Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor progression (TP) is often accompanied by evolution of drug resistant clones. Decreased intracellular accumulation of cytotoxic agents is probably the major mechanism of drug resistance. In the present study, we tried to examine the possibility to overcome the resistance to adriamycin (ADR) treatment, by cyclosporin A (CS) in two models of TP in the Lewis lung carcinoma (3LL) system. The first model consisted in the comparison of primary tumor cells (3LL-PT) to metastatic cells (3LL-MT) and the second consisted in comparison of lung metastases of the highly malignant variant D122 to those of the parental 3LL tumor. Cyclosporin had a weak augmenting effect on ADR uptake, in the two more malignant cell variants and no influence on the 3LL-PT cells, according to FACS analysis. Cytofluorometry also showed practically no effect of CS on cell size, unlike the effect of other chemosensitizers, such as membrane active agents. In order to find out whether CS counteracts resistance to ADR despite the fact that it does not increase cytotoxic agent uptake, we examined its effect on in vitro proliferative capacity of the 3LL-PT cells. CS in combination with ADR had a more pronounced effect, as compared to single treatments on cell proliferation. The low effect of CS on ADR uptake according to FACS analysis, and by contrast, its efficiency to overcome resistance to ADR according to the in vitro growth results, suggest that the mechanism of the CS action as a chemosensitizer is not related to the p-glycoprotein (P-G-P), known to be overexpressed in the typical multidrug-resistance (MDR) phenotype. A better understanding of the complexity of MDR mechanisms may contribute to the design of new modalities to overcome this phenomenon, which still limits effectiveness of cancer cure, to the early stages of the disease.
Cell Mol Biol (Noisy-le-grand) 1994 Jun
PMID:Drug resistance and its counteraction by cyclosporin A in function of metastatic potential in the Lewis lung carcinoma system. 806 72

Cytokines and immune cells are likely to be involved in the control of lung metastasis. We have therefore investigated the possibility of inhibiting lung metastases by the means of interferon-gamma (IFN-gamma) aerosolizations in a murine model of lung cancer. A Lewis lung carcinoma (3LL) was inoculated in the thigh of C57BL/6 mice. Randomized groups of 10 mice each were then treated by repeated aerosols of IFN-gamma (4,000 U/mouse) of aerosols of a Hanks' solution as controls. When the animals were killed at 18 days, the number of lung metastatic nodules was significantly reduced (by 50%; P < 0.01) after IFN-gamma aerosols, compared with controls. When the primary tumor was resected at 18 days and aerosols were continued, in the absence of local recurrence, mice treated by IFN-gamma aerosols survived longer than did controls (P < 0.05). In vitro, IFN-gamma exerted no direct antitumoral effect on 3LL cells in culture. Macrophages recovered from mice receiving IFN-gamma aerosols showed a higher antiproliferative effect on 3LL cells in vitro than did controls. Nevertheless, the higher antiproliferative effect of activated macrophages seems insufficient to explain the difference of survival that we observed between IFN-gamma-treated mice and controls.
Am J Respir Cell Mol Biol 1994 Feb
PMID:Antitumoral potential of aerosolized interferon-gamma in mice bearing lung metastases. 811 Apr 75

Cyclin D1, which is suggested to have a role in G1 control during the cell cycle, is genetically linked to BCL-1 and is widely overexpressed in parathyroid, breast, and squamous cancer cells. We postulated that cyclin D1 regulation may also be important in lung cancer. Therefore, we characterized the cell cycle-dependent expression of cyclin D1 at both mRNA and protein levels in synchronized human A549 lung carcinoma cells. Monospecific anti-cyclin D1 C-terminal peptide antibodies recognized both p36cyclinD1 and an as-yet uncharacterized 45 kD protein (p45). A549 cells were synchronized with well-studied drugs. Cyclin D1 mRNA expression remained relatively constant, with less than a twofold fluctuation during the cell cycle and with a minor peak at M phase. However, the p36cyclinD1 protein fluctuated during the A549 cell cycle and was expressed at very low levels in late G1 and at the G1/S boundary, but then increased in S phase and peaked at M phase. In contrast, p45 protein was expressed at relatively high levels in late G1 and reached maximal levels at the G1/S boundary, was expressed at decreased levels in S phase, and then had disappeared by M phase. Moreover, p45 was highly expressed only in transformed alveolar epithelial cells, but not in normal rat alveolar epithelial cells or fetal rat lung fibroblasts in primary cultures. In mink Mv1Lu cells, the expression of p45 was totally blocked by transforming growth factor-beta 1 treatment or contact inhibition. p45 protein was phosphorylated on serine, threonine, and tyrosine residues in A549 cells in culture. The phosphorylation of the p45 protein was cell cycle-regulated and reached its maximal levels at G2/M phase. The p45 protein had a different peptide map from p36cyclinD1 after cleavage with N-chlorosuccinimide. Immunoprecipitation studies showed that p45 was also anti-ubiquitin immunoreactive during the cell cycle. We conclude that p36cyclinD1 and the p45 protein are differentially regulated in a cell cycle-dependent manner in A549 cells. Although p45 is antigenically related to p36cyclinD1, it is probably not a closely cyclin-related protein. We speculate that p45 may be associated with malignant transformation and may play a distinct role from p36cyclinD1 in regulation of the cell cycle in A549 cells.
Am J Respir Cell Mol Biol 1994 Apr
PMID:Cell cycle-dependent expression of cyclin D1 and a 45 kD protein in human A549 lung carcinoma cells. 813 59

Lipid peroxidation products have recently been proposed among the possible regulators of tumour cell growth. According to our current working hypothesis, the greatly diminished content of such products in tumour cells might relieve the inhibition of cell growth thus leading to uncontrolled proliferation. Hydroperoxy- and hydroxy derivatives of long chain fatty acids have been identified and determined in normal and tumour cells. Among these, hydroxystearic acid (HSA) has been shown to have a different cytostatic and cytotoxic effect when administered to murine lung carcinoma cells or to human colon tumour cells. It interferes with cell cycle kinetics, blocking the murine cells in G2-M and the human ones in G0-G1. The molecular target of HSA in both cell lines has been shown to be the cdc2 kinase complex. The results so far obtained in tumour as long as in normal highly proliferating cells do not exclude a potential future use of this class of compounds as selective anti tumour drugs.
Mol Aspects Med 1993
PMID:Influence of hydroxystearic acid on in vitro cell proliferation. 826 35

The enzyme glutathione reductase (GR) (GSSG+NADPH+H+-->2 GSH+NADP+) plays a key role in the cellular defense against oxidative stress. High levels of GR activity are often associated with tumor growth and/or resistance mechanisms against drug and radiation therapy. In order to investigate the molecular basis of elevated glutathione reductase activities we studied the enzyme at the DNA, mRNA and protein levels in murine experimental tumor cell lines and in human lung tumors. A modified ultracentrifugation procedure was developed which allowed the simultaneous isolation of DNA and total cellular RNA. Out of 11 human bronchial carcinomas obtained from patients without prior chemotherapy, five tumors showed a GR activity which was 2.4 to 3.8 times higher than in the respective control tissues. In each case the elevated enzyme activity was accompanied by an elevated GRmRNA levels. For none of the tumors, GR gene rearrangement or amplification was observed by Southern blot analyses. The mouse tumor cell lines ASB XIV, Lewis lung carcinoma and EAT cells, also showed high levels of GRmRNA whereas this mRNA was hardly detectable in normal mouse lung tissue.
Cell Mol Biol (Noisy-le-grand) 1993 Jun
PMID:Glutathione reductase in human and murine lung tumors: high levels of mRNA and enzymatic activity. 832 79

In the normal pituitary, glucocorticoids are the principal negative regulatory of the pro-opiomelanocortin (POMC) gene which gives rise to the biologically active peptides ACTH and beta-endorphin. In Cushing's syndrome, ACTH-secreting pituitary tumours show a degree of glucocorticoid resistance, whilst ACTH-secreting extra-pituitary tumours have an even greater resistance to glucocorticoid excess. In an attempt to understand the mechanism of this phenomenon, we have compared the effects of glucocorticoids on POMC mRNA and peptide secretion in human and mouse corticotroph adenoma cells and in small cell lung carcinoma (SCLC) cells. ACTH precursor peptides were inhibited within 24 h by 25-50 nM hydrocortisone in primary cultures from a human corticotroph adenoma. In the mouse corticotroph adenoma cell line (AtT20), inhibition of both ACTH precursors and ACTH was not observed after 24 h but, by 10 days, glucocorticoids suppressed peptide levels with a concentration causing 50% inhibition of 50 nM hydrocortisone and maximal inhibition at 500 nM hydrocortisone. In marked contrast, there was no response to 500 nM hydrocortisone in the five SCLC cell lines (COR L103, COR L42, COR L24, COR L31, DMS 79) all of which secrete ACTH precursors. However, two of the five SCLC cell lines (COR L31 and DMS 79) were responsive to 1000 nM hydrocortisone. POMC mRNA, quantitated by slot-blot analysis, gave similar results for the five SCLC cell lines, implying that the abnormality may occur at the level of gene expression. When one of the three resistant cell lines (COR L103) was incubated with 2000 nM hydrocortisone or 2000 nM dexamethasone a clear suppression of precursor peptides and POMC mRNA was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Endocrinol 1993 Feb
PMID:Glucocorticoid inhibition of ACTH peptides: small cell lung cancer cell lines are more resistant than pituitary corticotroph adenoma cells. 838 76

The regulation of proteinases secreted by neutrophils is very important for the prevention of tissue injury. We recently described the isolation of elafin from bronchial secretions, a new elastase-specific inhibitor that is also found in the skin of patients with psoriasis. In this study, we investigated the secretion of elafin and mucus proteinase inhibitor (MPI), another inhibitor showing sequence similarity with elafin, in two lung carcinoma cell lines, NCI-H322 and A549, which have features of Clara cells and type II alveolar cells, respectively. The results presented show that the two inhibitors are produced when the cells are cultured either in serum-free or in serum-containing media. MPI was detected immunologically as a unique molecule of M(r) 14 kD, in accordance with previous studies. Conversely, one or two elafin-immunoreactive species were detected depending on the cell line: a 12- to 14-kD species was observed in the A549 cell line, regardless of the culture conditions, whereas in the NCI-H322 cell line we detected a 6-kD species in serum-containing (10% fetal calf serum) conditions and a 12- to 14-kD species in serum-free conditions. The 12- to 14-kD molecule probably represents an active precursor of elafin. Whether the cleavage of the 12- to 14-kD precursor giving rise to the elafin molecule is of any physiologic significance is not known. In showing for the first time that MPI and elafin (and its precursor) are secreted by the A549 cell line, this report implicates the type II alveolar cell in the defense of the peripheral lung against the neutrophil elastase secreted during inflammation.
Am J Respir Cell Mol Biol 1993 Feb
PMID:Secretion of mucus proteinase inhibitor and elafin by Clara cell and type II pneumocyte cell lines. 842 5

It is known that transfer of the wild-type p53 gene into p53-negative cells from transgenic mice increases their sensitivity to drug and radiation-induced apoptosis. However, unlike many human tumors, these transgenic cells do not express mutant p53, and it is not known from these earlier studies whether wild-type p53 dominates the effects of mutant p53 with respect to drug and radiation sensitivity. We addressed this question in glioblastoma, a disease characterized by an unusually high level of intrinsic resistance to therapy and poor prognosis: mean survival time from diagnosis is only about 1 yr. We introduced the gene for wild-type p53 into human T98G glioblastoma cells, which express endogenous mutant p53 but not wild-type p53. Stable transfectants that co-expressed mutant and wild-type p53 had enhanced sensitivity to cisplatin and gamma radiation, compared with parental cells, control vector-transduced cells, and transduced cells that had lost expression of wild-type p53. Transient wild-type p53 expression after high-efficiency gene transfer by a p53 adenovirus also sensitized the cells to cisplatin and correlated with the induction of apoptosis. The sensitization effect was also observed in p53 adenovirus-infected H23 small cell lung carcinoma cells, which express endogenous mutant p53. Therefore, wild-type p53 gene transfer has dominant effects over mutant p53 in sensitizing tumor cells to therapy, which supports the potential of p53 gene therapy to enhance the efficacy of traditional therapy.
Mol Carcinog 1995 Dec
PMID:Use of wild-type p53 to achieve complete treatment sensitization of tumor cells expressing endogenous mutant p53. 851 17

Members of the myc oncogene family such as c, N-, and L-myc are expressed in many malignant tumors. Expression of c-, N-, and L-myc oncogenes in 7 human neuroblastoma cell lines (GOTO, IMR-32, TGW, SCCH-26, TNB 9, NBL-S, and SK-N-SH), a human small cell lung carcinoma SBC-5 cell line, and a human monocytic leukemia THP-1-S cell line at mRNA and protein levels was studied to know the specificity of a newly developed antibody against homologous region at C-terminus of N-Myc, designated as anti pan-Myc antibody. By RT-PCR and immunoblot analysis, coexpression of three myc genes was detected in all neuroblastoma cell lines tested. c-and L-myc expression were observed that anti pan-Myc antibody recognizes c-Myc and N-Myc proteins but not L-Myc. These results indicate that neuroblastoma cells may acquire an aberrant transcriptional control system in myc family gene expression.
Biochem Mol Biol Int 1995 Aug
PMID:Coexpression of the myc gene family members in human neuroblastoma cell lines. 853 84

Buthionine sulfoximine (BSO) inhibits proliferation of human lung carcinoma A549 cells, and exogenous glutathione (GSH) overcomes the antiproliferative effect. The BSO antiproliferation may result from inhibition of cellular uptake of amino acids, and the antagonistic effect of GSH would result from supplementation of amino acids via the gamma-glutamyl cycle. To explore these possibilities, the present study was undertaken to determine effects of BSO on glutamate- and GSH-stimulated cell proliferation. A549 cells were cultured in a glutamine-deficient Dulbecco's modified Eagle's medium (Gln-(-)DMEM), in which they did not proliferate. Addition of glutamate or GSH in the medium to a concentration of 4 mM stimulated cell proliferation. BSO of 0.1 mM enhanced the GSH-stimulated cell proliferation and attenuated the glutamate-stimulated cell proliferation. This BSO effect correlated with changes in cellular glutamate levels; that is, BSO increased and decreased glutamate concentrations, respectively, in GSH- and glutamate-stimulated cells. GSH or glutamate alone significantly increased cellular GSH levels. BSO depleted cellular GSH in both GSH- and glutamate-stimulated cells to the same level. These changes in GSH levels did not correlate with the respective growth modulatory effect. Because BSO inhibits cellular uptake of some amino acids and the A549 cells contain high levels of gamma-glutamyl transpeptidase activity, the results suggest that the BSO inhibition of glutamate-stimulated cell proliferation may result from decreased glutamate uptake. GSH would supplement the cells with glutamate via the gamma-glutamyl pathway to bypass the inhibition of amino acid uptake and overcome the BSO-antiproliferative effect.
Cell Mol Biol Res 1995
PMID:Buthionine sulfoximine enhances glutathione-but attenuates glutamate-stimulated cell proliferation. 858 Oct 64


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