UMLS:C0242379 - FACTA Search

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

In the planning of future intervention trials using chemopreventive agents against lung cancer, it is critical to evaluate the effect on biomarkers implicated specifically in lung carcinogenesis. With the use of the H520 and H522 human lung cancer cell lines, the present study showed that treatment with selenium (in the form of methylseleninic acid) inhibited cell growth, arrested cell cycle progression at G(1), and induced apoptosis as a late event. Because H520 cells were more sensitive to selenium than H522 cells (IC(50) of MSA was 2.5 or 10 micro M for H520 or H522 cells, respectively, at 24 h), a panel of nine cell cycle regulatory proteins known to be involved in G(1)-->S transition was assessed by Western analysis using whole cell lysate from H520 cells. These nine proteins (DP1, cdc25A, cyclin A, cyclin B(1), cyclin D(1), cdk1, cdk5, p21(WAF1), and GADD153) have been reported previously by our laboratory to be modulated by MSA in human breast and prostate cancer cells. Our data showed that only four (DP1, cdc25A, p21(WAF1), and GADD153) of nine biomarkers produced the expected changes after treatment of lung cancer cells with MSA. This finding raises the possibility that the molecular targets sensitive to selenium modulation may be tissue specific. Thus, the selection of selenium biomarkers for evaluation in an intervention trial must be based on empirical data derived from the cancer cell type of interest.
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PMID:Cell cycle arrest biomarkers in human lung cancer cells after treatment with selenium in culture. 1465 89

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

The p57KIP2 gene belongs to the Cip/Kip family of CDK inhibitors and has been demonstrated to be a tumor suppressor gene, being inactivated in various types of human cancers. We analyzed the methylation and expression status of p57KIP2 in lung and breast cancers, and in malignant mesotheliomas (MMs). The promoter region of p57KIP2 was determined by methylation-specific PCR (MSP) in samples of lung and breast cancer, and of MM. The expression of the gene in the cell lines was determined by RT-PCR and correlated with the methylation status. Aberrant methylation was detected by MSP in 9 of 27 (33%) and 25 of 78 (32%) lung cancer cell lines and tumors, respectively, 11 of 18 (61%) and 17 of 38 (45%) breast cancer cell lines and tumors, respectively, and 1 of 25 (4%) MM tumors. DNA methylation was detected but rarely in the corresponding non-malignant tissues. In addition, the gene expression was restored in the methylated cell lines following 5-aza-2'-deoxycytidine treatment, confirming that the methylation was indeed responsible for the gene down-regulation. We also examined the relationship between the p57KIP2 methylation status and the clinicopathological features of the primary tumors, and found that there was no relationship between the p57KIP2 methylation status and any of the examined clinicopathological features. In summary, our results demonstrate that p57KIP2 methylation associated with the gene down-regulation is frequently present in lung and breast cancers and plays an important role at the molecular level in the pathogenesis of these cancers.
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PMID:Aberrant methylation of p57KIP2 gene in lung and breast cancers and malignant mesotheliomas. 1549 97

The Cdc25 dual-specificity phosphatases are key regulators of cell cycle progression through activation of cyclin-dependent kinases (Cdk). Three homologs exist in humans: Cdc25A, Cdc25B, and Cdc25C. Cdc25A and Cdc25B have oncogenic properties and are overexpressed in some types of tumors. Compounds that inhibit Cdc25 dual-specificity phosphatase activity might thus be potent anticancer agents. We screened several hundred compounds in a library using an in vitro phosphatase assay, with colorimetric measurement of the conversion of p-nitrophenyl phosphate (pNPP) to p-nitrophenol by the catalytic domain of recombinant human Cdc25, and discovered TPY-835, which inhibits Cdc25A and Cdc25B activity (IC50 = 5.1 and 5.7 microM, respectively). TPY-835 had mixed inhibition kinetics for Cdc25A and Cdc25B. TPY-835 caused cell cycle arrest in the G1 phase in human lung cancer cells (A549 and SBC-5) but not cell cycle arrest in the G2/M phase. After treatment with TPY-835, the activation of Cdk2 was suppressed and phosphorylation of the retinoblastoma (Rb) protein was decreased in SBC-5 cells. In addition, TPY-835 induced an increase of the sub-G1 phase cell population after 48-72 h treatment. The growth inhibitory effects of TPY-835 against cisplatin (CDDP)-, camptothecin- and 5-FU-resistant cell lines are comparable to the growth inhibitory effect on their parental lines, thus indicating that TPY-835 did not show cross-resistance to these cell lines. These results suggest that TPY-835 is a promising candidate for constructing a novel class of antitumor agents that can control the cell cycle progression of cancer cells.
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PMID:A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity. 1612 47

Protective effects of Allium vegetables against cancers have been shown extensively in experimental animals and epidemiologic studies. We investigated cell proliferation and the induction of apoptosis by onion oil extracted from Allium cepa, a widely consumed Allium vegetable, in human lung cancer A549 cells. GC/MS analysis suggested that propyl sulfides but not allyl sulfides are major sulfur-containing constituents of onion oil. Onion oil at 12.5 mg/L significantly induced apoptosis (13% increase of apoptotic cells) as indicated by sub-G1 DNA content. It also caused cell cycle arrest at the G2/M phase; 25 mg/L onion oil increased the percentage of G2/M cells almost 6-fold compared with the dimethyl sulfoxide control. The action of onion oil may occur via a reactive oxygen species-dependent pathway because cell cycle arrest and apoptosis were blocked by the antioxidants N-acetylcysteine and exogenous glutathione. Marked collapse of the mitochondrial membrane potential suggested that dysfunction of the mitochondria may be involved in the oxidative burst and apoptosis induced by onion oil. Expression of phospho-cdc2 and phospho-cyclin B1 were downregulated by onion oil, perhaps accounting for the G2/M arrest. Overall, these results suggest that onion oil may exert chemopreventive action by inducing cell cycle arrest and apoptosis in tumor cells.
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PMID:The production of reactive oxygen species and the mitochondrial membrane potential are modulated during onion oil-induced cell cycle arrest and apoptosis in A549 cells. 1648 32

Developing novel mechanism-based chemopreventive approaches for lung cancer through the use of dietary substances which humans can accept has become an important goal. In the present study, employing normal human bronchial epithelial cells (NHBE) and human lung carcinoma A549 cells, we first compared the growth inhibitory effects of pomegranate fruit extract (PFE). Treatment of PFE (50-150 microg/ml) for 72 h was found to result in a decrease in the viability of A549 cells but had only minimal effects on NHBE cells as assessed by the MTT and Trypan blue assays. PFE treatment of A549 cells also resulted in dose-dependent arrest of cells in G0-G1 phase of the cell cycle (as assessed by DNA cell cycle analysis). We further found that PFE treatment also resulted in (i) induction of WAF1/p21 and KIP1/p27, (ii) decrease in the protein expressions of cyclins D1, D2 and E, and (iii) decrease in cyclin-dependent kinase (cdk) 2, cdk4 and cdk6 expression. The treatment of cells with PFE inhibited (i) phosphorylation of MAPK proteins, (ii) inhibition of PI3K, (iii) phosphorylation of Akt at Thr308, (iv) NF-kappaB and IKKalpha, (v) degradation and phosphorylation of IkappaBalpha, and (vi) Ki-67 and PCNA. We also found that PFE treatment to A549 cells resulted in inhibition of NF-kappaB DNA-binding activity. Oral administration of PFE (0.1 and 0.2%, wt/vol) to athymic nude mice implanted with A549 cells resulted in a significant inhibition in tumor growth. Our results provide a suggestion that PFE can be a useful chemopreventive/chemotherapeutic agent against human lung cancer.
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PMID:Pomegranate fruit extract inhibits prosurvival pathways in human A549 lung carcinoma cells and tumor growth in athymic nude mice. 1692 Jul 36

Chemoprevention has the potential to be a major component of colon, breast, prostate and lung cancer control. Epidemiological, experimental, and clinical studies provide evidence that antioxidants, anti-inflammatory agents, n-3 polyunsaturated fatty acids and several other phytochemicals possess unique modes of action against cancer growth. However, the mode of action of several of these agents at the gene transcription level is not completely understood. Completion of the human genome sequence and the advent of DNA microarrays using cDNAs enhanced the detection and identification of hundreds of differentially expressed genes in response to anticancer drugs or chemopreventive agents. In this review, we are presenting an extensive analysis of the key findings from studies using potential chemopreventive agents on global gene expression patterns, which lead to the identification of cancer drug targets. The summary of the study reports discussed in this review explains the extent of gene alterations mediated by more than 20 compounds including antioxidants, fatty acids, NSAIDs, phytochemicals, retinoids, selenium, vitamins, aromatase inhibitor, lovastatin, oltipraz, salvicine, and zinc. The findings from these studies further reveal the utility of DNA microarray in characterizing and quantifying the differentially expressed genes that are possibly reprogrammed by the above agents against colon, breast, prostate, lung, liver, pancreatic and other cancer types. Phenolic antioxidant resveratrol found in berries and grapes inhibits the formation of prostate tumors by acting on the regulatory genes such as p53 while activating a cascade of genes involved in cell cycle and apoptosis including p300, Apaf-1, cdk inhibitor p21, p57 (KIP2), p53 induced Pig 7, Pig 8, Pig 10, cyclin D, DNA fragmentation factor 45. The group of genes significantly altered by selenium includes cyclin D1, cdk5, cdk4, cdk2, cdc25A and GADD 153. Vitamine D shows impact on p21(Waf1/Cip1) p27 cyclin B and cyclin A1. Genomic expression profile with vitamin D indicated differential expression of gene targets such as c-JUN, JUNB, JUND, FREAC-1/FoxF1, ZNF-44/KOX7, plectin, filamin, and keratin-13, involved in antiproliferative, differentiation pathways. The agent UBEIL has a remarkable effect on cyclin D1. Curcumin mediated NrF2 pathway significantly altered p21(Waf1/Cip1) levels. Aromatase inhibitors affected the expression of cyclin D1. Interestingly, few dietary compounds listed in this review also have effect on APC, cdk inhibitors p21(Waf1/Cip1) and p27. Tea polyphenol EGCG has a significant effect on TGF-beta expression, while several other earlier studies have shown its effect on cell cycle regulatory proteins. This review article reveals potential chemoprevention drug targets, which are mainly centered on cell cycle regulatory pathway genes in cancer.
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PMID:Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets. 1716 75

The protein kinase C (PKC) family of proteins plays important roles in growth regulation and is implicated in tumorigenesis. It has become clear that the role of PKC in tumorigenesis is cell context dependent and/or isoform specific. In this study, we showed for the first time by immunohistochemistry that overexpression of PKC epsilon was detected in the vast majority (>90%) of primary human non-small cell lung cancers (NSCLC) compared with normal lung epithelium. Inhibition of the PKC epsilon pathway using a kinase-inactive, dominant-negative PKC epsilon, PKC epsilon(KR), led to a significant inhibition of proliferation and anchorage-independent growth of human NSCLC cells in a p53-independent manner. This was accompanied by a specific induction of the cyclin-dependent kinase (cdk) inhibitor p21/Cip1 but not p27/Kip1. In response to serum stimulation, PKC epsilon(KR)-expressing cells showed a prolonged G(1)-S transition and delayed and reduced activation of cdk2 complexes, which was likely attributed to the increased binding of p21/Cip1 to cdk2. Furthermore, inhibition of PKC epsilon function either by expressing PKC epsilon(KR) or by small interfering RNA (siRNA)-mediated gene knockdown resulted in c-Myc down-regulation, which, in turn, regulated p21/Cip1 expression. Knockdown of PKC epsilon or c-Myc expression using siRNA led to induction of p21/Cip1 and attenuation of G(1)-S transition in NSCLC cells. Using p21(+/+) and p21(-/-) HCT116 isogenic cell lines, we further showed that growth inhibition by PKC epsilon(KR) required the function of p21/Cip1. Collectively, these results reveal an important role for PKC epsilon signaling in lung cancer and suggest that one potential mechanism by which PKC epsilon exerts its oncogenic activity is through deregulation of the cell cycle via a p21/Cip1-dependent mechanism.
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PMID:Protein kinase C epsilon is overexpressed in primary human non-small cell lung cancers and functionally required for proliferation of non-small cell lung cancer cells in a p21/Cip1-dependent manner. 1761 61

Hoechst is developing flavopiridol, a synthetic flavonoid based on an extract from an Indian plant, for the potential treatment of cancer. Flavopiridol, a cyclin-dependent kinase inhibitor, arrests cell division and causes apoptosis in non-small lung cancer cells [283660]. A phase II trial, in collaboration with the National Cancer Institute, has commenced at the University of Chicago Medical Center, which involves patients with high or intermediate-grade lymphoma or multiple myeloma [272937], [277372]. In ex vivo experiments with tumor cells from refractory chronic lymphoblastic leukemia, dose-dependent CDK2 inhibition associated with apoptotic changes was seen at concentrations greater than 100 nM of flavopiridol. In vitro pharmacokinetic studies have shown that flavopiridol undergoes hepatic biotransformation to its corresponding glucoronide by uridine diphosphate glucoronosyltransferases [283791]. Flavopiridol inhibits CDK with an IC50 value of 0.4 mM [285707]. Preclinical toxicology studies in rats and dogs demonstrated dose-related leukopenia and drug-related lesions in the thymus, spleen and bone marrow. The gastrointestinal and bone marrow toxicity was dose-limiting [178579]. Hoechst Marion Roussel expects to launch flavopiridol in the year 2001, with potential sales in excess of DM 750 million [288651].
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PMID:Flavopiridol Hoechst AG. 1846 38

1. The Wnt/beta-catenin pathway plays a critical role in carcinogenesis and so agents that target Wnt/beta-catenin may have potential in cancer prevention and therapy. The aim of the present study was to evaluate the anticancer activity of the novel natural product dammarane-type triterpene sapogenin (20(S)-25-OCH3-PPD; PPD25) isolated from the leaves of Panax notoginseng. 2. The anticancer activity of PPD25 was evaluated in three colon cancer cell lines and in one lung cancer cell line. The effects of PPD25 to inhibit proliferation and to induce apoptosis were evaluated. In addition, the potential mechanisms underlying the effects of PPD25 were investigated. 3. It was found that the addition of 5 or 25 micromol/L PPD25 to the culture medium significantly inhibited cell proliferation and induced apoptosis in all four cancer cell lines. Mechanistic studies revealed that PPD25 significantly reduced the expression of beta-catenin, a key mediator in the Wnt pathway, as well as transcriptional targets of beta-catenin, namely c-myc, cyclin D1, cdk4 and T cell factor (TCF)-4. In addition, beta-catenin/TCF transcriptional activity was significantly suppressed by PPD25. 4. The data demonstrate that the PPD25 exerts its anticancer effect by targetting beta-catenin signalling, suggesting that PPD25 may have potential as a chemotherapeutic and/or chemopreventive agent for colon and lung cancer.
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PMID:Anticancer activity of Panax notoginseng extract 20(S)-25-OCH3-PPD: Targetting beta-catenin signalling. 1941 87

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