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)

Histone proteins are subject to a range of post-transcriptional modifications in living cells. The combinatorial nature of these modifications constitutes the "histone code" that dictates chromatin structure and function during development, growth, differentiation, and homeostasis of cells. Deciphering of the histone code is hampered by the lack of analytical methods for monitoring the combinatorial complexity of reversible multisite modifications of histones, including acetylation and methylation. To address this problem, we used LC-MSMS technology and Virtual Expert Mass Spectrometrist software for qualitative and quantitative proteomic analysis of histones extracted from human small cell lung cancer cells. A total of 32 acetylations, methylations, and ubiquitinations were located in the human histones H2A, H2B, H3, and H4, including seven novel modifications. An LC-MSMS-based method was applied in a quantitative proteomic study of the dose-response effect of the histone deacetylase inhibitor (HDACi) PXD101 on histone acetylation in human cell cultures. Triplicate LC-MSMS runs at six different HDACi concentrations demonstrated that PXD101 affects acetylation of histones H2A, H2B, H3, and H4 in a site-specific and dose-dependent manner. This unbiased analysis revealed that a relative increase in acetylated peptide from the histone variants H2A, H2B, and H4 was accompanied by a relative decrease of dimethylated Lys(57) from histone H2B. The dose-response results obtained by quantitative proteomics of histones from HDACi-treated cells were consistent with Western blot analysis of histone acetylation, cytotoxicity, and dose-dependent expression profiles of p21 and cyclin A2. This demonstrates that mass spectrometry-based quantitative proteomic analysis of post-translational modifications is a viable approach for functional analysis of candidate drugs, such as HDAC inhibitors.
Mol Cell Proteomics 2006 Jul
PMID:Quantitative proteomic analysis of post-translational modifications of human histones. 1662 69

Vascular endothelial growth factor (VEGF) is one of the most important mediators of tumor angiogenesis. In addition to hypoxia, peptide growth factors are known to regulate VEGF expression but the effect of stem cell factor (SCF), the ligand for c-Kit, on VEGF expression has not been characterized. We therefore studied the effect of SCF-mediated c-Kit activation on VEGF expression by the H526 small cell lung cancer (SCLC) cell line. SCF treatment doubled VEGF mRNA expression and VEGF secretion in the absence of other exogenous growth factors, an effect efficiently blocked by imatinib. The increase in VEGF mRNA occurred within the first 2 hours of treatment and was not caused by alterations in mRNA stability. The phosphatidylinositol 3-kinase inhibitor LY294002 blocked the increase in VEGF mRNA, implicating c-Kit-mediated activation of phosphatidylinositol 3-kinase in the phenomenon. VEGF promoter-reporter transfections indicated that a SCF-mediated increase in VEGF promoter activity paralleled the increase in VEGF mRNA, documenting that SCF mediated its effects through enhanced VEGF transcription. Mutation of the core hypoxia-inducible factor (HIF)-1 binding element in the VEGF promoter significantly blunted SCF-responsiveness. SCF increased nuclear levels of the HIF-1alpha transcription factor, which correlated well with increased HIF-1alpha binding to a consensus hypoxia-responsive element. SCF-mediated effects on HIF-1alpha expression were additive with those produced by CoCl2, a hypoxia-mimetic agent. These data indicate that activation of c-Kit by SCF leads to a predominantly HIF-1alpha-mediated enhancement of VEGF expression and that inhibition of c-Kit signaling with imatinib could result in inhibition of tumor angiogenesis.
Mol Cancer Ther 2006 Jun
PMID:Imatinib inhibits c-Kit-induced hypoxia-inducible factor-1alpha activity and vascular endothelial growth factor expression in small cell lung cancer cells. 1681 99

Based on the topoisomerase IIalpha catalytic inhibitory activity of a previous hit compound, NSC35866, we screened 40 substituted purines or purine-like compounds from the National Cancer Institute repository for their ability to inhibit the ATPase activity of human topoisomerase IIalpha. Several compounds, including NSC348400, NSC348401 and NSC348402, were inhibitory at submicromolar concentrations. Three-dimensional quantitative structure-activity relationship models using comparative molecular field and comparative molecular similarity indices analyses were constructed using 24 of these compounds. The ability of 10 selected compounds to inhibit the complete DNA strand passage reaction of topoisomerase IIalpha correlated well with their potency as ATPase inhibitors. None of the 40 compounds significantly increased levels of the topoisomerase IIalpha-DNA covalent complex, suggesting that they functioned as catalytic topoisomerase II inhibitors and not as topoisomerase II poisons. Although some of these compounds could antagonize the effect of etoposide on the level of topoisomerase IIalpha-DNA covalent complex formation in vitro, in contrast to NSC35866, they were not capable of antagonizing etoposide-induced cytotoxicity and DNA strand breaks in cells. Two independently selected human SCLC cell lines with reduced topoisomerase IIalpha expression displayed cross-resistance to NSC348400, NBSC348401, and NSC348402, whereas an MDR1 line was fully sensitive. These results suggest that topoisomerase IIalpha is a functional cellular target for most of these substituted purine compounds and that these compounds do not display MDR1 liability.
Mol Pharmacol 2006 Nov
PMID:A three-dimensional quantitative structure-activity relationship study of the inhibition of the ATPase activity and the strand passing catalytic activity of topoisomerase IIalpha by substituted purine analogs. 1688 Feb 87

Neuroendocrine tumors of the lung are carcinomas characterized by different impact on the patients' prognosis, ranging from relatively indolent, low- to intermediate-grade neoplasms with longer life expectation (i.e., typical and atypical carcinoids) to very aggressive and poorly differentiated neoplasms with dismal prognosis (i.e., large cell neuroendocrine carcinoma and small cell lung cancer). The standard treatment of typical or atypical carcinoids is the complete surgical resection, whereas the role of radio-chemotherapy in a multimodality treatment or for palliation remains controversial. Conversely, high-grade neuroendocrine carcinomas are in primis treated by aggressive combination chemotherapy, deserving surgical resection for uncommon low-stage tumors. Since evidence has been accumulated that neuroendocrine tumors of the lung are supplied with a wide array of peptide receptors detectable on cell membranes by immunohistochemical methods, innovative strategies for diagnosis and radiometabolic therapy have been devised to target these molecules for the correct clinical management of the patients. In this paper, the structural and functional aspects and the clinical applications of the detection of several peptide receptors in pulmonary neuroendocrine tumors will be reviewed, including somatostatin receptors, vasoactive intestinal peptide/pituitary adenylate cyclase activating peptide family receptors, cholecystokinin /gastrin receptors, bombesin/gastrin releasing peptide receptors, neurotensin receptors, substance P receptors, neuroepeptide Y receptors, calcitonin/calcitonin gene-related peptide receptors, atrial natriuretic peptide receptors, glucagon-like-peptide-1 receptors, oxytocin receptors and endothelin receptors. Only a detailed knowledge of the peptide receptor distribution in these tumor types, especially in uncommon neoplasms such as atypical carcinoids and large cell neuroendocrine carcinomas, is pivotal for planning the most adequate interventions for the patients' diagnosis and therapy.
Q J Nucl Med Mol Imaging 2006 Dec
PMID:Peptide receptors in neuroendocrine tumors of the lung as potential tools for radionuclide diagnosis and therapy. 1704 25

Optimization of therapy for individual patients remains a goal of clinical practice. Radionuclide imaging can identify those patients who may benefit from subsequent targeted therapy by providing regional information on the distribution of the target. An ideal situation may be when the imaging and the therapeutic compounds are the same agent. Two antibodies ([ [90Y]ibritumomab, [131I]tositumomab) are now approved for the systemic radiotherapy of non-Hodgkin's lymphoma. The main hurdle is to deliver higher absorbed doses to the more refractory solid tumors paying particular regard to the bone marrow toxicity. The low dose is thought to be a result of the large size of antibodies slowing delivery to the target. Peptides having high affinity to receptors expressed on cancer cells are a promising alternative. They are usually rapidly excreted from the body through renal and/or hepatobiliary excretion thus creating a prolonged accumulation of the radioactivity in the kidneys, which represents a recognized issue for systemic radiotherapy. The first radiopeptide developed was a somatostatin analogue, which led to a major breakthrough in the field. Beside the kidney issue, somatostatin use remains limited to few cancers that express receptors in sufficiently large quantities, mainly neuroendocrine tumors. The gastrin releasing peptide (GRP) receptor is an attractive target for development of new radiopeptides with diagnostic and therapeutic potential. This is based upon the functional expression of GRP receptors in several of the more prevalent cancers including prostate, breast, and small cell lung cancer. This review covers the efforts currently underway to develop new and clinically promising GRP-receptor specific molecules labeled with imageable and therapeutic radionuclides.
Q J Nucl Med Mol Imaging 2006 Dec
PMID:Lutetium-177-labeled gastrin releasing peptide receptor binding analogs: a novel approach to radionuclide therapy. 1704 28

The Drosophila protein, Rbp9, is homologous to human Hu, which is reported to be involved in small cell lung cancer. Rbp9 functions in cystocyte differentiation, and mutations in Rbp9 cause ovarian tumors. Here we show that the antimicrobial peptide, Attacin, is upregulated in Rbp9 mutants, especially in ovaries where tumors form. Upregulation seems to result from activation of the NF-kappaB pathway since we detected nuclear localization of Relish in Rbp9 mutant ovaries but not in wild type ovaries. Inactivation of NF-kappaB in the Rbp9 mutant allows prolonged survival of malformed egg chambers. We conclude that Drosophila initiates an anti-tumor defense response via activation of NF-kappaB.
Mol Cells 2006 Oct 31
PMID:Ovarian tumors in Rbp9 mutants of Drosophila induce an immune response. 1708 76

Small cell lung cancer (SCLC) is a difficult disease to treat and sometimes has overexpression or mutation of c-Met receptor tyrosine kinase. The effects of c-Met/hepatocyte growth factor (c-Met/HGF, ligand for c-Met) on activation of reactive oxygen species (ROS) was determined. HGF stimulation of c-Met-overexpressing H69 SCLC cells (40 ng/ml, 15 min) resulted in an increase of ROS, measured with fluorescent probe 2'-7'-dichlorofluorescein diacetate (DCFH-DA) or dihydroethidine (DHE) but not in c-Met-null H446 cells. ROS was increased in juxtamembrane (JM)-mutated variants (R988C and T1010I) of c-Met compared with wild-type c-Met-expressing cells. ROS was significantly inhibited by preincubation of SCLC cells with pyrrolidine dithiocarbamate (PDTC, 100 microM) and/or SU11274 (small molecule c-Met tyrosine kinase inhibitor, 2 microM) for 3 h. PDTC and SU11274 also abrogated the HGF proliferative signal and cell motility in a cooperative fashion. H(2)O(2) treatment of SCLC cells (over 15 min) led to phosphorylation of c-Met receptor tyrosine kinase and further upregulated downstream phosphorylation of phospho-AKT, ERK1/2, and paxillin in a dose-dependent manner (125 microM to 500 microM). c-Met is an important target in lung cancer, and the pathways responsible for ROS generation together may provide novel therapeutic intervention.
Am J Physiol Lung Cell Mol Physiol 2007 Jun
PMID:Activation of HGF/c-Met pathway contributes to the reactive oxygen species generation and motility of small cell lung cancer cells. 1732 84

In the present work, we have investigated the antitumor activity of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on aggressive small cell lung cancer. NBDHEX not only is cytotoxic toward the parental small cell lung cancer H69 cell line (LC(50) of 2.3 +/- 0.6 micromol/L) but also overcomes the multidrug resistance of its variant, H69AR, which overexpresses the ATP-binding cassette transporter multidrug resistance-associated protein 1 (MRP1; LC(50) of 4.5 +/- 0.9 micromol/L). Drug efflux experiments, done in the presence of a specific inhibitor of MRP1, confirmed that NBDHEX is not a substrate for this export pump. Interestingly, NBDHEX triggers two different types of cell death: a caspase-dependent apoptosis in the H69AR cells and a necrotic phenotype in the parental H69 cells. The apoptotic pathway triggered by NBDHEX in H69AR cells is associated with c-Jun NH(2)-terminal kinase and c-Jun activation, whereas glutathione oxidation and activation of p38(MAPK) is observed in the NBDHEX-treated H69 cells. In contrast to the parental cells, the higher propensity to die through apoptosis of the H69AR cell line may be related to the lower expression of the antiapoptotic protein Bcl-2. Therefore, down-regulation of a factor crucial for cell survival makes H69AR cells more sensitive to the cytotoxic action of NBDHEX, which is not a MRP1 substrate. We have previously shown that NBDHEX is cytotoxic toward P-glycoprotein-overexpressing tumor cell lines. Therefore, NBDHEX seems a very promising compound in the search for new molecules able to overcome the ATP-binding cassette family of proteins, one of the major mechanisms of multidrug resistance in cancer cells.
Mol Cancer Ther 2008 Feb
PMID:6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, a specific glutathione S-transferase inhibitor, overcomes the multidrug resistance (MDR)-associated protein 1-mediated MDR in small cell lung cancer. 1828 20

We used the paclitaxel-resistant human small cell lung cancer subline PC-6/TAX1-1, selected from PC-6 cells by paclitaxel, to test whether MRP7/ABCC10 (ABCC10) confers paclitaxel resistance. We found that gene expression of both ABCB1/MDR1 (ABCB1) and ABCC10 was higher in PC-6/TAX1-1 cells than in PC-6 cells. The expression levels of ABCC10 showed a significant inverse correlation with paclitaxel sensitivity (r = 0.574; P < 0.05) in 17 non-small cell lung cancer (NSCLC) cells unlike the expression levels of ABCB1. Pretreatment with the ABCC10 inhibitor sulfinpyrazone altered the sensitivity to paclitaxel in ABCC10-expressing NSCLC cells, concomitant with increased intracellular paclitaxel accumulation. These findings suggest that expression of the ABCC10 gene is induced by paclitaxel and that ABCC10 confers paclitaxel resistance by enhancing the efflux for paclitaxel. To confirm this hypothesis, we tested the effect on paclitaxel cytotoxicity of decreasing the expression of ABCC10 by small interfering RNA and found that this enhanced paclitaxel cytotoxicity in NCI-H23 cells concomitant with increased intracellular paclitaxel accumulation. These data indicate that ABCC10 may be one of the biomarkers for paclitaxel resistance in NSCLC.
Mol Cancer Ther 2008 May
PMID:MRP7/ABCC10 expression is a predictive biomarker for the resistance to paclitaxel in non-small cell lung cancer. 1844 59

Garlic-derived organosulfur compounds (OSCs) are highly effective in affording protection against chemically induced pulmonary carcinogenesis in animal models. We now demonstrate that garlic constituent diallyl trisulfide (DATS) suppresses viability of cultured human lung cancer cell lines H358 (anon-small cell lung cancer cell line) and H460 (a large cell lung cancer cell line) by causing G2-M phase cell cycle arrest and apoptotic cell death. On the other hand, a normal human bronchial epithelial cell line BEAS-2B was significantly more resistant to growth inhibition and apoptosis induction by DATS compared with lung cancer cells. We also found that even a subtle change in the OSC structure could have a significant impact on its biological activity. For example, DATS was significantly more effective than either diallyl sulfide or diallyl disulfide against proliferation of lung cancer cells. The DATS-mediated G2-M phase cell cycle arrest was explained by down-regulation of cyclin-dependent kinase 1 (Cdk1) and cell division cycle 25C protein expression leading to accumulation of Tyr15 phosphorylated (inactive) Cdk1. The DATS-induced apoptosis correlated with induction of pro-apoptotic proteins Bax, Bak and BID, and a decrease in the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL in lung cancer cells but not in BEAS-2B. Knockdown of Bax and Bak proteins conferred significant protection against DATS-induced apoptotic cytoplasmic histone-associated DNA fragmentation. On the other hand, BID protein was dispensable for DATS-induced apoptosis. In conclusion, the present study indicates that Bax and Bak proteins are critical targets of DATS-induced apoptosis in human lung cancer cells.
Environ Mol Mutagen 2009 Apr
PMID:Diallyl trisulfide selectively causes Bax- and Bak-mediated apoptosis in human lung cancer cells. 1880 Mar 51


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