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)

Isoliquiritigenin is a natural flavonoid isolated from licorice, shallot and bean sprouts. The effect of isoliquiritigenin on cell proliferation and cell cycle progression was examined in the A549 human lung cancer cell line. Isoliquiritigenin significantly inhibited the proliferation of lung cancer cells in a dose- and time-dependent manner. Flow cytometric analysis demonstrated that isoliquiritigenin restrained the cell cycle progression at G2/M phase. Further examinations using cDNA arrays and real-time quantitative RT-PCR revealed that isoliquiritigenin enhanced the expression of p21(CIP1/WAF1), a universal inhibitor of cyclin-dependent kinases. These results suggest that isoliquiritigenin will be a promising agent for use in chemopreventive or therapeutics against lung cancer.
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PMID:Induction of cell cycle arrest and p21(CIP1/WAF1) expression in human lung cancer cells by isoliquiritigenin. 1505 Jul 31

Cysteine-rich protein 61 (Cyr61) is a growth factor-inducible, immediate-early gene that has multifaceted activities in various cancers. In a previous study, we found that Cyr61 inhibited the growth of the H520 and H460 non-small-cell lung cancer (NSCLC) cell lines. In further studies, we now report that p53 plays a pivotal role in Cyr61-dependent cellular growth arrest. Blocking Cyr61 with a Cyr61 antibody resulted in the downregulation of expression of p53 and p21, as well as partially reversing the growth suppression of H520-Cyr61 cells. Proliferation of NSCLC cell lines (NCI-H157, H125, H1299), having a mutant p53, were not suppressed by Cyr61. Inhibition of wild-type p53, by either human papilloma virus type 16 E6 or a dominant-negative p53, resulted in the rescue of the growth suppression mediated by Cyr61 in the H520-Cyr61 cells. The enhanced levels of p21WAF1 and p130/RB2, in the Cyr61-expressing H520-Cyr61 cells, were also inhibited by blocking p53 showing that p21 and p130 were induced by p53 in these cells. In addition, levels of both c-myc and beta-catenin increased in Cyr61 stably transfected H520 cells. Moreover, beta-catenin was translocated into the nucleus in these cells. Inhibition of c-myc expression in the H520-Cyr61 cells with antisense c-myc resulted in their decreased levels of p53. Transfecting cells with a dominant-negative T-cell factor (TCF4), the specific inhibitor of the beta-catenin/TCF4 complex, downregulated the expression of c-myc. Taken together, the data suggest that Cyr61 suppressed the growth of NSCLC cells by triggering a signal transduction pathway through beta-catenin. In this pathway, Cyr61 activated the beta-catenin/TCF4 complex, which promoted the expression of c-myc and the latter induced expression of p53, and p53 upregulated p21WAF1 and p130/RB2, resulting in growth arrest.
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PMID:Cyr61 suppresses the growth of non-small-cell lung cancer cells via the beta-catenin-c-myc-p53 pathway. 1507 66

New promising compounds, derived from the esterification of hyaluronic acid with butyric acid, were investigated in vitro on a non-small cell lung carcinoma cell line (NCI-H460) and an its metastatic subclone (NCI-H460M). All new compounds exerted a dose-dependent inhibitory effect on both cell lines, which expressed CD44, the specific surface receptor for hyaluronic acid, in a very high percentage of cells (90%). HE1, the most effective of these compounds, was 10-fold more effective than sodium butyrate (NaB) in inhibiting cell proliferation. Similarly to NaB, after 24 hours of treatment, HE1 affected the expression of three cell cycle-related proteins (p27(kip1), p53 and p21(waf1)) responsible for growth arrest, indicating that the presence of the hyaluronic acid backbone does not interfere with the biologic activity. Intratumoral treatment with HE1 demonstrated a marked efficacy on primary tumor growth and on lung metastases formation of the murine Lewis Lung Carcinoma model. Altogether, present findings suggest a possible clinical application of these novel butyric pro-drugs in primary and metastatic lung cancer.
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PMID:Hyaluronic-acid butyric esters as promising antineoplastic agents in human lung carcinoma: a preclinical study. 1512 68

Bortezomib (PS-341, Velcade, Millennium Pharmaceuticals, Cambridge, MA) is a novel inhibitor of the proteasome. The proteasome plays a critical role in the degradation and, therefore, regulation of many proteins involved in cell cycle regulation, apoptosis, and angiogenesis. Bortezomib inhibits the growth of lung cancer cell lines in vitro and in vivo in athymic nude mouse xenografts. Bortezomib produces a G(2)-M arrest, increases in cyclin A and cyclin B, increases in p21, and increases apoptosis in these preclinical models. Phase I studies established that a dose of 1.4 mg/m(2) given i.v. on days 1, 4, 8, and 11 of a 3-week cycle produced acceptable toxicity and serum levels that resulted in proteasome inhibition. Phase II studies showed high-response rates in refractory multiple myeloma. These response rates were sufficiently high to allow accelerated approval of bortezomib by the Food and Drug Administration for this indication. Phase II trials in both non-small cell lung cancer and small cell lung cancer are in progress. A number of Phase I combination studies are also underway. Hopefully, bortezomib will show sufficient activity in lung cancer to improve survival in this dread disease.
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PMID:The potential role of proteasome inhibitors in the treatment of lung cancer. 1521 71

Saikosaponin D is a saponin extract derived from several species of Bupleurum (Umbelliferae), which is used for the treatment of various liver diseases in traditional Chinese medicine. In this study, we report that Saikosaponin D inhibits the cell growth of human lung cancer cell line A549 and provide a molecular understanding of this effect. The results showed that Saikosaponin D inhibited the proliferation of A549 by inducing apoptosis and blocking cell cycle progression in the G1 phase. ELISA assay showed that Saikosaponin D significantly increased the expression of p53 and p21/WAF1 protein, contributing to cell cycle arrest. An enhancement in Fas/APO-1 and its two form ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), as well as Bax protein, was responsible for the apoptotic effect induced by Saikosaponin D. Taken together, our study suggests that the induction of p53 and activity of the Fas/FasL apoptotic system may participate in the antiproliferative activity of Saikosaponin D in A549 cells.
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PMID:The proliferative inhibition and apoptotic mechanism of Saikosaponin D in human non-small cell lung cancer A549 cells. 1521 11

In an effort to begin developing a non-invasive strategy for in-vivo detection of the cellular DNA damage response, we engineered a molecular beacon to detect expression of p21(WAF1/CIP1), a gene whose transcription is directly activated by the p53 tumor suppressor protein. Introduction of a phosphorothioate-modified p21-beacon by transfection in human tumor cells led to a slight background signal that increased in a dose dependent manner between 50 and 400 nM beacon. Strong nuclear signal was observed following treatment of wild-type p53-expressing human H460 lung cancer cells for 8 hours with the chemotherapeutic agent doxorubicin (adriamycin). Similar induction was observed in wild-type p53-expressing HCT116 cells. Interestingly, following doxorubicin exposure, there was activation of the p21-beacon in p21-null HCT116 cells, which was not observed in p53-null HCT116, or mutant p53-expressing DLD1 cells that are either wild-type or p21-null. Increased signal from the phosphorothioate-modified p21-beacon in doxorubicin-treated cells likely resulted from sequence-specific hybridization as well as sequence-independent cleavage that may occur due to p53-dependent activation of endonucleases during apoptosis. We conclude that activation of p53 by chemotherapy leads to a strong signal from a p21-beacon that may be useful in further testing both in vitro and in vivo. Strategies need to be developed to optimize the gene or damage specificity as well as the sensitivity to therapeutic response of this non-invasive imaging approach.
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PMID:p53-Dependent activation of a molecular beacon in tumor cells following exposure to doxorubicin chemotherapy. 1525 27

K-ras is frequently mutated in lung adenocarcinomas. Recent discovery that wild-type K-ras is tumor suppressive in the lung raises a question: how is mutant K-ras aggressively oncogenic? We hypothesized that mutant K-ras might lead to generation of reactive oxygen species (ROS) and DNA damage, contributing to malignant transformation. We stably transfected human mutant K-ras(V12) into non-transformed peripheral mouse lung epithelial cells (E10 line). Constitutively active mutant K-ras(V12) in E10 cells led to a highly significant (P < 0.001) increased level of peroxides, and a corresponding increase in the amount of DNA strand-break damage, compared with the parental line E10 and the vector control. Levels of superoxide were not increased, suggesting a direct source of peroxides, such as cyclooxygenase-2 (COX-2). COX-2 protein and activity measured as prostaglandin E(2) level were up-regulated in cells expressing mutant K-ras(V12); COX-2 activity correlated with K-ras activity (K-ras p21-GTP). Both peroxide generation and DNA single strand breaks were significantly reduced by pre-treatment with COX-2-specific inhibitor SC 58125, confirming COX-2 as the source of the ROS. COX-2 has been repeatedly implicated in lung cancer, and is known to be regulated by ras and to release ROS. Our data suggest that up-regulation of COX-2, with a consequent increase in peroxides and DNA damage, contributes to the dominant oncogenicity of mutant K-ras.
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PMID:Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. 1528 81

Apoptosis (programmed cell death) plays a very important role in the development regulation, homeostasis maintenance as well as in the origin of many diseases, including neoplasms. This process is genetically regulated and reflected in characteristic morphological and biochemical changes taking place in cells. The process is considered to be of great significance in tumour originating and growth as well as in tumour cell response to chemotherapy. There are many genes and their products that are involved in apoptosis. The following genes: p53, bcl-2 and p21 seem to have the greatest significance. Our study aimed at evaluating p53 gene expression in non-small-cell lung cancer patients after neoadjuvant chemotherapy. We examined the tissue material from 35 patients after three-cycle inductive chemotherapy (Vepesid and Cisplatin). The material was obtained before chemotherapy during bronchofiberoscopy and four weeks after drug treatment during surgery. The control group comprised patients who had not undergone inductive chemotherapy. After deparaffinising of tissue slides, gene p53 activity using in situ hybridisation technique was evaluated. Moreover, apoptosis valuation with TUNEL method was performed. The results were documented as photographs. Gene p53 activity level was estimated using cytophotometric technique. Our study revealed significantly higher percentage of cells undergoing apoptosis and increased gene p53 activity in tumour tissue slides of patients after neoadjuvant chemotherapy.
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PMID:Expression of p53 gene in stage IIIA non-small cell lung cancer in patients after neoadjuvant chemotherapy with Vepesid and Cisplatin. 1531 76

Ursolic acid (UA) is a pentacyclic triterpene compound isolated from many types of medicinal plants and is present in human diet. It has been reported to possess a wide range of pharmacological properties, and is one of the most promising chemopreventive agents for cancer. Here, we report that UA inhibits the cell proliferation of human lung cancer cell line A549 and provide a molecular understanding of this effect. The results showed that UA blocked cell cycle progression in the G1 phase that was associated with a marked decrease in the protein expression of cyclin D1, D2, and E and their activating partner cdk2, 4, and 6 with concomitant induction of p21/WAF1. This accumulation of p21/WAF1 might be through a p53-dependent manner. Further, UA treatment also resulted in the triggering of apoptosis as determined by DNA fragmentation assay. This effect was found to correlate with the up-regulation of Fas/APO-1, Fas ligand, and Bax, and down-regulation of NF-kappaB, Bcl-2, and Bcl-XL. Taken together, our study indicated that UA might be a potential chemopreventive agent for lung cancer.
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PMID:Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells. 1535 Aug 28

Stilbenoids, including resveratrol (3,5,4'-trihydroxy-trans-stilbene) which is a naturally occurring phytoalexin abundant in grapes and several plants, have been shown to be active in inhibiting proliferation and inducing apoptosis in human cancer cell lines. Using resveratrol as the prototype, we have synthesized various analogs and evaluated their growth inhibitory effects in cultured human cancer cells. In the present study, we show that one of the stilbenoids, 3,4,5-trimethoxy-4'-bromo-cis-stilbene (BCS), was more effective than its corresponding trans-isomer and resveratrol on the inhibition of cancer cell growth. Prompted by the strong growth inhibitory activity of BCS (IC50; 0.03 microM) compared to its trans-isomer (IC50; 6.36 microM) and resveratrol (IC50; 33.0 microM) in cultured human lung cancer cells (A549), we investigated its mechanism of action. BCS induced arrest at the G2/M phase cell cycle in the early time and subsequently increased in the sub-G1 phase DNA contents in a time-dependent manner, indicating induction of apoptosis. Morphological observation with round-up shape and DNA fragmentation was also revealed the apoptotic phenomena. BCS treatment elevated the expression levels of the pro-apoptotic protein p53, the cyclin-dependent kinase inhibitor p21, and the release of cytochrome c in the cytosol. The down-regulation of checkpoint protein cyclin B1 by BCS was well correlated with the cell cycle arrest at G2/M. These data suggest the potential of BCS to serve as a cancer chemotherapeutic or chemopreventive agent by virtue of arresting the cell cycle and induction of apoptosis of human lung cancer cells.
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PMID:G2/M cell cycle arrest and induction of apoptosis by a stilbenoid, 3,4,5-trimethoxy-4'-bromo-cis-stilbene, in human lung cancer cells. 1546 34


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