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

Triptolide (TPL), a small molecule purified from the herb Tripterygium wilfordii, has potential clinical application for suppression of chronic autoimmune disorders and inhibition of tumor growth. However, its mechanism of action is largely unknown. In this study, the effect of TPL on mitochondria was explored with a panel of molecular probes that detect the alteration of mitochondrial functions. When Lewis lung carcinoma (LLC) cells were treated with different doses of TPL for four hours, impaired mitochondrial functions were detected. This included an increased production of reactive oxygen species, the opening of the transition pore of mitochondria, the depolarization of the mitochondria membrane, the inhibition of the production of ATP and increased release of ATP as well as the induction of apoptosis. It is likely that by impairment of mitochondrial function, TPL exerts its inhibitory effect on growth of tumor and progression of inflammatory disease.
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PMID:Triptolide alters mitochondrial functions. 1772 58

The goal of this study was to characterize the effects of non-small cell lung carcinoma (NSCLC)-associated mutations in epidermal growth factor receptor (EGFR/ErbB1) and HER2 (ErbB2) on interactions with the dual tyrosine kinase inhibitor lapatinib. Biochemical studies show that commonly observed variants of EGFR [G719C, G719S, L858R, L861Q, and Delta746-750 (del15)] are enzyme activating, increasing the tyrosine kinase V(max) and increasing the K(m)((app)) for ATP. The point mutations G719C and L861Q had minor effects on lapatinib K(i)s, whereas EGFR mutations L858R and del15 had a higher K(i) for lapatinib than wild-type EGFR. Structural analysis of wild-type EGFR-lapatinib complexes and modeling of the EGFR mutants were consistent with these data, suggesting that loss of structural flexibility and possible stabilization of the active-like conformation could interfere with lapatinib binding, particularly to the EGFR deletion mutants. Furthermore, EGFR deletion mutants were relatively resistant to lapatinib-mediated inhibition of receptor autophosphorylation in recombinant cells expressing the variants, whereas EGFR point mutations had a modest or no effect. Of note, EGFR T790M, a receptor variant found in patients with gefitinib-resistant NSCLC, was also resistant to lapatinib-mediated inhibition of receptor autophosphorylation. Two HER2 insertional variants found in NSCLC were less sensitive to lapatinib inhibition than two HER2 point mutants. The effects of lapatinib on the proliferation of human NSCLC tumor cell lines expressing wild-type or variant EGFR and HER2 cannot be explained solely on the basis of the biochemical activity or receptor autophosphorylation in recombinant cells. These data suggest that cell line genetic heterogeneity and/or multiple determinants modulate the role played by EGFR/HER2 in regulating cell proliferation.
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PMID:Impact of common epidermal growth factor receptor and HER2 variants on receptor activity and inhibition by lapatinib. 1819 54

Brevinin-2R is a novel non-hemolytic defensin that was isolated from the skin of the frog Rana ridibunda. It exhibits preferential cytotoxicity towards malignant cells, including Jurkat (T-cell leukemia), BJAB (B-cell lymphoma), HT29/219, SW742 (colon carcinomas), L929 (fibrosarcoma), MCF-7 (breast adenocarcinoma), A549 (lung carcinoma), as compared to primary cells including peripheral blood mononuclear cells (PBMC), T cells and human lung fibroblasts. Jurkat and MCF-7 cells overexpressing Bcl2, and L929 and MCF-7 over-expressing a dominant-negative mutant of a pro-apoptotic BNIP3 (DeltaTM-BNIP3) were largely resistant towards Brevinin-2R treatment. The decrease in mitochondrial membrane potential (DeltaPsim), or total cellular ATP levels, and increased reactive oxygen species (ROS) production, but not caspase activation or the release of apoptosis-inducing factor (AIF) or endonuclease G (Endo G), were early indicators of Brevinin-2R-triggered death. Brevinin-2R interacts with both early and late endosomes. Lysosomal membrane permeabilization inhibitors and inhibitors of cathepsin-B and cathepsin-L prevented Brevinin-2R-induced cell death. Autophagosomes have been detected upon Brevinin-2R treatment. Our results show that Brevinin-2R activates the lysosomalmitochondrial death pathway, and involves autophagy-like cell death.
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PMID:Brevinin-2R(1) semi-selectively kills cancer cells by a distinct mechanism, which involves the lysosomal-mitochondrial death pathway. 1849 41

Inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-1 (IL-1), trigger the activation of transcription factor NF-kappaB that induces the expression of a variety of genes, including intercellular adhesion molecule (ICAM)-1. Odoroside A [3beta-O-(beta-D-diginosyl)-14-hydroxy-5beta,14beta-card-20(22)-enolide] was found to inhibit the cell-surface expression of ICAM-1 induced by TNF-alpha and IL-1 at comparable concentrations in human lung carcinoma A549 cells. In this study, the molecular mechanism underlying the inhibition of TNF-alpha-induced cell-surface ICAM-1 expression by odoroside A together with the specific Na(+)/K(+)-ATPase inhibitor ouabain was further investigated. Odoroside A and ouabain neither prevented IkappaBalpha degradation nor NF-kappaB translocation to the nucleus upon TNF-alpha stimulation. While odoroside A and ouabain had no inhibitory effect on the induction of ICAM-1 mRNA, they inhibited the TNF-alpha-induced ICAM-1 expression at the protein level. Consistent with these results, odoroside A and ouabain potently reduced de novo protein synthesis, largely due to its ability to block Na(+)-dependent transport of amino acids across the plasma membrane, but not to interfering with the translation machinery. As a direct molecular target, odoroside A was found to inhibit the ATP-hydrolyzing activity of Na(+)/K(+)-ATPase as potently as ouabain. These results clearly demonstrate that odoroside A and ouabain prevent NF-kappaB-inducible protein expression by blocking the Na(+)-dependent amino acid transport.
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PMID:Odoroside A and ouabain inhibit Na+/K+-ATPase and prevent NF-kappaB-inducible protein expression by blocking Na+-dependent amino acid transport. 1955 78

Jasmonates act as signal transduction intermediates when plants are subjected to environmental stresses such as UV radiation, osmotic shock and heat. In the past few years several groups have reported that jasmonates exhibit anti-cancer activity in vitro and in vivo and induce growth inhibition in cancer cells, while leaving the non-transformed cells intact. Recently, jasmonates were also discovered to have cytotoxic effects towards metastatic melanoma both in vitro and in vivo. Three mechanisms of action have been proposed to explain this anti-cancer activity. The bio-energetic mechanism - jasmonates induce severe ATP depletion in cancer cells via mitochondrial perturbation. Furthermore, methyl jasmonate (MJ) has the ability to detach hexokinase from the mitochondria. Second, jasmonates induce re-differentiation in human myeloid leukemia cells via mitogen-activated protein kinase (MAPK) activity and were found to act similar to the cytokinin isopentenyladenine (IPA). Third, jasmonates induce apoptosis in lung carcinoma cells via the generation of hydrogen peroxide, and pro-apoptotic proteins of the Bcl-2 family. Combination of MJ with the glycolysis inhibitor 2-deoxy-d-glucose (2DG) and with four conventional chemotherapeutic drugs resulted in super-additive cytotoxic effects on several types of cancer cells. Finally, jasmonates have the ability to induce death in spite of drug-resistance conferred by either p53 mutation or P-glycoprotein (P-gp) over-expression. In summary, the jasmonates are anti-cancer agents that exhibit selective cytotoxicity towards cancer cells, and thus present hope for the development of cancer therapeutics.
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PMID:Methyl jasmonate: a plant stress hormone as an anti-cancer drug. 1966 Jul 69

When cellular glucose concentrations fall below normal levels, in general the extent of protein O-GlcNAc modification (O-GlcNAcylation) decreases. However, recent reports demonstrated increased O-GlcNAcylation by glucose deprivation in HepG2 and Neuro-2a cells. Here, we report increased O-GlcNAcylation in non-small cell lung carcinoma A549 cells and various other cells in response to glucose deprivation. Although the level of O-GlcNAc transferase was unchanged, the enzyme contained less O-GlcNAc, and its activity was increased. Moreover, O-GlcNAcase activity was reduced. The studied cells contain glycogen, and we show that its degradation in response to glucose deprivation provides a source for UDP-GlcNAc required for increased O-GlcNAcylation under this condition. This required active glycogen phosphorylase and resulted in increased glutamine:fructose-6-phosphate amidotransferase, the first and rate-limiting enzyme in the hexosamine biosynthetic pathway. Interestingly, glucose deprivation reduced the amount of phosphofructokinase 1, a regulatory glycolytic enzyme, and blocked ATP synthesis. These findings suggest that glycogen is the source for increased O-GlcNAcylation but not for generating ATP in response to glucose deprivation and that this may be useful for cancer cells to survive.
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PMID:O-GlcNAc protein modification in cancer cells increases in response to glucose deprivation through glycogen degradation. 1983 29

Treatments of non-small cell lung cancer (NSCLC), the most common form of lung cancer, still remain poor. Interferon alpha (IFN-alpha), an important physiological immunomodulator, possesses direct cytotoxic and cytostatic effects on tumour cells, antiangiogenic effects, and activates anti-tumour immunity. Recently, the IFN-alpha oncologic indications have included melanoma, renal carcinoma, and different types of leukaemia. However, the application of IFN-alpha in therapy of lung cancer has not been validated yet. Herein the human lung carcinoma cell line A549, a model of NSCLC in vitro, was used to pursue the effect of IFN-alpha on A549 cell proliferation and differentiation together with the effect on protein expression and activity of three ATP-transporters mediating multi-drug resistance (MDR). IFN-alpha significantly inhibited the proliferation of A549 cells which was not connected with arrest in a particular cell cycle phase. Further, IFN-alpha-mediated differentiation of A549 was observed based on an increase in alkaline phosphatase activity. Simultaneously, IFN-alpha increased the expression and activity of ATP-transporters mediating MDR. Thus, the IFN-alpha down-regulation of NSCLC cell proliferation was accompanied by a potential of cells to exclude potential therapeutic substances such as chemotherapeutic agents. These effects could have a significant impact on considerations of IFN-alpha as a therapeutic agent for NSCLC.
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PMID:Modulation of cell proliferation and differentiation of human lung carcinoma cells by the interferon-alpha. 2003 95

Cancer chemotherapy is believed to be impeded by multidrug resistance (MDR). Pluronic (triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), PEO-b-PPO-b-PEO) were previously shown to sensitize MDR tumors to antineoplastic agents. This study uses animal models of Lewis lung carcinoma (3LL-M27) and T-lymphocytic leukemia (P388/ADR and P388) derived solid tumors to delineate mechanisms of sensitization of MDR tumors by Pluronic P85 (P85) in vivo. First, non-invasive single photon emission computed tomography (SPECT) and tumor tissue radioactivity sampling demonstrate that intravenous co-administration of P85 with a Pgp substrate, 99Tc-sestamibi, greatly increases the tumor uptake of this substrate in the MDR tumors. Second, 31P magnetic resonance spectroscopy (31P-MRS) in live animals and tumor tissue sampling for ATP suggest that P85 and doxorubicin (Dox) formulations induce pronounced ATP depletion in MDR tumors. Third, these formulations are shown to increase tumor apoptosis in vivo by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and reverse transcription polymerase chain reaction (RT-PCR) for caspases 8 and 9. Altogether, formulation of Dox with P85 results in increased inhibition of the growth solid tumors in mice and represents novel and promising strategy for therapy of drug resistant cancers.
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PMID:Effects of pluronic and doxorubicin on drug uptake, cellular metabolism, apoptosis and tumor inhibition in animal models of MDR cancers. 2007 98

Arsenic is a heavy metal that is ubiquitous in the environment. The toxicity of arsenic depends upon its chemical form; the organic forms being usually less harmful than inorganic ones. The primary source of human exposure is through drinking water and food. Arsenic acts on cells through a variety of mechanisms, influencing numerous signal transduction pathways and resulting in a vast range of cellular effects that include apoptosis induction, growth inhibition, promotion or inhibition of differentiation, and angiogenesis inhibition. The primary objective of this research is to evaluate the effects of arsenic trioxide on DNA synthesis and to determine whether arsenic induces apoptosis via caspase activation and the activation the mitogen -activated protein kinase (MAPK) in lung carcinoma cells. To achieve this goal, the lung cancer (A549) cells were cultured following standard protocols, and exposed to various doses (0, 2, 4, 6, 8, and 10 mug/ml) of arsenic trioxide for 48 h with LC(50) being 7.8mug/ml. The proliferative response (DNA synthesis) to arsenic trioxide was determined by [(3)H] thymidine incorporation assay. Arsenic trioxide-induced apoptosis was determined by DNA laddering. Caspase -3 activation was assessed by the caspase-3 fluorescein isothiocyanate (FITC) assay. p38 MAP kinase activity was examined by immunoblot analysis using phospho p38 MAPK mab primary antibody in the presence of ATP and transcription factor (ATF-2) as a substrate. [(3)H] thymidine incorporation assay revealed biphasic reaction; showing cell proliferation at a lower level of exposure, and a dose-related cytotoxic response at higher levels of exposure in A549 cell line. Findings from the DNA laddering assay indicated that arsenic trioxide induced apoptosis in the lung carcinoma cells. Our findings revealed that arsenic trioxide modulated caspase 3 activity and induced p38 map kinase activation in lung carcinoma (A549) cells.
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PMID:Arsenic Trioxide Modulates DNA Synthesis and Apoptosis in Lung Carcinoma Cells. 2045 3

Tumor aerobic glycolysis, or the Warburg effect, plays important roles in tumor survival, growth, and metastasis. Pyruvate kinase isoenzyme M2 (PKM2) is a key enzyme that regulates aerobic glycolysis in tumor cells. Recent research has shown that PKM2 can be used as a tumor marker for diagnosis and, in particular, as a potential target for cancer therapy. We investigated the effects of combining shRNA targeting PKM2 and docetaxel on human A549 lung carcinoma cells both in vivo and in vitro. We observed that the shRNA can significantly downregulate the expression level of PKM2. The decrease of PKM2 resulted in a decrease in ATP synthesis, which caused intracellular accumulation of docetaxel. Furthermore, the combination of pshRNA-pkm2 and docetaxel inhibited tumor growth and promoted more cancer cell apoptosis both in vivo and in vitro. Our findings suggest that targeting tumor glycolysis can increase the efficacy of chemotherapy. In particular, the targeting of PKM2 could, to some extent, be a new way of reversing chemotherapy resistance to cancer therapy.
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PMID:Silencing of pkm2 increases the efficacy of docetaxel in human lung cancer xenografts in mice. 2050 18


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