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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Macromolecular crowding and the presence of organelles in the cytosol present barriers to particle mobility, such that it is unclear how nano-carriers can deliver their active agents to the nucleus. In this work a sixth generation amino terminated polyamide polylysine dendrimer (Gly-Lys(63) (NH(2))(64)) (MW 8149, diameter 6.5 nm) which is fluorescent allowed the study of nuclear uptake and mobility in living lung carcinoma (SK/MES-1) and colon adenocarcinoma (Caco-2) cells. The dendrimer is found within 25-45 min of incubation inside the cell nuclei. Living cells were then used to develop a method for the dynamic nuclear uptake study using confocal microscopy. The dynamic uptake of the dendrimer demonstrated here allowed the apparent cytoplasmic diffusion coefficient (D) of the dendrimer to be calculated. Values were found in the range 5.99 x 10(-11)cm(2)s(-1) (SK/MES-1 cells) to 9.82 x 10(-11)cm(2)s(-1) (Caco-2 cells). The difference must reflect variation in the intracellular architecture of the cell types.
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PMID:Cell uptake, cytoplasmic diffusion and nuclear access of a 6.5 nm diameter dendrimer. 1723 70

Based on the membrane-modifying peptaibol trichocellin-A-I (1) from Trichoderma viride, we designed a vehicle for the cellular delivery of antisense oligodeoxynucleotides by attaching a (Lys)10 stretch to the C-terminus of 1. The resulting transporter peptide 2, prepared by solid-phase synthesis using Fmoc protocol in combination with amino acid fluorides, was found to be mainly alpha-helical in solution, in contrast to its precursors 1 and 3. The uptake of the complex formed between carrier 2 and a fluorescence-tagged oligonucleotide, i.e., 4, was studied at different charge ratios by confocal laser-scanning microscopy, using two different eukaryotic cell lines: mouse embryonal fibroblast (NIH3T3) and human lung carcinoma (A549) cells. Peptide 2 readily translocated 4 into the cytoplasms of NIH3T3 cells. However, the peptide/oligonucleotide complex was accumulated around the plasma membrane of the A549 cells.
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PMID:A functionalized 20-residue peptaibol derivative for nucleic acid delivery. 1751 Sep 94

Two generations of poly(l-lysine) dendrigrafts (DGLs) were studied with regard to their ability to interact with and translocate through liposomal and cellular membranes. Partial guanidinylation of the surface amino groups of the starting dendrigrafts afforded the guanidinylated derivatives whose membrane translocation properties were also assessed. Mixed liposomes, consisting of dihexadecyl phosphate, phosphatidylcholine, and cholesterol, were employed as model membranes, while A549 human lung carcinoma cells were used for cellular uptake studies. At high surface group/liposomal phosphate molar ratios and depending on the structure of the DGL, the interaction led to aggregation. Dendrigraft liposomal internalization was achieved, however, at low molar ratios. Thus translocation of the second generation dendrigrafts was rather limited at 25 degrees C, which, however, was enhanced when the bilayer was in the liquid-crystalline phase. In contrast, third-generation counterparts exhibited minor translocational ability. Furthermore, the introduction of a guanidinium group to dendrigrafts was found to enhance their transport through liposomal membranes. On the other hand, cellular uptake by A549 cells was monitored up to 3 h incubation time via fluorescence registration employing fluorescein-labeled dendrigrafts. The efficiency of dendrigraft internalization was enhanced by the presence of the guanidinium groups, while DGLs were preferentially localized in the nucleus and nuclear membrane, as revealed by fluorescence microscopy.
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PMID:Interaction and transport of poly(L-lysine) dendrigrafts through liposomal and cellular membranes: the role of generation and surface functionalization. 1788 Feb 35

Exonuclease 1 (EXO1) is an important nucleases involved in mismatch repair system that contributes to maintain genomic stability, to modulate DNA recombination, and to mediate cell cycle arrest. Potentially functional polymorphisms in EXO1 may alter cancer risks by influencing the repair activity of EXO1. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in EXO1 were associated with risk of lung cancer. To test this hypothesis, we genotyped five common SNPs (rs1776177A/G, rs1047840G/A (Glu589Lys), rs1776148G/A (Gly670Glu), rs9350C/T (Leu757Pro) and rs851797T/C) that tag eight SNPs located at exon regions of EXO1 by using the Illumina high-throughput genotyping platform in 500 incident lung cancer cases and 517 cancer-free controls in a Chinese population. Significant differences of allele and genotype distributions were observed in Glu589Lys (rs1047840) of EXO1 between the cases and controls (P=0.028 and 0.025 for allele and genotype distributions, respectively). Logistic regression analyses revealed that individuals carrying the variant 589Lys allele (589Glu/Lys or 589Lys/Lys) had a significantly increased risk of lung cancer [adjusted odds ratio (OR)=1.41, 95% confidential interval (CI)=1.09-1.84] compared with those who carried the wild-type homozygote (589Glu/Glu). Furthermore, we found that haplotype AAGTT was more frequent in cases than in controls (P<0.001 for both two-sided chi(2)-test and 1000 times permutation tests). These results suggest that the EXO1 Glu589Lys polymorphism and its surrounding regions might be genetic susceptibility markers for lung cancer in this study population.
Lung Cancer 2008 Jun
PMID:Potentially functional polymorphisms of EXO1 and risk of lung cancer in a Chinese population: A case-control analysis. 1807 15

Previous studies demonstrated that ING4 as a novel member of ING (inhibitor of growth) family has potential effect on tumor inhibition via multiple pathways. However, adenovirus-mediated ING4 expression in inhibition of human tumors has not been reported. To explore its therapeutic effect on human lung carcinoma, we constructed a recombinant adenoviral vector Ad-ING4 expressing the humanized ING4 gene derived from murine ING4 with two amino acid modifications at residue 66 (Arg to Lys) and 156 (Ala to Thr) by site-directed mutagenesis. We demonstrated that Ad-ING4-mediated transfection of A549 human lung carcinoma cells induced cell apoptosis, altered cell cycle with S phase reduction and G2/M phase arrest, suppressed cell invasiveness, and down-regulated IL-6, IL-8, MMP-2, and MMP-9 expression of transfected tumor cells. In athymic mice bearing A549 lung tumors, intratumoral injections of Ad-ING4 suppressed the tumor growth and reduced the tumor microvessel formation. Therefore, Ad-ING4 may be useful in gene therapy of human lung carcinoma.
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PMID:Adenovirus-mediated ING4 expression suppresses lung carcinoma cell growth via induction of cell cycle alteration and apoptosis and inhibition of tumor invasion and angiogenesis. 1878 75

The overexpression of peptide receptors in a variety of human carcinomas has generated considerable interest in peptide-based radiopharmaceuticals for peptide receptor imaging and peptide receptor radiotherapy. The gastrin-releasing peptide receptor is overexpressed in human prostate-, breast-, colon- and small cell lung carcinoma cells. We have developed metabolically stable (99m)Tc-radiolabeled bombesin ([Cha(13), Nle(14)]BBS(7-14)) analogs, which bind with high affinity to the gastrin-releasing peptide receptors. However, because of their lipophilicity, they showed unfavorable biodistribution with high hepatic accumulation and hepatobiliary excretion. We now report a study of different glycation methods for [Cha(13), Nle(14)]BBS(7-14) analogs to improve their biodistribution profile. Whereas the glycation using the Maillard reaction was problematic, resulting in low yields, selective introduction of the glycomimetic shikimic acid to the side chain of a Lys residue was possible. A chemoselective ligation of alpha-D-glucose to an amino-oxyacetylated [Cha(13), Nle(14)]BBS(7-14) analog could be achieved, but was complicated by the co-elution of starting peptide and glycopeptide. The best procedure consisted of the [1,3]-cycloaddition of N(3)-beta-D-glucose to a propargylglycine-containing [Cha(13), Nle(14)]BBS(7-14) analog, using a catalytic amount of Cu(I)I. All glycated [Cha(13), Nle(14)]BBS(7-14) analogs showed high affinity for the gastrin-releasing peptide receptor and rapid accumulation into PC-3 tumor cells.
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PMID:Glycation methods for bombesin analogs containing the (NalphaHis)Ac chelator for 99mTc(CO)3 radiolabeling. 1901 95

We have developed lipid-polycation-DNA (LPD) nanoparticles containing DOTAP and targeted with polyethylene glycol (PEG) tethered with anisamide (AA) to specifically deliver siRNA to H460 human lung carcinoma cells which express the sigma receptor. A novel non-glycerol based cationic lipid which contains both a guanidinium and a lysine residue as the cationic headgroup, i.e. DSGLA, downregulated pERK more efficiently in H460 cells than DOTAP. As demonstrated by using fluorescently labeled siRNA, LPD-PEG-AA prepared with DSGLA efficiently delivered siRNA to the cytoplasm of the H460 cells. Although the siRNA delivered by LPD-PEG-AA containing either DOTAP or DSGLA could effectively silence EGFR expression, a synergistic cell killing effect in promoting cellular apoptosis was only observed with DSGLA. The fluorescently labeled siRNA was efficiently delivered into the cytoplasm of H460 xenograft tumor by the LPD-PEG-AA containing either DOTAP or DSGLA 4 h after intravenous injection. Three daily injections (0.6 mg/kg) of siRNA formulated in the LPD-PEG-AA containing either DOTAP or DSGLA could effectively silence the epidermal growth factor receptor (EGFR) in the tumor, but the formulation containing DSGLA could induce more cellular apoptosis. A significant improvement in tumor growth inhibition was observed after dosing with LPD-PEG-AA containing DSGLA. Thus, DSGLA served as both a formulation component as well as a therapeutic agent which synergistically enhanced the activity of siRNA.
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PMID:Novel cationic lipid that delivers siRNA and enhances therapeutic effect in lung cancer cells. 1926 51

Histone H3 lysine 4 (H3K4) trimethylation (H3K4me3) at the promoter region of genes has been linked to transcriptional activation. In the present study, we found that hypoxia (1% oxygen) increased H3K4me3 in both normal human bronchial epithelial Beas-2B cells and human lung carcinoma A549 cells. The increase of H3K4me3 from hypoxia was likely caused by the inhibition of H3K4 demethylating activity, as hypoxia still increased H3K4me3 in methionine-deficient medium. Furthermore, an in vitro histone demethylation assay showed that 1% oxygen decreased the activity of H3K4 demethylases in Beas-2B nuclear extracts because ambient oxygen tensions were required for the demethylation reaction to proceed. Hypoxia only minimally increased H3K4me3 in the BEAS-2B cells with knockdown of JARID1A, which is the major histone H3K4 demethylase in this cell line. However, the mRNA and protein levels of JARID1A were not affected by hypoxia. GeneChip and pathway analysis in JARID1A knockdown Beas-2B cells revealed that JARID1A regulates the expression of hundreds of genes involved in different cellular functions, including tumorigenesis. Knocking down of JARID1A increased H3K4me3 at the promoters of HMOX1 and DAF genes. Thus, these results indicate that hypoxia might target JARID1A activity, which in turn increases H3K4me3 at both the global and gene-specific levels, leading to the altered programs of gene expression and tumor progression.
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PMID:Hypoxia induces trimethylated H3 lysine 4 by inhibition of JARID1A demethylase. 2040 91

Prognosis of small cell lung carcinoma (SCLC) is particularly poor, less than 5% of patients with extensive stage being alive after two years. We hypothesized that SCLC chemotherapy could be improved by using histone deacetylase (HDAC) inhibitors based on their ability to interfere with lysine acetylation and to alter gene expression. The goal of this study was to evaluate the anticancer efficacy of a HDAC inhibitor (valproate: VPA) on SCLC cells in combination with the standard chemotherapeutic first-line regimen (cisplatin+etoposide). We show that VPA induces apoptosis of small cell lung cancer cell lines and improves efficacy of cisplatin combined with etoposide. Both mitochondrial and death receptor pathways are involved in VPA-induced apoptosis. As expected for an HDAC inhibitor, VPA hyperacetylates histone H3. The mechanism of VPA pro-apoptotic activity involves induction of p21, inhibition of Bcl-xL, cleavage of Bid and phosphorylation of Erk and H2AX. In the presence of VPA, Bax is translocated from the cytoplasm to the mitochondria and cleaved in an 18kDa isoform. Cytochrome c is released from the mitochondria into the cytosol. Transcriptomic analyses by microarray show that VPA modulates transcription of genes (Na(+)/K(+) ATPase, Bcl-xL) involved in chemoresistance to cisplatin and etoposide. Finally, the efficacy of VPA combined with cisplatin and etoposide is supported by preclinical models of SCLC cells engrafted into SCID mice. Together, these data demonstrate that VPA augments anticancer activity of cisplatin and etoposide, two components of the standard first-line chemotherapy of small cell lung cancer.
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PMID:Preclinical evidence for a beneficial impact of valproate on the response of small cell lung cancer to first-line chemotherapy. 2045 70


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