2 mRNA and protein, were 51 and 26%. Our analysis of clinicopathological findings revealed a significant positive relationship between MT1-MMP mRNA and p-M. The correlation between MMP2 protein-staining status and overall survival rate reached significance in the univariate analysis. However, an association was not demonstrated in the multivariate analysis. The detection of MT1-MMP and MMP2 is likely to be of limited value in informing the prognosis in NSCLC.
Lung Cancer 2002 Mar
PMID:Expression of membrane-type-1-matrix metalloproteinase and metalloproteinase-2 in nonsmall cell lung carcinomas. 1184 98

Matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix is a major factor for tumor development and expansion. This study analysed MMP-10 protein expression and activity in human lung tumors of various grade, stage, and type to address the relationship between MMP-10 and tumor characteristics and to evaluate MMP-10 as a therapeutic target in non small cell lung carcinoma (NSCLC). Unlike the majority of MMPs, MMP-10 was located in the tumor mass as opposed to tumor stroma. MMP-10 protein was observed at low levels in normal human lung tissues and at significantly higher levels in all types of NSCLC. No correlation was observed between MMP-10 protein expression and tumor type, stage, or lymph node invasion. To discriminate between active and inactive forms of MMP-10 in samples of human NSCLC, we have developed an ex vivo fluorescent assay. Measurable MMP-10 activity was detected in 42 of 50 specimens of lung cancer and only 2 of 10 specimens of histologically normal lung tissue. No relationship was observed between MMP-10 activity levels and clinicopathologic characteristics. Our results suggest that MMP-10 is expressed and active at high levels in human NSCLC compared to normal lung tissues, and, as such, is a potential target for the development of novel therapeutics for lung cancer treatment.
 ...
PMID:MMP-10 is overexpressed, proteolytically active, and a potential target for therapeutic intervention in human lung carcinomas. 1572 Aug 4

The exact role of a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) and the underlying mechanism of its involvement in tumor metastasis have not been established. We have now demonstrated that overexpression of ADAMTS-1 promotes pulmonary metastasis of TA3 mammary carcinoma and Lewis lung carcinoma cells and that a proteinase-dead mutant of ADAMTS-1 (ADAMTS-1E/Q) inhibits their metastasis, indicating that the prometastatic activity of ADAMTS-1 requires its metalloproteinase activity. Overexpression of ADAMTS-1 in these cells promoted tumor angiogenesis and invasion, shedding of the transmembrane precursors of heparin-binding epidermal growth factor (EGF) and amphiregulin (AR), and activation of the EGF receptor and ErbB-2, while overexpression of ADAMTS-1E/Q inhibited these events. Furthermore, we found that ADAMTS-1 undergoes auto-proteolytic cleavage to generate the NH(2)- and COOH-terminal cleavage fragments containing at least one thrombospondin-type-I-like motif and that overexpression of the NH(2)-terminal ADAMTS-1 fragment and the COOH-terminal ADAMTS-1 fragment can inhibit pulmonary tumor metastasis. These fragments also inhibited Erk1/2 kinase activation induced by soluble heparin-binding EGF and AR. Taken together, our results suggest that the proteolytic status of ADAMTS-1 determines its effect on tumor metastasis, and that the ADAMTS-1E/Q and the ADAMTS-1 fragments likely inhibit tumor metastasis by negatively regulating the availability and activity of soluble heparin-binding EGF and AR.
 ...
PMID:Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively. 1631 35

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.
 ...
PMID:Antimetastatic activities of Selaginella tamariscina (Beauv.) on lung cancer cells in vitro and in vivo. 1711 37

Interleukin-8 (IL-8; CXCL8) is a cytokine of the CXC chemokine family that is involved in neutrophil recruitment and activation. In addition, IL-8 has been implicated in a wide variety of other processes, including angiogenesis and metastasis in lung cancer. Lung adenocarcinoma and muco-epidermoid carcinoma cells produce substantial amounts of IL-8, and express both CXCR1 and CXCR2 IL-8 receptors. We hypothesized that IL-8 stimulates proliferation of non-small cell lung cancer cells, involving transactivation of the epidermal growth factor receptor (EGFR). The EGFR plays a central role in regulating cell proliferation and it has been therefore implicated in lung cancer. Both EGFR ligands and transactivation of the receptor may lead to downstream signalling events, including mitogen-activated protein kinase (MAPK) activation. Transactivation of the EGFR has been shown to occur in response to ligands of various G-protein coupled receptors (GPCRs) and involves metalloproteinase-mediated release of membrane bound EGFR ligands. The aim of the present study was to investigate the effect of IL-8 on proliferation of lung adenocarcinoma and muco-epidermoid carcinoma cells, and to explore the mechanisms leading to this proliferation in two different non-small cell lung cancer cell lines (A549 and NCI-H292). In both NSCLC cell lines, we observed that IL-8 stimulates epithelial cell proliferation in a dose-dependent manner. The ability of IL-8 to increase cell proliferation was blocked both by an inhibitor of EGFR tyrosine kinase, by a specific anti-EGFR blocking antibody and by a panmetalloproteinase inhibitor. Similar results were obtained using the GPCR inhibitor pertussis toxin. Inhibition of the MAPK p42/44 (ERK1/2) also blocked the mitogenic effect of IL-8, while a p38 MAPK inhibitor did not affect IL-8-induced cell proliferation. These results suggest that IL-8 increases cell proliferation in NSCLC cell lines via transactivation of the EGFR and that this mechanism involves metalloproteinase activity.
Lung Cancer 2007 Apr
PMID:Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation. 1717 59


1 2 3 Next >>