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

The probability that a mouse develops a pulmonary tumor, as well as the structure of that tumor, are dependent on several genes. Three pulmonary adenoma susceptibility (pas) genes predispose some inbred strains to develop lung tumors, even in the absence of carcinogen exposure, and cause others to be resistant. One pas gene is K-ras, which may also be overexpressed in these tumors in a mutated form capable of transforming cells. Mice with activated Ha-ras transgenes override the resistant pas alleles and are born with lung cancer. Susceptible strains have a higher turnover rate of alveolar type II and bronchiolar Clara cells, those cells from which lung tumors arise, than more resistant strains. A high precursor cell turnover rate correlates with a propensity to neoplasia in other animal models as well, possibly due to low concentrations of endogenous growth regulatory molecules such as corticosterone and protein kinase C (PKC). Neoplastic lung epithelial cells are relatively resistant to glucocorticoids and have low PKC levels. A set of genes other than the pas genes governs the response to tumor modulation by butylated hydroxytoluene (BHT). The genes that determine whether lung tumor multiplicity is enhanced by chronic BHT exposure may regulate the ability to hydroxylate BHT at a tert-butyl position to form BHT-OH, a metabolite with greater tumor-promoting potency than BHT. Inbred and recombinant inbred strain variations in adenoma growth patterns indicate that another set of genes, which we have designated pah for pulmonary adenoma histogenesis, may determine which cell type becomes neoplastic and whether adenomas will undergo malignant conversion.
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PMID:Genetic studies on lung tumor susceptibility and histogenesis in mice. 177 86

We analyzed protein kinase C (PKC) activity in twenty-two tumor cell lines derived from lung, pancreas, stomach, tongue and vulva, and found that lung cancer cells often (9 out of 13) exhibit significantly higher PKC activity than other types of cancer cells. The PKC in these lung cancer cells was separated into one major and one minor peaks by a Mono Q column chromatography. The PKC in the major peak had an absolute requirement for Ca2+, phosphatidylserine and 12-O-tetradecanoylphorbol-13-acetate (TPA), as expected. However, the PKC in the minor peak did not require TPA for its activation. Hydroxyapatite column chromatography revealed that the PKC in the major peak is type III. These results indicate that in lung cancer cells type III PKC activity is often elevated compared to other types of cancer cells. The growth of many lung cancer cell lines was inhibited by TPA.
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PMID:Lung cancer cells often express high levels of protein kinase C activity. 249 55

Phorbol ester tumor promoters enhance the ability of primary normal rat tracheal epithelial cells to form colonies in a time-dependent fashion. The potency of phorbol derivatives in inducing this effect is relative to their potency as tumor promoters in mouse epidermis. Agents which do not interact with the putative TPA receptor are not effective. In contrast, both hamster tracheal and human bronchial epithelial cells are inhibited from forming colonies by phorbol esters. The sensitivity of human cells varied among individuals but could not be related to age, smoking history, or presence of a cancerous condition. These results bear some similarity to those of Harris et al. where levels of BP-DNA binding were measured in organ cultures of human bronchus. An interindividual variation of 120-fold was observed in 37 specimens of human bronchus, however, no correlation was apparent between levels of binding and whether the specimens were from patients with cancer. It would be of interest to determine if there is a relationship between carcinogen metabolism or binding and the ability to respond to promoters in specimens from normal and lung cancer patients. It is conceivable that lung cancer arises in individuals that have rare peculiarities in carcinogen metabolism combined with peculiarities in their responses to promoters present in cigarette smoke. Several conclusions can be drawn from these data. Species vary in response to tumor promoting agents, and the type of response may be a result of the biochemical events which are triggered by interaction with protein kinase C or another cellular receptor. Both responses, that of enhanced growth of epithelial cells observed in the rat, or that of inhibition of growth (induction of terminal differentiation) seen in human and hamster epithelial cells are consistent with proposed mechanisms by which tumor promoters may function. A general enhancement of cell proliferation may lead to fixation or expansion of genetic damage in initiated cells, while induction of terminal differentiation in normal cells could lead to expanded cell proliferation in initiated cells resistant to differentiation controls. This indicates that both responses may be useful in detecting environmental promoting agents. In light of these studies perhaps the hamster trachea may more closely mimic the responses of the human bronchus than does the rat. This is consistent with observations of the difficulty in transforming hamster tracheal epithelium (Dr. Brooke Mossman, personal communication) and human bronchial epithelium compared with rat tissue.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Heterogeneity in responses of human and rodent respiratory epithelial cells to tumor promoters in culture. 398 21

Cord factors are mycoloyl glycolipids in cell walls of bacteria belonging to Actinomycetales, such as Mycobacterium, Nocardia and Rhodococcus. They induce granuloma formation in the lung and interstitial pneumonitis, associated with production of macrophage-derived cytokines. We studied how cord factors induce biological activities in the cells. Cord factors isolated from M. tuberculosis, trehalose 6-monomycolate (mTMM) and trehalose 6,6'-dimycolate (mTDM), enhanced protein kinase C (PKC) activation in the presence of phosphatidylserine (PtdSer), diacylglycerol and Ca2+, and mTMM activated PKC alpha more strongly than PKC beta or gamma under the same assay conditions. Kinetic studies of mTMM in response to PKC activation revealed that mTMM increased the apparent affinity of PKC to Ca2+ in the presence of both PtdSer and diolein. Although this is similar to observations with unsaturated fatty acids, such as arachidonic acid, mTMM was synergistic with PtdSer for PKC activation, but arachidonic acid was not. mTMM was also different as regards PKC activation, as phorbol ester was. A single i.p. administration of mTMM to mouse induced tumor necrosis factor-alpha (TNF-alpha) in serum and in the lung, which is a unique target tissue of cord factors. Based on our recent finding that TNF-alpha is an endogenous tumor promoter, the correlation between lung cancer and pulmonary tuberculosis is discussed.
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PMID:Activation of protein kinase C by mycobacterial cord factor, trehalose 6-monomycolate, resulting in tumor necrosis factor-alpha release in mouse lung tissues. 755 98

It has been shown that chronic lung diseases which increase the concentration of pulmonary carbon dioxide (CO2) at the expense of oxygen stimulate the secretion of biogenic amines and neuropeptides by pulmonary neuroendocrine cells (PNE cells) in man and laboratory animals. This increase in secretory activity is always accompanied by hyperplasia of PNE cells, and smokers with chronic obstructive lung disease are at high risk for the development of neuroendocrine lung cancer. We have previously shown that nicotine and the structurally related nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), stimulate the proliferation of neuroendocrine cell lines derived from lung carcinoid tumors via interaction with nicotinic acetylcholine receptors (nAChR). In our current experiment, we have addressed the mechanisms of cell proliferation in response to nicotine and NNK in normal PNE cells derived from fetal hamster lungs, and two cell lines derived from human neuroendocrine lung cancers. Our data show that in these systems the mitogenic effects of nicotine and NNK are potentiated in a concentration-dependent manner by elevated levels of CO2, an effect blocked by inhibitors of protein kinase C(PKC) and reduced by antagonists of receptors for 5-hydroxytryptamine (5-HT, serotonin) and mammalian bombesin. The observed effects of CO2 were saturable and independent of changes in the acidity of the tissue culture media. Our data suggest that increases in CO2 concentration at the expense of oxygen may stimulate signal transduction pathways in normal and neoplastic neuroendocrine lung cells thus enhancing their susceptibility to the mitogenic effects of tobacco-specific toxicants.
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PMID:Carbon dioxide potentiates the mitogenic effects of nicotine and its carcinogenic derivative, NNK, in normal and neoplastic neuroendocrine lung cells via stimulation of autocrine and protein kinase C-dependent mitogenic pathways. 771 58

The expression of protein kinase C (PKC) in 83 untreated solid human non-small cell lung carcinomas was determined and its correlation with inherent resistance to doxorubicin, with the expression of P-glycoprotein (P-170), and with the expression of glutathione S-transferase-pi (GST-pi) was analysed. Doxorubicin resistance was measured using an in vitro short-term test. The expression of PKC, P-170 and GST-pi was assessed immunohistochemically. Twenty-three tumors (= 28%) were PKC-positive, whereas 60 tumors (= 72%) were PKC-negative. Nineteen tumors (= 23%) were classified as sensitive and 64 tumors (= 77%) as resistant to doxorubicin. Thirty-nine tumors (= 47%) were P-170-positive and 51 tumors (= 61%) GST-pi-positive. Out of the PKC-positive tumors, 21 were resistant to doxorubicin and 2 were sensitive. Of the same 23 tumors, 18 were P-170-positive and 19 were GST-pi-positive. The correlations between the expression of PKC and the resistance to doxorubicin, the expression of P-170 and the expression of GST-pi were statistically significant. Corresponding results were obtained comparing the results of all tumors with the results of a subgroup of tumors having the same histology (squamous cell carcinomas). This supports the hypothesis that PKC is involved in the inherent doxorubicin-resistance of human lung cancer.
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PMID:Associated expression of protein kinase C with resistance to doxorubicin in human lung cancer. 776 22

Previously, we have shown that opioids acting via specific receptors inhibit the growth of human lung cancer cells while nicotine, acting through nicotinic acetylcholine receptors, reverses this inhibition. Therefore, we studied the role of apoptosis in these processes. Treatment of human lung cancer cells with 0.1-1 microM morphine or methadone resulted in morphological changes and cleavage of DNA into nucleosome-sized fragments characteristic of apoptosis. Quantitation of DNA fragmentation showed that a dose-dependent increase occurred within 2 h of opioid treatment and was blocked by the antagonist naloxone. The apoptotic effect of opioids was suppressed by nicotine, while the nicotinic acetylcholine receptor antagonists, hexamethonium and decamethonium, reversed this suppression. In contrast, sphingosine, a protein kinase C inhibitor, caused significant DNA fragmentation which was not suppressed by nicotine. Unexpectedly, the combination of hexamethonium and opioids or hexamethonium and nicotine stimulated apoptosis. We found that nicotine, like phorbol 12-myristate 13-acetate, increased total protein kinase C (PKC) activity, while morphine and sphingosine decreased PKC activity, and nicotine reversed morphine inhibition of PKC activity. In contrast, methadone unexpectedly increased PKC activity. These results indicate that engagement of opioid receptors in human lung cancer cells induces apoptosis, while engagement of nicotine receptors suppresses apoptosis, which in some cases appear to be working through a PKC pathway. They also suggest complexities in the system where blockade of C6 or C10 nicotinic receptors can lead to facilitation of apoptosis. These findings suggest new strategies for treatment and prevention of cancer using opioids or nicotine receptors antagonists and are consistent with the idea that nicotine functions as a tumor promoter.
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PMID:Opioids induce while nicotine suppresses apoptosis in human lung cancer cells. 784 4

Staurosporine aglycone (K252-c) (compound 1) and arcyriaflavin A (2) were isolated from a specimen of the marine ascidian, Eudistoma sp., collected off the coast of West Africa. In addition to expressing micromolar and submicromolar inhibition of enzyme activity against seven protein kinase C isoenzymes and inhibition of proliferation of the human lung cancer A549 and P388 murine leukemia cell lines, 1 also inhibited cell adhesion of the EL-4.IL-2 cell line and expressed activity in the K562 bleb and neutrophil assays.
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PMID:Staurosporine aglycone (K252-c) and arcyriaflavin A from the marine ascidian, Eudistoma sp. 792 52

The dihydropyridine, dexniguldipine hydrochloride (B859-35), has shown therapeutic activity in experimentally induced neuroendocrine hamster lung tumors and demonstrated antiproliferative effects in a mammary cancer cell line via inhibition of Ca2+ calmodulin. Studies in NIH 3T3 fibroblasts have provided evidence that dexniguldipine may also inhibit protein kinase C (PKC). In this study, we have tested the hypothesis that dexniguldipine may inhibit the proliferation of lung cancer cells in response to autocrine or exogenous activation of PKC. Using a panel of human lung cancer cell lines, we show that dexniguldipine is a potent inhibitor of mitogenic signal transduction pathways dependent on PKC activation in several small-cell and non-small-cell lung cancer cell lines while it failed to inhibit cyclic-AMP-dependent cell proliferation.
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PMID:Inhibition of protein-kinase-C--dependent cell proliferation of human lung cancer cell lines by the dihydropyridine dexniguldipine. 813 60

Suramin is a prototype of a new class of anticancer drugs. We investigated the action of suramin on the signal transduction pathways to DNA topoisomerase II (Topo II). Suramin showed a growth-inhibitory effect on a human lung cancer cell line (PC-9) with an IC50 of about 160 micrograms/ml. Suramin inhibited the catalytic activity of Topo II with an IC50 of about 100 micrograms/ml without stabilization of the cleavable complex of DNA and Topo II. Suramin decreased the phosphorylation of Topo II with an IC50 of 175 micrograms/ml, but did not change the degree of Topo II expression. These IC50 values for inhibition of catalytic activity and phosphorylation of Topo II were equivalent to the growth-inhibitory dose determined by tetrazolium dye assay. Phosphorylation of the tyrosine residues of Topo II was not changed by suramin. In the presence of okadaic acid, a potent inhibitor of serine/threonine protein phosphatase, suramin also decreased the phosphorylation of Topo II, suggesting that the drug did not act on the serine/threonine protein phosphatases inhibited by okadaic acid. Suramin also inhibited the protein kinase C (PKC) activity of PC-9 cells. These results suggest that suramin decreases the phosphorylation of Topo II mediated by PKC. This effect of suramin might cause the inhibition of Topo II activity resulting in the growth inhibition of tumor cells.
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PMID:Suramin inhibits the phosphorylation and catalytic activity of DNA topoisomerase II in human lung cancer cells. 829 4


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